US 2013 0331313A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0331313 A1 Berenson et al. (43) Pub. Date: Dec. 12, 2013

(54) METHODS AND COMPOSITIONS FOR Publication Classification TREATINGVIRAL OR VIRALLY-INDUCED CONDITIONS (51) Int. C. A638/2 (2006.01) (71) Applicants: Trustees of Boston University, Boston, A6II 45/06 (2006.01) MA (US); Hemaquest A613 L/4045 (2006.01) Pharmaceuticals, Inc., San Diego, CA A613 L/19 (2006.01) (US) A63/67 (2006.01) A613 L/18 (2006.01) (72) Inventors: Ronald J. Berenson, Mercer Island, WA (52) U.S. C. (US); Douglas V. Faller, Weston, MA CPC ...... A61K 38/12 (2013.01); A61 K3I/I67 (US) (2013.01); A61 K3I/18 (2013.01); A61 K 31/4045 (2013.01); A61K 31/19 (2013.01); (21) Appl. No.: 13/912,637 A61K 45/06 (2013.01) USPC ...... 514/3.7: 514/616; 514/603: 514/419; (22) Filed: Jun. 7, 2013 514/21.1; 514/557 (57) ABSTRACT Related U.S. Application Data Provided are methods and compositions for the prevention (63) Continuation of application No. 13/046,555, filed on and/or treatment of viral conditions, virally-induced condi Mar. 11, 2011, now abandoned. tions and inflammatory conditions. The methods can com (60) Provisional application No. 61/430.931, filed on Jan. prise administering to a Subject a viral inducing agent with an 7, 2011, provisional application No. 61/313,052, filed antiviral agent, and optionally an additional agent. The viral on Mar. 11, 2010. inducing agent can be a HDAC inhibitor administered orally. Patent Application Publication Dec. 12, 2013 Sheet 1 of 18 US 2013/0331313 A1

Patent Application Publication Dec. 12, 2013 Sheet 2 of 18 US 2013/0331313 A1

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1. Administer viral inducing agent

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FIG. 15 US 2013/0331313 A1 Dec. 12, 2013

METHODS AND COMPOSITIONS FOR deacetylase inhibitor (HDAC inhibitor) and an antiviral agent TREATINGVIRAL OR VIRALLY-INDUCED wherein the HDAC inhibitor is a pyrimidine hydroxamic acid CONDITIONS derivative is provided. 0007. In another aspect, a method for treating and/or pre CROSS-REFERENCE TO RELATED venting a viral or virally-induced condition is provided com APPLICATIONS prising administering a HDAC inhibitor and an antiviral agent 0001. This application is a continuation application of co wherein the viral or virally-induced condition is caused by a pending U.S. patent application Ser. No. 13/046,555 filed on DNA virus and the HDAC inhibitor is administered at dose of Mar. 11, 2011, which claims the benefit under 35 U.S.C. less than 2 mg/kg per dose. S119(e) U.S. Provisional Application No. 61/430,931 filedon 0008. In yet another aspect, a method for treating and/or Jan. 7, 2011, and U.S. Provisional Application No. 61/313, preventing a viral condition, a virally-induced condition, or 052 filed on Mar. 11, 2010, the contents of each of which are an inflammatory condition is provided comprising adminis incorporated herein by reference in their entireties. tering a HDAC inhibitor and an antiviral agent wherein the MW of the HDAC inhibitor is greater than 275 g/mol. SEQUENCE LISTING 0009. In another aspect, a method for treating and/or pre 0002 The instant application contains a Sequence Listing venting a viral condition or a virally-induced condition is which has been submitted in ASCII format via EFS-Web and provided, comprising administering a HDAC inhibitor is hereby incorporated by reference in its entirety. Said ASCII wherein the HDAC inhibitor is a pyrimidine hydroxamic acid copy, created on Jun. 5, 2013, is named 701586-070082 SL. derivative. txt and is 1.278 bytes in size. 0010. In another aspect, a composition comprising a (i) HDAC inhibitor and (ii) an antiviral agent is provided, BACKGROUND OF THE INVENTION wherein the HDAC inhibitor is a pyrimidine hydroxamic acid derivative. 0003. Many patients can have latent infections in which a 0011 Provided herein, in one aspect, is a method for treat virus is present but is not expressing viral proteins such as ing and/or preventing a viral or virally-induced condition viral thymidine kinase or protein kinase, the target for com comprising administering a HDAC inhibitor and an antiviral monanti-viral drugs such as acyclovir and ganciclovir. A viral agent wherein the viral or virally-induced condition is caused inducing drug such as a histone deacetylase inhibitor (HDAC by a DNA virus and the HDAC inhibitor is administered at inhibitor HDACi) can be used to re-induce the expression dose of less than 2 mg/kg per dose. In some embodiments, the of viral thymidine kinase or protein kinase in viral infected HDAC inhibitor is Vorinostat/suberoyl anilide hydroxamic cells in the subject; the subject can then be treatment with acid, JNJ-26481585 (N-hydroxy-2-(4-((((1-methyl-1H-in antiviral drugs to eliminate latent viral infections. As EBV dol-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine and/or other latent viral infections can be associated with a 5-carboxamide), R306465/JNJ-16241199 (N-hydroxy-5-(4- variety of conditions, many of which are inflammatory con (naphthalen-2-ylsulfonyl)piperazin-1-yl)pyrimidine-2- ditions, such as lymphomas, autoimmune conditions, allergic carboxamide), CHR-3996 (2-(6-(6-Fluoroquinolin-2-yl) conditions, eliminating the latent virus with this therapy can methylamino-3-azabicyclo[3.1.0 hex-3-yl)-N- be used to prevent or treat Such conditions. hydroxypyrimidine-5-carboxamide), Belinostat/PXD101, 0004 EBV can induce autoimmune conditions through a Panobinostat/LBH-589, trichostatin A/TSA (7-4-(dimethy number of potential mechanisms, e.g.: 1) activating B cells to lamino)phenyl-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4- produce auto-antibodies, 2) turning on T cells that attack host dienamide), ITF2357, CBHA, Givinostat/ITF2357, tissue, 3) molecular mimicry in which EBV antigens cross romidepsin (IstodaxTM), PCI-24781, depsipeptide react with host antigens such that autoimmune condition (FR901228 or FK228), butyrate, phenylbutyrate, valproic results when T cells or antibodies reactive with these antigens acid, AN-9, CI-994, Entinostat/MS-275, SNDX-275, moce cross react with host antigens causing damage to host tissues, tinostat/MGCD0103 (N-(2-aminophenyl)-4-(4-pyridin-3- 4) EBV infected B cells produce cytokines which turn on ylpyrimidin-2-ylamino)methyl)benzamide), m-carboxycin other elements of the immune system and increase inflamma namic acid, bishydroxamic acid, Suberic bishydroxamic acid, tion which can also exacerbate autoimmune condition, 5) oxamflatin, ABHA, SB-55629, pyroxamide, propenamides, EBV infected B or T cells can become immortalized via EBV aroyl pyrrolyl hydroxamides, and LAQ824 (((E)-N-hydroxy proteins indirectly turning out anti-apoptotic or Survival path 3-4-2-hydroxyethyl-2-(1H-indol-3-yl)ethylaminome ways. Autoimmune conditions with evidence of an EBV rela thylphenylprop-2-enamide). In other embodiments, the tionship include multiple Sclerosis, Systemic lupus erythema HDAC inhibitor is a largazole derivative. In certain embodi tosus, rheumatoid arthritis and Sjogren's syndrome. ments, the HDAC inhibitor is a N-hydroxypyrimidine-5-car Cytomegalovirus and herpes simplex virus have been associ boxamide, wherein the HDAC inhibitor comprises an azabi ated with coronary artery condition. cyclo-hexane, wherein the HDAC inhibitor comprises a 0005. There is a need for methods of treating and/or pre fluoroquinoline group, or wherein the HDAC inhibitor is a venting viral conditions, viral-induced conditions, and non-piperidine-containing pyrimidine hydroxamic acid related inflammatory conditions. derivative. 0012. In certain embodiments, the DNA virus is a herpes SUMMARY OF THE INVENTION virus. In some embodiments, the herpes virus is an Epstein 0006. In one aspect, a method for treating and/or prevent Barr virus. ing a viral condition, a virally-induced condition, or an 0013. In some embodiments, the HDAC inhibitor and the inflammatory condition comprising administering a histone antiviral agent are co-formulated. In certain embodiments, US 2013/0331313 A1 Dec. 12, 2013

the co-formulation comprises a unit dose of no greater than 80 virus, a herpes genitalis virus, a varicella Zoster virus, an mg of the HDAC inhibitor and no greater than 1500 mg of the Epstein-Barr virus, a human herpes virus 6, a herpes virus antiviral agent. type 1, herpes virus type 2, a human herpes virus type 8, or a 0014. In certain embodiments, the HDAC inhibitor can cytomegalovirus. In some embodiments, the herpes virus is penetrate the blood brain barrier. the Epstein-Barr virus. In certain embodiments, the viral con 0.015. In some embodiments, the method further com dition or virally-induced condition is caused by a DNA virus. prises administering an additional agent. In certain embodi In some embodiments, the viral condition or virally-induced ments, the additional agent is an antiviral agent, a HDAC condition is not caused by a retrovirus. inhibitor, or a chemotherapeutic. 0023. In certain embodiments, the virally-induced condi 0016. In certain embodiments, the virally-induced condi tion is a cancer, an inflammatory condition, an allergic con tion is a cancerous condition, an inflammatory condition, an dition, an autoimmune condition, or a skin condition. In some autoimmune condition, an allergic condition, or a skin con embodiments, the virally-induced condition is lymphoma, dition. In some embodiments, the virally-induced condition is chronic lymphocytic leukemia, nasopharyngeal carcinoma, alymphoma, chronic lymphocytic leukemia, nasopharyngeal gastric cancer, Kaposi's sarcoma, rheumatoid arthritis, sys carcinoma, gastric cancer, Kaposi's sarcoma, rheumatoid temic lupus erythematosus, or multiple Sclerosis. In certain arthritis, systemic lupus erythematosus, or multiple Sclerosis. embodiments, the virally-induced condition is not sepsis or 0017. Also provided herein, in an additional aspect, is a Viremia. In some embodiments, the inflammatory condition is method for treating and/or preventing a viral condition, a an autoimmune condition, and allergic condition, or a skin virally-induced condition, or an inflammatory condition condition. comprising administering a HDAC inhibitor and an antiviral 0024. In certain embodiments, the HDAC inhibitor can agent wherein the MW of the HDAC inhibitor is greater than penetrate the blood brain barrier. In some embodiments, the 275 g/mol. In some embodiments, the HDAC inhibitor is a antiviral agent is a HIV drug, a Herpes drug, a CMV drug, or N-hydroxypyrimidine-5-carboxamide, wherein the HDAC a hepatitis drug. In certain embodiments, the antiviral agent is inhibitor comprises an azabicyclo-hexane, wherein the acyclovir, ganciclovir or Valganciclovir. In some embodi HDAC inhibitor comprises a fluoroquinoline group, or ments, the antiviral agent is not a heat shock protein inhibitor, wherein the HDAC inhibitor is a non-piperidine-containing an immunosuppressant, an antibiotic, a glucocorticoid, a non pyrimidine hydroxamic acid derivative. In certain embodi steroidal anti-inflammatory drug, a Cox-2-specific inhibitor ments, the HDAC inhibitor is JNJ-26481585 (N-hydroxy-2- or a TNF-C. binding protein. In certain embodiments, the (4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)pip antiviral agent is not a Hsp90 inhibitor, tacrolimus, eridin-1-yl)pyrimidine-5-carboxamide), R306465/JNJ cyclosporin, rapamycin (sirolimus), methotrexate, cyclo 1624 11.99 (N-hydroxy-5-(4-(naphthalen-2-ylsulfonyl) phosphamide, azathioprine, mercaptopurine, mycopheno piperazin-1-yl)pyrimidine-2-carboxamide), or CHR-3996 late, FTY720, levofloxacin, amoxycillin, prednisone, corti (2-(6-(6-Fluoroquinolin-2-yl)methylamino-3-azabicy SO acetate, prednisolone, methylprednisolone, clo3.1.0 hex-3-yl)-N-hydroxypyrimidine-5-carboxamide). dexamethasone, betamethasone, triamcinolone, beclometa In other embodiments, the HDAC inhibitor is a largazole Sone, fludrocortisone acetate, deoxycorticosterone acetate, derivative. aldosterone, salicylates, arylalkanoic acids, a 2-arylpropionic 0018. In some embodiments, the viral or virally induced acid, a N-arylanthranilic acid, an oxicam, a coxib, a Sulpho condition is caused by a herpes virus. In certain embodi nanilide, Valdecoxib, celecoxib, rofecoxib, leflunomide, gold ments, the herpes virus is an Epstein-Barr virus. thioglucose, gold thiomalate, aurofin, Sulfasalazine, 0019. In some embodiments, the HDAC inhibitor and the hydroxychloroquinine, minocycline, infliximab, etanercept, antiviral agent are administered simultaneously. In certain adalimumab, abatacept, anakinra, interferon-B, interferon-Y, embodiments, the HDAC inhibitor and the antiviral agent are interleukin-2, an allergy vaccine, an antihistamine, an anti administered orally. leukotriene, a beta-agonist, theophylline, or an anticholin 0020. In some embodiments, the HDAC inhibitor is ergic. administered at 0.01-1 mg/kg per dose. In certain embodi 0025. In some embodiments, the method further com ments, 1, 2, 3, or 4 doses are administered daily. In some prises administering an additional agent. In certain embodi embodiments, the total daily dosage of the HDAC inhibitor is ments, the additional agent is an antiviral agent, a HDAC no greater than about 200 mg. In certain embodiments, the inhibitor, or a chemotherapeutic. antiviral agent is Valganciclovir and is administered at dose of 0026. Further provided herein, in one aspect, is a method 500-1500 mg/dose. for treating and/or preventing a viral condition, a virally 0021. In some embodiments, the HDAC inhibitor and the induced condition, or an inflammatory condition comprising antiviral agent are co-formulated. In certain embodiments, administering a HDAC inhibitor and an antiviral agent, the co-formulation comprises a unit dose of no greater than 80 wherein the HDAC inhibitor is a heterocyclic hydroxamic mg of the HDAC inhibitor and no greater than 1500 mg of the acid derivative. In some embodiments, the HDAC inhibitor is antiviral agent. In some embodiments, the antiviral agent is a pyrimidine hydroxamic acid derivative. In certain embodi Valganciclovir, and the Valganciclovir is a timed release or ments, the HDAC inhibitor is a N-hydroxypyrimidine-5-car slow release oral formulation. boxamide, wherein the HDAC inhibitor comprises an azabi 0022. In certain embodiments, the viral condition or cyclo-hexane, wherein the HDAC inhibitor comprises a virally-induced condition is caused by a human immunode fluoroquinoline group, or wherein the HDAC inhibitor does ficiency virus, aherpesvirus, a parvovirus, a coxsackie Virus, not comprise a piperidine group. In some embodiments, the a Human T-lymphotropic virus, a BK virus, or a hepatitis HDAC inhibitor is JNJ-26481585 (N-hydroxy-2-(4-((((1- virus. In some embodiments, the viral condition or virally methyl-1H-indol-3-yl)methyl)amino)methyl)piperidin-1-yl) induced condition is caused by a retrovirus or a herpes virus. pyrimidine-5-carboxamide), R306465/JNJ-16241,199 In certain embodiments, the herpes virus is a herpes simplex (N-hydroxy-5-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl) US 2013/0331313 A1 Dec. 12, 2013 pyrimidine-2-carboxamide), or CHR-3996 (2-(6-(6-Fluo aurofin, Sulfasalazine, hydroxychloroquinine, minocycline, roquinolin-2-yl)methylamino-3-azabicyclo[3.1.0 hex-3- infliximab, etanercept, adalimumab, abatacept, anakinra, yl)-N-hydroxypyrimidine-5-carboxamide). interferon-B, interferon-Y, interleukin-2, an allergy vaccine, 0027. In some embodiments, the HDAC inhibitor and the an antihistamine, an antileukotriene, a beta-agonist, theo antiviral agent are administered simultaneously. In certain phylline, or an anticholinergic. embodiments, the HDAC inhibitor and the antiviral agent are 0033. In some embodiments, the method further com administered orally. In some embodiments, the antiviral prises administering an additional agent. In certain embodi agent is Valganciclovir. In certain embodiments, the HDAC ments, the additional agent is an antiviral agent, a HDAC inhibitor is administered at 0.2-2 mg/kg per dose. In some inhibitor, or a chemotherapeutic therapy. embodiments, 1, 2, 3, or 4 doses are administered daily. In 0034. Also provided herein, in another aspect, is a method certain embodiments, the total daily dosage of the HDAC for treating and/or preventing a viral condition or a virally inhibitor is no greater than about 100 mg. In some embodi induced condition comprising administering a HDAC inhibi ments, Valganciclovir is administered at dose of 900 mg/dose tor wherein the HDAC inhibitor is a pyrimidine hydroxamic or less. acid derivative comprising an azabicyclo-hexane, or wherein 0028. In certain embodiments, the HDAC inhibitor and the the HDAC inhibitor is a non-piperidine-containing pyrimi antiviral agent are co-formulated. In some embodiments, the dine hydroxamic acid derivative. In some embodiments, the co-formulation comprises a unit dose of no greater than 80 mg HDAC inhibitor is a pyrimidine hydroxamic acid derivative of the HDAC inhibitor and no greater than 1500 mg of the comprising an azabicyclo-hexane. In certain embodiments, antiviral agent. the HDAC inhibitor is a non-piperidine-containing pyrimi 0029. In certain embodiments, the viral condition or dine hydroxamic acid derivative. In some embodiments, the virally-induced condition is caused by a human immunode HDAC inhibitor comprises a fluoroquinoline group. ficiency virus, aherpesvirus, a parvovirus, a coxsackie Virus, 0035. In some embodiments, the method further com a Human T-lymphotropic virus, a BK virus, or a hepatitis prises administering an antiviral agent. In certain embodi virus. In specific embodiments, the herpes virus is a herpes ments, the HDAC inhibitor and antiviral agent are adminis simplex virus, aherpes genitalis virus, a varicella Zoster virus, tered simultaneously. In some embodiments, the HDAC an Epstein-Barr virus, a human herpes virus 6, a herpesvirus inhibitor is administered orally. In certain embodiments, the type 1, herpes virus type 2, a human herpes virus type 8, or a HDAC inhibitor is administered at 0.01-1 mg/kg per dose. In cytomegalovirus. Some embodiments, 1, 2, 3, or 4 doses are administered daily. 0030. In some embodiments, the viral condition or virally In certain embodiments, the total daily dosage of the HDAC induced condition is caused by a DNA virus. In certain inhibitor is no greater than about 200 mg. In some embodi embodiments, the viral condition or virally-induced condi ments, the antiviral agent is administered at dose of 500-1500 tion is caused by an Epstein-Barr virus. In some embodi mg/dose. ments, the viral condition or virally-induced condition is not 0036. In certain embodiments, the HDAC inhibitor and the caused by a retrovirus. In certain embodiments, the virally antiviral agent are co-formulated. In some embodiments, the induced condition is a cancer, an inflammatory condition, an co-formulation comprises a unit dose of no greater than 80 mg allergic condition, an autoimmune condition, or a skin con of the HDAC inhibitor and no greater than 1500 mg of the dition. In some embodiments, the virally-induced condition is antiviral agent. In certain embodiments, the antiviral agent is lymphoma, chronic lymphocytic leukemia, nasopharyngeal Valganciclovir. carcinoma, gastric cancer, Kaposi's sarcoma, rheumatoid 0037. In some embodiments, the viral condition or virally arthritis, systemic lupus erythematosus, or multiple Sclerosis. induced condition is caused by a human immunodeficiency In certain embodiments, the virally-induced condition is not virus, a herpes virus, a parvovirus, a coxsackie virus, a sepsis or viremia. In specific embodiments, the inflammatory Human T-lymphotropic virus, a BK virus, or a hepatitis virus. condition is an autoimmune condition, and allergic condition, In specific embodiments, the herpesvirus is a herpes simplex or a skin condition. virus, a herpes genitalis virus, a varicella Zoster virus, an 0031. In some embodiments, the HDAC inhibitor can pen Epstein-Barr virus, a human herpes virus 6, a herpes virus etrate the blood brain barrier. type 1, herpes virus type 2, a human herpes virus type 8, or a 0032. In certain embodiments, the antiviral agent is a HIV cytomegalovirus. In some embodiments, the herpes virus is drug, a Herpes drug, a CMV drug, or a hepatitis drug. In some the Epstein-Barr virus. embodiments, the antiviral agent is acyclovir, ganciclovir, or 0038. In certain embodiments, the viral condition or Valganciclovir. In certain embodiments, the antiviral agent is virally-induced condition is caused by a DNA virus. In some not a heat shock protein inhibitor, an immunosuppressant, an embodiments, the viral condition or virally-induced condi antibiotic, a glucocorticoid, a non-steroidal anti-inflamma tion is not caused by a retrovirus. In certain embodiments, the tory drug, a Cox-2-specific inhibitor or a TNF-C. binding virally-induced condition is a cancer, an inflammatory con protein. In other embodiments, the antiviral agent is not a dition, an allergic condition, an autoimmune condition, or a Hsp90 inhibitor, tacrolimus, cyclosporin, rapamycin (siroli skin condition. In some embodiments, the virally-induced mus), methotrexate, cyclophosphamide, azathioprine, mer condition is a lymphoma, chronic lymphocytic leukemia, captopurine, mycophenolate, FTY720, levofloxacin, amoxy nasopharyngeal carcinoma, gastric cancer, Kaposi's Sar cillin, prednisone, cortisone acetate, prednisolone, coma, rheumatoid arthritis, systemic lupus erythematosus, or methylprednisolone, dexamethasone, betamethasone, triam multiple Sclerosis. In certain embodiments, the virally-in cinolone, beclometaSone, fludrocortisone acetate, deoxycor duced condition is not sepsis or viremia. ticosterone acetate, aldosterone, salicylates, arylalkanoic 0039. In some embodiments, the HDAC inhibitor can pen acids, a 2-arylpropionic acid, a N-arylanthranilic acid, an etrate the blood brain barrier. In certain embodiments, the oxicam, a coxib, a Sulphonanilide, Valdecoxib, celecoxib, antiviral agent is a HIV drug, a Herpes drug, a CMV drug, or rofecoxib, leflunomide, gold thioglucose, gold thiomalate, a hepatitis drug. In some embodiments, the antiviral agent is US 2013/0331313 A1 Dec. 12, 2013 acyclovir, ganciclovir or Valganciclovir. In certain embodi aurofin, Sulfasalazine, hydroxychloroquinine, minocycline, ments, the antiviral agent is not a heat shock protein inhibitor, infliximab, etanercept, adalimumab, abatacept, anakinra, an immunosuppressant, an antibiotic, a glucocorticoid, a non interferon-B, interferon-Y, interleukin-2, an allergy vaccine, steroidal anti-inflammatory drug, a Cox-2-specific inhibitor an antihistamine, an antileukotriene, a beta-agonist, theo or a TNF-C. binding protein. In other embodiments, the anti phylline, or an anticholinergic. viral agent is not a Hsp90 inhibitor, tacrolimus, cyclosporin, 0043. In certain embodiments, the composition further rapamycin (sirolimus), methotrexate, cyclophosphamide, comprises an additional agent. In some embodiments, the azathioprine, mercaptopurine, mycophenolate, FTY720, additional agent is an antiviral agent, a HDAC inhibitor, or a levofloxacin, amoxycillin, prednisone, cortisone acetate, chemotherapeutic drug. prednisolone, methylprednisolone, dexamethasone, 0044. In some embodiments, the HDAC inhibitor and the betamethasone, triamcinolone, beclometasone, fludrocorti antiviral agent are in an oral formulation. In certain embodi Sone acetate, deoxycorticosterone acetate, aldosterone, Sali ments, the HDAC inhibitor is present at 0.01-1 mg/kg per cylates, arylalkanoic acids, a 2-arylpropionic acid, a N-ary dose. In some embodiments, the oral formulation comprises a lanthranilic acid, an oxicam, a coxib, a Sulphonanilide, unit dose of no greater than 80 mg of the HDAC inhibitor and Valdecoxib, celecoxib, rofecoxib, leflunomide, gold thioglu no greater than 1500 mg of the antiviral agent. cose, gold thiomalate, aurofin, Sulfasalazine, hydroxychloro 0045. Additionally provided herein, in a further aspect, is quinine, minocycline, infliximab, etanercept, adalimumab, a method for treating and/or preventing a virus-induced abatacept, anakinra, interferon-B, interferon-Y, interleukin-2, inflammatory condition in a subject comprising administer an allergy vaccine, an antihistamine, an antileukotriene, a ing a viral inducing agent and an antiviral agent to the Subject, beta-agonist, theophylline, or an anticholinergic. thereby treating and/or preventing the inflammatory condi 0040. In some embodiments, the method further com tion. In some embodiments, the virus is a member of the prises administering an additional agent. In certain embodi herpes virus family, human immunodeficiency virus, par ments, the additional agent is an antiviral agent, a HDAC vovirus, or coxsackie virus. In certain embodiments, the inhibitor, or a chemotherapeutic therapy. member of the herpes virus family is herpes simplex virus, 0041 Further provided herein, in another aspect, is a com herpes genitalis virus, varicella Zoster virus, Epstein-Barr position comprising a (i) HDAC inhibitor and (ii) an antiviral virus, human herpesvirus 6, or cytomegalovirus. In some agent wherein the HDAC inhibitor is a pyrimidine hydrox embodiments, the member of the herpes virus family is amic acid derivative. In some embodiments, the HDAC Epstein-Barr virus, cytomegalovirus, or human herpesvirus inhibitor is JNJ-26481585 (N-hydroxy-2-(4-((((1-methyl 6 1H-indol-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimi 0046. In certain embodiments, the inflammatory condition dine-5-carboxamide), R306465/JNJ-16241199 (N-hydroxy is an autoimmune condition. In some embodiments, the 5-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)pyrimidine-2- autoimmune condition is rheumatoid arthritis, multiple scle carboxamide), or CHR-3996 (2-(6-(6-Fluoroquinolin-2- rosis, Sjogren's syndrome, systemic lupus erythematosus, yl)methylamino-3-azabicyclo[3.1.0 hex-3-yl)-N- autoimmune hepatitis, autoimmune thyroiditis, hemophago hydroxypyrimidine-5-carboxamide). In some embodiments, cytic syndrome, diabetes, Crohn's condition, ulcerative coli the HDAC inhibitor is not m-carboxycinnamic acid, bishy tis, psoriasis, psoriatic arthritis, idiopathic thrombocyton droxamic acid, Suberic bishydroxamic acid, Trichostatin A penic pupura, polymyositis, dermatomyositis, myasthenia (7-4-(dimethylamino)phenyl-N-hydroxy-4,6-dimethyl-7- gravis, autoimmune thyroiditis, Evans syndrome, autoim oxohepta-2,4-dienamide), SAHA (suberoyl anilide hydrox mune hemolytic anemia, aplastic anemia, autoimmune neu amic acid)/Vorinostat, oxamflatin, ABHA, SB-55629, tropenia, Scleroderma, Reiter's syndrome, ankylosing pyroxamide, propenamides, aroyl pyrrolyl hydroxamides, spondylitis, pemphinigus, pemphigoid or autoimmune hepa Belinostat/PXD101, Papobinostat, LAQ824 (((E)-N-hy titis. In certain embodiments, the inflammatory condition is droxy-3-4-2-hydroxyethyl-2-(1H-indol-3-yl)ethyl an allergic condition. In some embodiments, the inflamma aminomethylphenylprop-2-enamide), LBH589, or TSA. tory condition is a skin condition. In some embodiments, the In certain embodiments, the HDAC inhibitor can penetrate inflammatory condition is associated with coronary artery the blood brain barrier. condition or peripheral artery condition. In certain embodi 0042. In some embodiments, the antiviral agent is a HIV ments, the inflammatory condition is retinitis, pancreatitis, drug, a Herpes drug, a CMV drug, or a hepatitis drug. In cardiomyopathy, pericarditis, colitis, glomerulonephritis, certain embodiments, the antiviral agent is acyclovir, ganci lung inflammation, esophagitis, gastritis, duodenitis, ileitis, clovir, or Valganciclovir. In some embodiments, the antiviral meningitis, encephalitis, encephalomyelitis, transverse agent is not a heat shock protein inhibitor, an immunosup myelitis, cystitis, urethritis, mucositis, lymphadenitis, derma pressant, an antibiotic, a glucocorticoid, a non-steroidal anti titis, hepatitis, osteomyelitis, or herpes Zoster. In some inflammatory drug, a Cox-2-specific inhibitor or a TNF-C. embodiments, the inflammatory condition is atherosclerosis. binding protein. In other embodiments, the antiviral agent is In certain embodiments, the virus is cytomegalovirus or her not a Hsp90 inhibitor, tacrolimus, cyclosporin, rapamycin pes simplex virus. (sirolimus), methotrexate, cyclophosphamide, azathioprine, 0047. In some embodiments, the viral inducing agent is mercaptopurine, mycophenolate, FTY720, levofloxacin, one or more of a chemotherapeutic drug. HDAC inhibitor, or amoxycillin, prednisone, cortisone acetate, prednisolone, DNA demethylating agent. In certain embodiments, the methylprednisolone, dexamethasone, betamethasone, triam HDAC inhibitor is butyrate or MS-275. cinolone, beclometaSone, fludrocortisone acetate, deoxycor 0048. In some embodiments, the viral inducing agent can ticosterone acetate, aldosterone, salicylates, arylalkanoic penetrate the blood brain barrier. In certain embodiments, the acids, a 2-arylpropionic acid, a N-arylanthranilic acid, an viral inducing agent comprises arginine butyrate. In some oxicam, a coxib, a Sulphonanilide, Valdecoxib, celecoxib, embodiments, the antiviral agent is ganciclovir or Valganci rofecoxib, leflunomide, gold thioglucose, gold thiomalate, clovir. US 2013/0331313 A1 Dec. 12, 2013

0049. In certain embodiments, the method further com concentrations of GCV and PCV. FIG. 2C and FIG. 2D show prises administering an additional agent. In some embodi results from GCV and PCV used in combination with NaB. ments, the additional agent comprises a vaccine. In certain 0056 FIG. 3 illustrates results from analysis of efficacy of embodiments, the vaccine comprises myelin basic protein anti-virals using short chain fatty acids as inducing agents. and the condition is multiple Sclerosis. In some embodiments, FIG. 3A shows cell count results after using NaB. FIG. 3B the vaccine comprises an antigen and the condition is diabe shows results from VA. FIG. 3C shows fold of TK expression tes. In certain embodiments, the additional agent is aspirin, induced. naproxen, ibuprofen, or a statin. In some embodiments, the 0057 FIG. 4 illustrates results from analysis of efficacy of inflammatory condition is an autoimmune condition and the anti-virals using hydroxamic acids as inducing agents. FIG. additional agent is cyclosporine, azathiorprine, methotrexate, 4A shows cell count results after using scriptaid. FIG. 4B cyclophosphamide, FK506, tacrolimus, monoclonal anti shows fold of TK expression induced. body, anti-T cell monoclonal antibody, anti-B cell mono 0058 FIG. 5 illustrates results from analysis of efficacy of clonal antibody, IL-2 receptor antibody, or a TNF inhibitor. In anti-virals using SAHA (Vorinostat) as an inducing agent. certain embodiments, the monoclonal antibody is an anti-B FIG. 5A shows cell count results after using SAHA. FIG. 5B cell antibody. In some embodiments, the anti-B cell antibody shows fold of TK expression induced. is anti-CD20. In certain embodiments, the anti-T cell anti 0059 FIG. 6 illustrates results from analysis of efficacy of body is an anti-CD3 antibody. In some embodiments, the anti-virals using LHB589 (Panobinostat) as an inducing anti-CD3 antibody is OKT3. In certain embodiments, the agent. FIG. 6A shows cell count results after using LHB589. TNF inhibitor is infliximab (RemicadeTM), etanercept (En FIG. 6B shows fold of TK expression induced. brelTM), Adalimumab (HumiraTM), or an anti-IL-6 antibody. 0060 FIG. 7 illustrates results from analysis of efficacy of 0050. In certain embodiments, the inflammatory condition anti-virals using PXD101, which induced a high level of TK is atherosclerosis and the additional agent is a lipid lowering expression at the 5uM concentration. agent. In some embodiments, the lipid lowering agent is 0061 FIG. 8 illustrates results from analysis of efficacy of rosuvastatin, atorvastatin, simvastatin, or lovastatin. In cer anti-virals using oXamflatin as an inducing agent. FIG. 8 tain embodiments, the inflammatory condition is multiple shows cell count results after using oXamflatin. Sclerosis and the additional agent is mitoxantrone, cladribine, 0062 FIG. 9 illustrates results from analysis of efficacy of or Campath antibody. In some embodiments, the viral induc anti-virals using a cyclic tetrapeptide as an inducing agent. ing agent is administered to the Subject before the antiviral FIG. 9 shows cell count results after using apicidin. agent. 0063 FIG. 10 illustrates results from analysis of efficacy of anti-virals using a benzamide (MS-275) as an inducing INCORPORATION BY REFERENCE agent. FIG. 10A shows cell count results after using MS-275. FIG. 10B shows fold of TK expression induced. FIG. 10C 0051 All publications, patents, and patent applications shows cell count results after treating cells in combination for mentioned in this specification are herein incorporated by shorter time periods. reference to the same extent as if each individual publication, 0064 FIG. 11 illustrates chemical structures of largazole patent, or patent application was specifically and individually compounds used. Shown in both FIG. 11A and FIG. 11B. indicated to be incorporated by reference. 0065 FIG. 12 illustrates results from analysis of efficacy 0052. The following are also incorporated by reference: of anti-virals using largaZoles as an inducing agent. FIGS. U.S. Pat. No. 6,677,302; U.S. Pat. No. 7,399,787; US 2009/ 12A, B, C, D and E show cell count results after using various 0270497; US 2010/0093.824; US 2010/0152155; WO1998/ largazole compounds. FIG. 12F shows fold of TK expression 04290; WO 2004/113336; WO 2008/097654; Moffat, D. et induced from various largazole compounds. al, Discovery of 2-(6-(6-Fluoroquinolin-2-yl)methyl 0066 FIG. 13 illustrates results from treatment of an HIV amino bicyclo[3.1.0 hex-3-yl)-N-hydroxypyrimidine-5- 1-infected monocyte cell line with combination therapy. Viral carboxamide (CHR-3996), a Class I Selective Orally Active release (p24 release) was measured through optical density HDAC inhibitor, Journal of Medicinal Chemistry (2010), 53. (OD) measurement. 8663-8678; Glaser, KB, HDAC inhibitors: Clinical update 0067 FIG. 14 illustrates results from treatment of an HIV and mechanisms-based potential, Biochem. Pharmacol. 1-infected monocyte cell line with combination therapy. Viral (2007); Ghosh, S. K., et al. 2007 Blood Cells, Molecules, and release (p24 release) was measured through optical density Diseases 38:57-65. (OD) measurement and then converted into pg of protein. 0068 FIG. 15 is a flow diagram of one embodiment of the BRIEF DESCRIPTION OF THE DRAWINGS provided invention. 0053. The novel features of the invention are set forth with particularity in the appended claims. A better understanding DETAILED DESCRIPTION OF THE INVENTION of the features and advantages of the present invention will be 0069 Provided herein are methods and compositions for obtained by reference to the following detailed description treating and/or preventing viral conditions, virally-induced that sets forth illustrative embodiments, in which the prin conditions, or inflammatory conditions in a subject. The con ciples of the invention are utilized, and the accompanying dition can be associated with latent viral infections. The drawings of which: methods can comprise the steps of administering a viral 0054 FIG. 1 illustrates a CT scan of tumor reduction after inducing agent and an antiviral agent to the Subject. The treatment with arginine butyrate (AB) and GCV. FIG. 1A and method can comprise steps of administering a viral inducing FIG. 1B show pre- and post-treatment, respectively. agent, an antiviral agent, and one or more additional agents to 0055 FIG. 2 illustrates results from toxicity assays with a Subject. The methods include the co-administration of an anti-herpesvirus drugs ganciclovir (GCV) and penciclovir oral HDAC inhibitor and an antiviral agent, either in the same (PCV). FIG. 2A and FIG. 2B show results from various or separate formulations. US 2013/0331313 A1 Dec. 12, 2013

0070 The methods and compositions provided can be lytic-phase infection in cultured cells, but these in vitro stud used to treat and/or prevent infection by any of the viruses ies have generally not resulted in clinical application. For described herein. The methods and compositions can be used instance, arginine butyrate and GCV has successfully been to treat and/or prevent any of the inflammatory conditions used to treat EBV-positive lymphoid malignancies in a recent described herein. Any of the viral inducing agents and/or Phase I/II clinical trial. In this study of 15 patients with antiviral agents described herein can be used in the methods relapsed or refractory EBV-positive lymphoid tumors, 4 and compositions of the provided invention. The viral induc patients achieved complete tumor remissions and 6 patients ing agent can be an HDAC inhibitor. The HDAC inhibitor can partial tumor remissions. However, the rapid metabolism of be a pyrimidine hydroxamic acid derivative. butyrate requires continuous IV administration of high doses. 0071. One or more additional agents described herein can Butyrate has pan-HDAC inhibitory activity, and it has been be administered to a Subject. An additional agent can be established that this activity is responsible for the induction of selected for administration based on the type of condition the the EBV-TK protein. HDAC inhibitors have been shown to Subject has or is Suspected of having. induce both EBV-TK and EBV-PK in EBV infected tumors. 0072 Another aspect of the present invention relates to (0077. In recent years, several potent HDAC inhibitors formulations, routes of administration and effective doses for (HDACi) have been tested in the clinic as anti-cancer agents. pharmaceutical compositions comprising an agent or combi In certain instances, HDAC inhibitors, including some new, nation of agents, e.g., Viral inducing agents, antiviral agents, highly-potent compounds, induce EBV lytic phase gene or one or more additional agents. A viral inducing agent, expression and kill EBV-infected cells in combination with antiviral agent, or one or more additional agents can be antiviral drugs. In some instances, HDAC inhibitors induce administered to a subject in separate pharmaceutical compo lytic phase gene expression in viruses and kill virus-infected sitions or can be co-formulated in a single pharmaceutical cells in combination with antiviral drugs. HDAC inhibitors composition. include, but are not limited to, short-chain fatty acids (sodium 0073. Also provided are methods relating to dosing sched butyrate and valproic acid), hydroxamic acids (OXamflatin, ules for administering a viral inducing agent, antiviral agent, Scriptaid, CHR-3996, Suberoyl anilide hydroxamic acid or one or more additional agents. One or more pharmaceutical (SAHA), Panobinostat (LBH589) and Belinostat(PXD101)), compositions can be administered to a Subject by “pulsed the benzamide MS275, cyclic tetrapeptide Apicidin, and administration' over a period of time. newly-identified HDAC inhibitor Largazole, which was originally isolated from a marine cyanobacterium. In any of Overview the embodiments herein, the HDAC inhibitor is preferably 0074. Like all other herpesviruses, EBV has two stages of suitable for oral administration. replication, the lytic and the latent. Soon after primary infec tion, immunological surveillance by the host forces EBV to Methods and Compositions enter the latent state of infection, where only few selected 0078. In one aspect, provided herein are methods for treat genes are expressed. EBV maintains this latent state in all ing and/or preventing a viral condition, a virally-induced EBV-associated tumors. Conventional anti-herpes virus condition, or an inflammatory condition. In some embodi drugs, such as ganciclovir, acyclovir, etc., fail to act on these ments, the condition is associated with a latent viral infection. latently-infected cells because the viral enzyme thymidine In certain embodiments, the methods comprise administering kinase (TK) or protein kinase (PK), which is necessary for the a viral inducing agent (e.g., an HDAC inhibitor) and an anti conversion of the prodrugs to their toxic metabolites, is not viral agent. In some embodiments, the methods comprise expressed in latently-infected cells. Provided herein, in some administering an HDAC inhibitor and an antiviral agent. In embodiments, is a combination treatment wherein lytic rep certain embodiments, the HDAC inhibitor and the antiviral lication is induced and antiviral drugs are administered con agent are co-formulated. In some embodiments, the methods currently. comprise further administering an additional viral inducing 0075 Previous studies using patient-derived cells in vitro, agent. In other embodiments, the methods comprise further and also from phase I/II clinical studies on a series of patients administering an additional antiviral agent. In some embodi with EBV-associated lymphomas, have clearly shown the ments, the methods comprise administering additional indi great promise of this combination therapy approach. Strong vidual doses of the viral inducing agent and/or the antiviral epidemiological association of Epstein-Barr Virus (EBV) agent. with various human lymphoid malignancies and in vitro stud 007.9 Further provided herein are methods for treating ies demonstrating tumorigenic activity of many EBV latent and/or preventing a viral condition, a virally-induced condi gene products suggest a causal relationship between EBV and tion, or an inflammatory condition comprising administering these diseases. However, as EBV maintains a latent state of an HDAC inhibitor. In some embodiments, the HDAC inhibi infection in these lymphomas, typical anti-herpesviral drugs, tor is a pyrimidine hydroxamic acid derivative. In certain Such as the nucleoside analogs ganciclovir (GCV) or acyclo embodiments, the HDAC inhibitor is a pyrimidine hydrox Vir, are ineffective as these pro-drugs require expression of a amic acid derivative not containing a piperidine, or a pyrimi lytic phase EBV protein, thymidine kinase (TK) or protein dine hydroxamic acid derivative comprising an azabicyclo kinase (EBV-PK), for their activity. Therefore, selective hexane. In certain embodiments, the methods further induction of EBV lytic-phase gene expression in lymphoma comprise administering an antiviral agent. In some embodi cells that harbor latent EBV, coupled with simultaneous expo ments, the HDAC inhibitor and the antiviral agent are co Sure to antiviral drugs, has been advanced as promising tar formulated. geted therapy, because of resulting targeting of cytotoxicity to 0080. Also provided herein are methods for treating and/ the EBV-infected tumor cells. or preventing a viral or virally-induced condition, or an 0076 A variety of agents including short-chain fatty acids inflammatory condition comprising administering an HDAC and chemotherapeutic drugs, have been used to induce EBV inhibitor and an antiviral agent. In some embodiments, the US 2013/0331313 A1 Dec. 12, 2013

viral or virally-induced condition is caused by a DNA virus. HDAC inhibitor is JNJ-26481585, JNJ-1624 1199, or CHR In certain embodiments, the HDAC inhibitor is administered 3996. In some embodiments, the antiviral agent is acyclovir, at a dose of less than 2 mg/kg perdose. In some embodiments, ganciclovir, or Valganciclovir. In certain embodiments, the the HDAC inhibitor is administered at a dose of less than 20 composition comprises an additional agent. In some embodi mg/kg, less than 19 mg/kg, less than 18 mg/kg, less than 17 ments, the additional agent is a antiviral agent, an HDAC mg/kg, less than 16 mg/kg, less than 15 mg/kg, less than 14 inhibitor, or a chemotherapeutic agent. In certain embodi mg/kg, less than 13 mg/kg, less than 12 mg/kg, less than 11 ments, the compositions are formulated as a capsule, gel. mg/kg, less than 10 mg/kg, less than 9 mg/kg, less than 8 tablet, Solution, or Suspension. In some embodiments, the mg/kg, less than 7 mg/kg, less than 6 mg/kg, less than 5 compositions are formulated for oral administration. In other mg/kg, less than 4 mg/kg, less than 3 mg/kg, less than 2 embodiments, the compositions are formulated for parenteral mg/kg, less than 1 mg/kg, less than 0.5 mg/kg, less than 0.2 administration. In some embodiments, the compositions are mg/kg, or less than 0.1 mg/kg. formulated for intravenous, intraperitoneal, oral, Subcutane 0081 Further provided herein are methods for treating ous, intrathecal, or intratumoral administration. In certain and/or preventing a viral condition, a virally-induced condi embodiments, the compositions are formulated for adminis tion, or an inflammatory condition comprising administering tration at the site of a viral infection. In some embodiments, an HDAC inhibitor and an antiviral agent wherein the HDAC the compositions are formulated for modified release of the inhibitor has a molecular weight of greater than 275 g/mol. In HDAC inhibitor and the antiviral agent. In specific embodi some embodiments, the HDAC inhibitor has a molecular ments, the HDAC inhibitor is dissolved before the antiviral weight of greater than 200 g/mol, greater than 225 g/mol. agent is dissolved. In other specific embodiments, the HDAC greater than 250 g/mol, greater than 275 g/mol, greater than inhibitor is dissolved after the antiviral agent is dissolved. In 300 g/mol, greater than 325 g/mol, greater than 350 g/mol, Some embodiments, the compositions are formulated for greater than 375 g/mol, greater than 400 g/mol, greater than once daily administration. In other embodiments, the compo 425 g/mol, greater than 450 g/mol, greater than 475 g/mol. sitions are formulated for twice daily, thrice daily, four times greater than 500 g/mol, greater than 525 g/mol, greater than daily, once every other day, once weekly, once bi-weekly, or 550 g/mol, greater than 575 g/mol, greater than 600 g/mol, monthly. greater than 625 g/mol, greater than 650 g/mol, greater than 675 g/mol, greater than 700 g/mol, greater than 725 g/mol, DEFINITIONS greater than 750 g/mol, greater than 775 g/mol, greater than I0085. The terms “viral,” “virus-associated,” and “virally 800 g/mol, greater than 850 g/mol, greater than 900 g/mol, induced with reference to disorders are used interchange greater than 950 g/mol, or greater than 1000 g/mol. In certain ably throughout the instant specification. embodiments, the HDAC inhibitor has a molecular weight of I0086. The term “obtaining as in “obtaining the composi less than 200 g/mol, less than 225 g/mol, less than 250 g/mol, tion' is intended to include purchasing, synthesizing, or oth less than 275 g/mol, less than 300 g/mol, less than 325 g/mol, erwise acquiring the composition (or agent(s) of the compo less than 350 g/mol, less than 375 g/mol, less than 400 g/mol, sition). less than 425 g/mol, less than 450 g/mol, less than 475 g/mol, I0087. The terms “comprises”, “comprising, are intended less than 500 g/mol, less than 525 g/mol, less than 550 g/mol, to have the broad meaning ascribed to them and can mean less than 575 g/mol, less than 600 g/mol, less than 625 g/mol, “includes”, “including and the like. less than 650 g/mol, less than 675 g/mol, less than 700 g/mol, I0088. The term “subject”, “patient” or “individual” are less than 725 g/mol, less than 750 g/mol, less than 775 g/mol, used interchangeably herein and refer to mammals and non less than 800 g/mol, less than 850 g/mol, less than 900 g/mol, mammals, e.g., Suffering from a disorder described herein. less than 950 g/mol, or less than 1000 g/mol. In some embodi Examples of mammals include, but are not limited to, any ments, the HDAC inhibitor has a molecular weight of less member of the Mammalian class: humans, non-human pri than 500 g/mol and more than 250 g/mol. In other embodi mates Such as chimpanzees, and otherapes and monkey spe ments, the HDAC inhibitor has a molecular weight of less cies; farm animals such as cattle, horses, sheep, goats, Swine; than 400 g/mol and more than 300 g/mol. In some instances, domestic animals such as rabbits, dogs, and cats; laboratory the HDAC inhibitor is not butyric acid or arginine butyrate. animals including rodents, such as rats, mice and guinea pigs, 0082 Also provided herein are methods for treating and/ and the like. Examples of non-mammals include, but are not or preventing Epstein-Barr virus (EBV) associated lym limited to, birds, fish and the like. In one embodiment of the phoma. In some embodiments, the methods comprise admin methods and compositions provided herein, the mammal is a istering an HDAC inhibitor and acyclovir and/or ganciclovir human. and/or Valganciclovir. I0089. The terms “treat,” “treating or “treatment,” and 0083. Further provided here are methods for treating and/ other grammatical equivalents as used herein, include allevi or preventing a virus-induced inflammatory condition. In ating, inhibiting or reducing symptoms, reducing or inhibit Some embodiments, the methods comprise administering a ing severity of reducing incidence of prophylactic treatment viral inducing agent and an antiviral agent. In certain embodi of reducing or inhibiting recurrence of delaying onset of ments the virus is a member of the herpes family (e.g., herpes delaying recurrence of abating or ameliorating a disease or simplex virus, herpes genitalis virus, varicella Zoster virus, condition symptoms, ameliorating the underlying metabolic Epstein-Barr virus, human herpes virus 6, or cytomegalovi causes of symptoms, inhibiting the disease or condition, e.g., rus), human immunodeficiency virus, parvovirus, or cox arresting the development of the disease or condition, reliev sackie virus. ing the disease or condition, causing regression of the disease 0084. In another aspect, provided herein are compositions or condition, relieving a condition caused by the disease or comprising an HDAC inhibitor and an antiviral agent. In condition, or stopping the symptoms of the disease or condi certain embodiments, the HDAC inhibitor is a pyrimidine tion. The terms further include achieving a therapeutic ben hydroxamic acid derivative. In some embodiments, the efit. By therapeutic benefit is meant eradication or ameliora US 2013/0331313 A1 Dec. 12, 2013

tion of the underlying disorder being treated, and/or the carriers and vehicles are known to those of extraordinary skill eradication or amelioration of one or more of the physiologi in the art. The term “excipient’ as used herein will encompass cal symptoms associated with the underlying disorder Such all Such carriers, adjuvants, diluents, solvents, or other inac that an improvement is observed in the patient. tive additives. Suitable pharmaceutically acceptable excipi 0090. The terms “prevent,” “preventing” or “prevention.” ents include, but are not limited to, water, salt Solutions, and other grammatical equivalents as used herein, include alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, preventing additional symptoms, preventing the underlying amylose, magnesium Stearate, talc, silicic acid, viscous par metabolic causes of symptoms, inhibiting the disease or con affin, perfume oil, fatty acid monoglycerides and diglycer dition, e.g., arresting the development of the disease or con ides, petroethral fatty acid esters, hydroxymethyl-cellulose, dition and are intended to include prophylaxis. The terms polyvinylpyrrolidone, etc. The pharmaceutical compositions further include achieving a prophylactic benefit. For prophy of the invention can also be sterilized and, if desired, mixed lactic benefit, the compositions are optionally administered to with auxiliary agents, e.g., lubricants, preservatives, stabiliz a patient at risk of developing a particular disease, to a patient ers, wetting agents, emulsifiers, salts for influencing osmotic reporting one or more of the physiological symptoms of a pressure, buffers, colorings, flavorings and/or aromatic Sub disease, or to a patient at risk of reoccurrence of the disease. stances and the like, which do not deleteriously react with the 0091. The terms “effective amount” or “therapeutically active compounds of the invention. effective amount’ as used herein, refer to a sufficient amount (0095. The invention can be understood more fully by ref of at least one agent being administered which achieve a erence to the following detailed description and illustrative desired result, e.g., to relieve to Some extent one or more examples, which are intended to exemplify non-limiting symptoms of a disease or condition being treated. In certain embodiments of the invention. instances, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired Viral Inducing Agents alteration of a biological system. In certain instances, an 0096. The methods of the provided invention comprise use “effective amount' for therapeutic uses is the amount of the of one or more pharmaceutical compositions provided herein composition comprising an agent as set forth herein required comprising an inducing agent to induce expression of a gene to provide a clinically significant decrease in a disease. An product in a virus-infected cell. The gene product expressed appropriate 'effective' amount in any individual case is can be a viral enzyme or a cellular enzyme or activity that is determined using any Suitable technique, Such as a dose esca largely expressed in virus-infected cells. Expression products lation study. that can be targeted include enzymes involved with DNA 0092. The terms “administer,” “administering”, “adminis replication, for example, for repair or replication of the tration, and the like, as used herein, refer to the methods that genome, assembly of complete virus particles, generation of are used to enable delivery of agents or compositions to the viral membrane or walls, RNA transcription or protein trans desired site of biological action. These methods include, but lation or combinations of these activities. Interference with are not limited to oral routes, intraduodenal routes, parenteral these processes can be performed by inducing and then acting injection (including intravenous, Subcutaneous, intraperito on an enzyme and, preferably, a critical enzyme in the pro neal, intramuscular, intravascular or infusion), topical and cess. Inducing agents that can be used in the methods and rectal administration. Administration techniques that in some compositions of the provided invention are described, for instances are employed with the agents and methods example, in U.S. Pat. Nos. 6,197,743 and 6,677.302, which described herein include, e.g., as discussed in Goodman and are herein incorporated by reference in their entireties. Gilman, The Pharmacological Basis of Therapeutics (current 0097 Inducing agents according to the methods or com edition), Pergamon; and Remington's, Pharmaceutical Sci positions provided herein include, without limitation, short ences (current edition), Mack Publishing Co., Easton, Pa. In chain fatty acid (SCFA) derivatives, histone deacetylase certain embodiments, the agents and compositions described (HDAC) inhibitors, phorbol esters, anticancer agents, and herein are administered orally. In some embodiments, the cytokines. In some embodiments, the viral inducing agent is compositions described herein are administered parenterally. a chemotherapeutic drug, an HDAC inhibitor, or a DNA dem 0093. The term “pharmaceutically acceptable' as used ethylating agent. herein, refers to a material that does not abrogate the biologi 0098. In some embodiments, the inducing agent is a SCFA cal activity or properties of the agents described herein, and is derivative. Examples of SCFA inducing agents include pro relatively nontoxic (i.e., the toxicity of the material signifi pionic acid, butyric acid. Succinic acid, fumaric acid mono cantly outweighs the benefit of the material). In some ethyl ester, dimethylbutyric acid, trifluorobutanol, chloropro instances, a pharmaceutically acceptable material is admin pionic acid, isopropionic acid, 2-oxypentanoic acid, 2.2- or istered to an individual without causing significant undesir 3.3-dimethylbutyric acid, 2.2- or 3.3-diethylbutyric acid, able biological effects or significantly interacting in a delete butyric acid ethyl ester, 2-methylbutanoic acid, fumaric acid, rious manner with any of the components of the composition and amides and salts thereof. Other examples include meth in which it is contained. oxy acetic acid, methoxy propionic acid, N-acetylglycine, 0094. The term “pharmaceutically acceptable excipient.” mercaptoacetic acid, 1- or 2-methyl cyclopropane carboxylic as used herein, refers to carriers and vehicles that are com acid, squaric acid, 2- or 3-phenoxy propionic acid, methoxy patible with the active ingredient (for example, a compound butyric acid, phenoxy acetic acid, 2- or 3-phenoxybutyric of the invention) of a pharmaceutical composition of the acid, phenyl acetic acid, phenyl propionic acid, 3-phenyl invention (and preferably capable of stabilizing it) and not butyric acid, ethyl-phenyl acetic acid, 4-chloro-2-phenoxy deleterious to the subject to be treated. For example, solubi 2-propionic acid, n-dimethyl butyric acid glycine amide, lizing agents that form specific, more soluble complexes with o-benzoyl lactic acid, o-dimethyl butyric acid lactate, cin the compounds of the invention can be utilized as pharma namic acid, dihydrocinnamic acid (CHCHCHCOOH), ceutical excipients for delivery of the compounds. Suitable alpha-methyl-dihydrocinnamic acid, thiophenoxy acetic US 2013/0331313 A1 Dec. 12, 2013

acid, and amines, amides and salts of these chemicals. Useful Releasing Hormone Analogs like buserelin, goserelin, leu amines and amides can include isobutylhydroxylamine, prorelin, triptorelin; Anti-Estrogens like fulvestrant, tamox fumaric acid monoamide, fumaramide, Succinamide, or ifen, toremifene; Anti-Androgens like bicalutamide, fluta isobutyramide. mide, nilutamide; Enzyme Inhibitors like 0099. In other embodiments, inducing agents include ret aminoglutethimide, anastrozole, exemestane, formestane, inoic acid, retinol, cytosine arabinoside, phorbols such as the letrozole, Vorozole; Other Hormone Antagonists like phorbol diester 12-0-tetradecanoylphorbol 13-acetate (TPA), abarelix, degarelix; Immunostimulants like histamine dihy teleocidine B, indole alkaloids, cytotoxin, plant lectins from drochloride, mi?amurtide, pidotimod, plerixafor, roquinimex, Streptomyces, glucocorticoids such as estrogen and progest thymopentin: Immunosuppressants like everolimus, Zotaroli erone, phytohemagglutinin (PHA), bryostatin, growth factors mus, gusperimus, leflunomide, mycophenolic acid, siroli (e.g. PDGF, VEGF, EGF, FGF, NGF, TGF, BCGF), anti-sense mus; Calcineurin Inhibitors like ciclosporin, tacrolimus; nucleic acids (e.g. DNA, RNA or PNA), aptamers (nucleic Other Immunosuppressants like azathioprine, lenalidomide, acid oligonucleotides with secondary or tertiary structures methotrexate, thalidomide; and Radiopharmaceuticals like which bind with high affinity and selectivity to a target mol iobenguane. ecule), erythropoietin (EPO), the interleukins (IL-1, IL-2, 0101. In certain embodiments, the viral inducing agent is a IL-3, etc.). cAMP and cAMP analogs such as dibutyryl demethylating agent. For example, demethylating agents cAMP, activin, inhibin, steel factor, interferon, the bone mor include decitabine and azacytidine. In other embodiments, phogenic proteins (BMBs), hydroxyurea and dimethyl sul the inducing agent is a chemotherapy drug, such as cyclo foxide (DMSO). Other inducing agents include interferons phosphamide, cisplatin, melphalan, doxorubicin, daunorubi (e.g. Cl-, 3-, y-interferon), cytokines such as tumor necrosis cin, Vincristine, methotrexate, cytarabine, ifosfamide, etopo factor (TNF), cell receptors, and growth factor antagonists, side, or rituximab. which may be purified or recombinantly produced. 0102. In further embodiments, inducing agents include 0100. In some embodiments, the inducing agent is a anti histone deacetylase (HDAC) inhibitors (including those of cancer agent. In certain embodiments, the anticancer agent is the hydroxamic acid class and the benzamide class), DNA a chemotherapeutic anticancer agent. Examples of chemo methyltransferase inhibitors, and proteasome inhibitors. therapeutic anticancer agents include Nitrogen Mustards like HDAC inhibitors, a class of compounds that interfere with the bendamustine, chlorambucil, chlormethine, cyclophospha function of histone deacetylase, include, without limitation, mide, ifosfamide, melphalan, prednimustine, trofosfamide; short-chain fatty acids (butyrate, phenylbutyrate, Valproate, Alkyl Sulfonates like busulfan, mannosulfan, treosulfan; Eth AN-9, etc., as described above), hydroxamic acids (for ylene Imines like carboquone, thiotepa, triaziquone; example m-carboxycinnamic acid, bishydroxamic acid, Nitrosoureas like carmustine, fotemustine, lomustine, nimus suberic bishydroxamic acid, Trichostatin A (7-4-(dimethy tine, ranimustine, Semustine, Streptozocin, Epoxides like eto lamino)phenyl-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4- glucid; Other Alkylating Agents like dacarbazine, mitobroni dienamide), SAHA (suberoylanilide hydroxamic acid)/Vori tol, pipobroman, temozolomide; Folic Acid Analogues like nostat, oxamflatin, ABHA, SB-55629, pyroxamide, methotrexate, permetrexed, pralatrexate, raltitrexed: Purine propenamides, aroyl pyrrolyl hydroxamides, Belinostat/ Analogs like cladribine, clofarabine, fludarabine, mercap PXD101, Papobinostat, LAQ824 (((E)-N-hydroxy-3-4-2- topurine, nelarabine, tioguanine: Pyrimidine Analogs like hydroxyethyl-2-(1H-indol-3-yl)ethylaminomethylphe aZacitidine, capecitabine, carmofur, cytarabine, decitabine, nylprop-2-enamide), LBH589, CHR-3996 (2-(6-(6- fluorouracil, gemcitabine, tegafur, Vinca Alkaloids like Vin Fluoroquinolin-2-yl)methylamino-3-azabicyclo[3.1.0 blastine, Vincristine, vindesine, Vinflunine, vinorelbine; hex-3-yl)-N-hydroxypyrimidine-5-carboxamide, TSA), Podophyllotoxin Derivatives like etoposide, teniposide: Pivanex, Spiruchostatins, cyclic tetrapeptides (for example, Colchicine derivatives like demecolcine; Taxanes like doc trapoxin A (cyclo(S)-phenylalanyl-(S)-phenylalanyl-(R)- etaxel, paclitaxel, paclitaxel poliglumex: Other Plant Alka pipecolinyl-(2S,9S)-2-amino-8-oxo-9,10-epoxydecanoyl)), loids and Natural Products like trabectedin; Actinomycines trapoxin B (cyclo(S)-phenylalanyl-phenylalanyl-(R)-prolyl like dactinomycin; Antracyclines like aclarubicin, daunoru 2-amino-8-oxo-9,10-epoxydecanoyl)), HC-toxin, chlamydo bicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, cin, diheteropeptin, WF-3161, Cy 1-1, Cy 1-2, azumamide A), pirarubicin, valrubicin, Zorubincin; Other Cytotoxic Antibi cyclic peptides (for example, FK-228, FR901228), depsipep otics like bleomycin, ixabepilone, mitomycin, plicamycin; tides (for example, romidepsin, FK228 (E)-(1S,4S, 10S, Platinum Compounds like carboplatin, cisplatin, oxaliplatin, 21R)-7 (Z)-ethylideno-4,21-diisopropyl-2-oxa-12,13 satraplatin: Methylhydrazines like procarbazine: Sensitizers dithia-5,8,20.23-tetraazabicyclo8,7,6-tricos-16-ene-3,6,9. like aminolevulinic acid, efaproxiral, methyl aminolevuli 22-pentanone), FK228 analogs and derivatives, largazole, nate, porfimer sodium, temoporfin; Protein Kinase Inhibitors largaZole analogs and derivatives), peptide antibiotics (apici like dasatinib, erlotinib, everolimus, Zotarolimus, gefitinib, din), benzamides (MS275 (3-pyridinylmethyl 4-(2-ami imatinib, lapatinib, nilotinib, paZonanib, Sorafenib, Sunitinib, nophenyl)aminocarbonylphenylmethylcarbamate, N-(2- temsirolimus; Other Antineoplastic Agents like alitretinoin, Aminophenyl)-4-N-(pyridine-3-ylmethoxycarbonyl) altretamine, amzacrine, anagrelide, arsenic trioxide, aspara aminomethylbenzamide), CI994 (4-(Acetylamino)-N-(2- ginase, bexarotene, bortezomib, celecoxib, denileukin difti aminophenyl)benzamide), MGCD0103), electrophilic toX, estramustine, hydroxycarbamide, irinotecan, ketones (TPX, AOR, Depudecin), FR901375, nicotinamide, lonidamine, masoprocol, miltefosein, mitoguaZone, mito NAD derivatives, Sirtinol, splitomycin, dihydrocoumarin, tane, oblimersen, pegaspargase, pentostatin, romidepsin, siti naphthopyranone, 2-hydroxynaphthaldehydes, PCYC-0402. magene ceradenovec, tiazofurine, topotecan, tretinoin, Vori PCYC-0403, PCI-24781 (3-(dimethylaminomethyl)-N-2- nostat; Estrogens like diethylstilbenol, ethinylestradiol, 4-(hydroxycarbamoyl)phenoxyethyl-1-benzofuran-2-car foSfestrol, polyestradiol phosphate; Progestogens like gesto boxamide), depudecin, tubacin, organosulfur compounds, norone, medroxyprogesterone, megestrol; Gonadotropin and dimethyl sulfoxide (DMSO). Other compounds which US 2013/0331313 A1 Dec. 12, 2013 may also be administered as inducing agents, which include than 850 g/mol, greater than 900 g/mol, greater than 950 CHAPs, Scriptaid, Tubacin, JNJ16241199, A-161906, 6-(3- g/mol, or greater than 1000 g/mol. In certain embodiments, Chlorophenylureido)caproic hydroxamic acid, SB939, the HDAC inhibitor has a molecular weight of less than 200 ITF2357 (6-(diethylamino)methyl-2-naphthylmethyl g/mol, less than 225 g/mol, less than 250 g/mol, less than 275 {4-(hydroxyamino)carbonylphenylcarbamate), 4SC-201, g/mol, less than 300 g/mol, less than 325 g/mol, less than 350 AR-42, OPB-801, RG2833, CUDC-101, JNJ-26481585, g/mol, less than 375 g/mol, less than 400 g/mol, less than 425 MK0683 (suberoylanilide hydroxamic acid), M344 (4-(Di g/mol, less than 450 g/mol, less than 475 g/mol, less than 500 ethylamino)-N-7-(hydroxyamino)-7-oxoheptylbenza g/mol, less than 525 g/mol, less than 550 g/mol, less than 575 mide), BML-210 (N-(2-aminophenyl)-N'-phenyl-octanedia g/mol, less than 600 g/mol, less than 625 g/mol, less than 650 mide), dacinostat (NVP-LAQ824), PDX-101, BAY36-5274, g/mol, less than 675 g/mol, less than 700 g/mol, less than 725 SB939, droxinostat, and pivaloyloxymethylbutyrate. g/mol, less than 750 g/mol, less than 775 g/mol, less than 800 0103) In some embodiments, the viral inducing agent is an g/mol, less than 850 g/mol, less than 900 g/mol, less than 950 HDAC inhibitor. In some embodiments, the HDAC inhibitor g/mol, or less than 1000 g/mol. In some embodiments, the is a hydroxamic acid, for example, Vorinostat/Suberoyl anil HDAC inhibitor has a molecular weight of less than 500 ide hydroxamic acid (SAHA), JNJ-26481585 (N-hydroxy-2- g/mol and more than 250 g/mol. In other embodiments, the (4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)pip HDAC inhibitor has a molecular weight of less than 400 eridin-1-yl)pyrimidine-5-carboxamide), R306465/JNJ g/mol and more than 300 g/mol. 1624 11.99 (N-hydroxy-5-(4-(naphthalen-2-ylsulfonyl) 0107. In a particular embodiment, the HDAC inhibitor is piperazin-1-yl)pyrimidine-2-carboxamide), CHR-3996 (2- not m-carboxycinnamic acid, bishydroxamic acid, Suberic (6-(6-Fluoroquinolin-2-yl)methylamino-3-azabicyclo bishydroxamic acid, Trichostatin A (7-4-(dimethylamino) 3.1.0 hex-3-yl)-N-hydroxypyrimidine-5-carboxamide), phenyl-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-diena Belinostat/PXD101, Panobinostat/LBH-589, trichostatin mide), SAHA (suberoylanilide hydroxamic acid)/Vorinostat, A/TSA (7-4-(dimethylamino)phenyl-N-hydroxy-4,6-dim oxamflatin, ABHA, SB-55629, pyroxamide, propenamides, ethyl-7-oxohepta-2,4-dienamide), ITF2357, CBHA, and aroyl pyrrolyl hydroxamides, Belinostat/PXD101, Papobin Givinostat/ITF2357. In certain embodiments, the HDAC ostat, LAQ824 (((E)-N-hydroxy-3-4-2-hydroxyethyl-2- inhibitor is a pyrimidine hydroxamic acid, for example, JNJ (1H-indol-3-yl)ethylaminomethylphenylprop-2-enam 26481585, JNJ-16241199, or CHR-3996. In other embodi ide), or LBH589. ments, the HDAC inhibitor is a benzamide, for example, 0108. In some embodiments, a viral inducing agent, for CI-994, Entinostat/MS-275, SNDX-275, and mocetinostat/ example an HDAC inhibitor, penetrates the blood brain bar MGCD0103 (N-(2-aminophenyl)-4-(4-pyridin-3-ylpyrimi rier. In certain embodiments, a viral inducing agent that pen din-2-ylamino)methyl)benzamide). etrates the blood brain barrier comprises arginine butyrate, 0104. In some embodiments, the HDAC inhibitor is a SAHA, or CHR-3996. hydroxamic acid derivative. In certain embodiments, the 0109. In certain embodiments, the HDAC inhibitor is HDAC inhibitor is a pyrimidine hydroxamic acid. In some administered at a dose of less than 400 mg/day. In some embodiments, the HDAC inhibitor is a non-piperidine-con embodiments, the HDAC inhibitor is administered at a dose taining pyrimidine hydroxamic acid derivative. In certain of about 1 mg/day, about 2 mg/day, about 5 mg/day, about 10 embodiments, the HDAC inhibitor comprises an azabicyclo mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, hexane. In other embodiments, the HDAC inhibitor com about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 prises fluorine. In certain embodiments, the HDAC inhibitor mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, comprises a fluoroquinoline group. about 80 mg/day, about 90 mg/day, about 100 mg/day, about 0105. In one embodiment the HDAC inhibitor is JNJ 120 mg/day, about 125 mg/day, about 140 mg/day, about 150 26481585 (N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)me mg/day, about 160 mg/day, about 175 mg/day, about 180 thyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxam mg/day, about 190 mg/day, about 200 mg/day, about 225 ide). In a further embodiment, the HDAC inhibitor is mg/day, about 250 mg/day, about 275 mg/day, about 300 R306465/JNJ-16241199 (N-hydroxy-5-(4-(naphthalen-2-yl mg/day, about 325 mg/day, about 350 mg/day, about 375 Sulfonyl)piperazin-1-yl)pyrimidine-2-carboxamide). In a mg/day, about 400 mg/day, about 425 mg/day, about 450 specific embodiment, the HDAC inhibitor is CHR-39962 mg/day, about 475 mg/day, or about 500 mg/day. In certain (6-(6-Fluoroquinolin-2-yl)methylamino-3-azabicyclo embodiments, the HDAC inhibitor is administered at a dose 3.1.0 hex-3-yl)-N-hydroxypyrimidine-5-carboxamide, or of less than 1 mg/day, less than 2 mg/day, less than 5 mg/day, N-hydroxy 2-(6-(6-Fluoroquinolin-2-yl)methylamino less than 10 mg/day, less than 15 mg/day, less than 20 mg/day, 3-azabicyclo[3.1.0 hex-3-yl)-pyrimidine-5-carboxamide. less than 25 mg/day, less than 30 mg/day, less than 35 mg/day, 0106. In another embodiment, the molecular weight of the less than 40 mg/day, less than 45 mg/day, less than 50 mg/day, HDAC inhibitor is greater than 275 g/mol. In some embodi less than 60 mg/day, less than 70 mg/day, less than 80 mg/day, ments, the HDAC inhibitor has a molecular weight of greater less than 90 mg/day, less than 100 mg/day, less than 120 than 200 g/mol, greater than 225 g/mol, greater than 250 mg/day, less than 125 mg/day, less than 140 mg/day, less than g/mol, greater than 275 g/mol, greater than 300 g/mol, greater 150 mg/day, less than 160 mg/day, less than 175 mg/day, less than 325 g/mol, greater than 350 g/mol, greater than 375 than 180 mg/day, less than 190 mg/day, less than 200 mg/day, g/mol, greater than 400 g/mol, greater than 425 g/mol, greater less than 225 mg/day, less than 250 mg/day, less than 275 than 450 g/mol, greater than 475 g/mol, greater than 500 mg/day, less than 300 mg/day, less than 325 mg/day, less than g/mol, greater than 525 g/mol, greater than 550 g/mol, greater 350 mg/day, less than 375 mg/day, less than 400 mg/day, less than 575 g/mol, greater than 600 g/mol, greater than 625 than 425 mg/day, less than 450 mg/day, less than 475 mg/day, g/mol, greater than 650 g/mol, greater than 675 g/mol, greater or less than 500 mg/day. In some embodiments, the HDAC than 700 g/mol, greater than 725 g/mol, greater than 750 inhibitor is administered at a dose of more than 1 mg/day, g/mol, greater than 775 g/mol, greater than 800 g/mol, greater more than 2 mg/day, more than 5 mg/day, more than 10 US 2013/0331313 A1 Dec. 12, 2013

mg/day, more than 15 mg/day, more than 20 mg/day, more of the HDAC inhibitor CHR-3996 and about 450 mg of val than 25 mg/day, more than 30 mg/day, more than 35 mg/day, ganciclovir. In certain embodiments, the unit dose comprises more than 40 mg/day, more than 45 mg/day, more than 50 about 40 mg of the HDAC inhibitor CHR-3996 and about 900 mg/day, more than 60 mg/day, more than 70 mg/day, more mg of Valganciclovir. In some embodiments, the antiviral than 80 mg/day, more than 90 mg/day, more than 100 mg/day, agent is formulated as controlled release. more than 120 mg/day, more than 125 mg/day, more than 140 0.112. In some embodiments, the HDAC inhibitor is ITF mg/day, more than 150 mg/day, more than 160 mg/day, more 2357. In certain embodiments, ITF-2357 is administered at a than 175 mg/day, more than 180 mg/day, more than 190 dose of 100 mg/day. In some embodiments, ITF-2357 is mg/day, more than 200 mg/day, more than 225 mg/day, more administered at a dose of about 1 mg/day, about 2 mg/day, than 250 mg/day, more than 275 mg/day, more than 300 about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, more than 325 mg/day, more than 350 mg/day, more mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, than 375 mg/day, more than 400 mg/day, more than 425 about 40 mg/day, about 45 mg/day, about 50 mg/day, about 60 mg/day, more than 450 mg/day, more than 475 mg/day, or mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, more than 500 mg/day. In certain embodiments, the HDAC about 100 mg/day, about 120 mg/day, about 125 mg/day, inhibitor is administered at a dose of more than 1 mg/day and about 140 mg/day, about 150 mg/day, about 160 mg/day, less than 500 mg/day. In some embodiments, the HDAC about 175 mg/day, about 180 mg/day, about 200 mg/day, inhibitoris administered at a dose of more than 20 mg/day and about 225 mg/day, about 250 mg/day, about 275 mg/day, or less than 80 mg/day. In certain embodiments, the HDAC about 300 mg/day. In certain embodiments, ITF-2357 is inhibitor is administered once a day (q.d.), twice a day (b.id.). administered at a dose of less than 1 mg/day, less than 2 or thrice a day (t.i.d.). In some embodiments, the HDAC mg/day, less than 5 mg/day, less than 10 mg/day, less than 15 inhibitor is administered daily, once a week, twice a week, mg/day, less than 20 mg/day, less than 25 mg/day, less than 30 three times a week, four times a week, or five times a week. mg/day, less than 35 mg/day, less than 40 mg/day, less than 45 0110. In some embodiments, the HDAC inhibitoris CHR mg/day, less than 50 mg/day, less than 60 mg/day, less than 70 3996. In certain embodiments, CHR-3996 is administered at mg/day, less than 80 mg/day, less than 90 mg/day, less than a dose of 40 mg/day. In some embodiments, CHR-3996 is 100 mg/day, less than 120 mg/day, less than 125 mg/day, less administered at a dose of about 1 mg/day, about 2 mg/day, than 140 mg/day, less than 150 mg/day, less than 160 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 less than 175 mg/day, less than 180 mg/day, less than 200 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, mg/day, less than 225 mg/day, less than 250 mg/day, less than about 40 mg/day, about 45 mg/day, about 50 mg/day, about 60 275 mg/day, or less than 300 mg/day. In some embodiments, mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, ITF-2357 is administered at a dose of more than 1 mg/day, or about 100 mg/day. In certain embodiments, CHR-3996 is more than 2 mg/day, more than 5 mg/day, more than 10 administered at a dose of less than 1 mg/day, less than 2 mg/day, more than 15 mg/day, more than 20 mg/day, more mg/day, less than 5 mg/day, less than 10 mg/day, less than 15 than 25 mg/day, more than 30 mg/day, more than 35 mg/day, mg/day, less than 20 mg/day, less than 25 mg/day, less than 30 more than 40 mg/day, more than 45 mg/day, more than 50 mg/day, less than 35 mg/day, less than 40 mg/day, less than 45 mg/day, more than 60 mg/day, more than 70 mg/day, more mg/day, less than 50 mg/day, less than 60 mg/day, less than 70 than 80 mg/day, more than 90 mg/day, more than 100 mg/day, mg/day, less than 80 mg/day, less than 90 mg/day, or less than more than 120 mg/day, more than 125 mg/day, more than 140 100 mg/day. In some embodiments, CHR-3996 is adminis mg/day, more than 150 mg/day, more than 160 mg/day, more tered at a dose of more than 1 mg/day, more than 2 mg/day, than 175 mg/day, more than 180 mg/day, more than 200 more than 5 mg/day, more than 10 mg/day, more than 15 mg/day, more than 225 mg/day, more than 250 mg/day, more mg/day, more than 20 mg/day, more than 25 mg/day, more than 275 mg/day, or more than 300 mg/day. In certain than 30 mg/day, more than 35 mg/day, more than 40 mg/day, embodiments, ITF-2357 is administered at a dose of more more than 45 mg/day, more than 50 mg/day, more than 60 than 80 mg/day and less than 120 mg/day. In some embodi mg/day, more than 70 mg/day, more than 80 mg/day, more ments, ITF-2357 is administered at a dose of more than 40 than 90 mg/day, or more than 100 mg/day. In certain embodi mg/day and less than 120 mg/day. In certain embodiments, ments, CHR-3996 is administered at a dose of more than 30 ITF-2357 is administered at a dose of more than 50 mg/day mg/day and less than 50 mg/day. In some embodiments, and less than 240 mg/day. In some embodiments, ITF-2357 is CHR-3996 is administered at a dose of more than 20 mg/day administered once a day (q.d.), twice a day (b.id.), or thrice a and less than 80 mg/day. In certain embodiments, CHR-3996 day (t.i.d.). In some embodiments, ITF-2357 is administered is administered once a day (q.d.), twice a day (b.id.), or thrice daily, once a week, twice a week, three times a week, four a day (t.i.d.). In some embodiments, CHR-3996 is adminis times a week, or five times a week. tered daily, once a week, twice a week, three times a week, 0113. In some embodiments, the HDAC inhibitor is JNJ four times a week, or five times a week. 16241 199/R306465. In certain embodiments, JNJ 0111. In some embodiments, a unit dose of a co-formu 16241 199/R306465 is administered at a dose of 100 mg/day. lated HDAC inhibitor and antiviral agent comprises less than In some embodiments, JNJ-16241 199/R306465 is adminis 100 mg of the HDAC inhibitor and less than 1000 mg of the tered at a dose of about 1 mg/day, about 2 mg/day, about 5 antiviral agent. In certain embodiments, the unit dose com mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, prises less than 50 mg of the HDAC inhibitor and less than about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 500 mg of the antiviral agent. In other embodiments, the unit mg/day, about 45 mg/day, about 50 mg/day, about 60 mg/day, dose comprises less than 80 mg of the HDAC inhibitor and about 70 mg/day, about 80 mg/day, about 90 mg/day, about less than 1500 mg of the antiviral agent. In some embodi 100 mg/day, about 120 mg/day, about 125 mg/day, about 140 ments, the unit dose comprises less than 50 mg of the HDAC mg/day, about 150 mg/day, about 160 mg/day, about 175 inhibitor CHR-3996 and less than 1000 mg of valganciclovir. mg/day, about 180 mg/day, about 200 mg/day, about 225 In some embodiments, the unit dose comprises about 20 mg mg/day, about 250 mg/day, about 275 mg/day, or about 300 US 2013/0331313 A1 Dec. 12, 2013

mg/day. In certain embodiments, JNJ-16241 199/R3.06465 is mg/day. In some embodiments, JNJ-26481585 is adminis administered at a dose of less than 1 mg/day, less than 2 tered at a dose of more than 5 mg/day and less than 30 mg/day. mg/day, less than 5 mg/day, less than 10 mg/day, less than 15 In certain embodiments, JNJ-26481585 is administered once mg/day, less than 20 mg/day, less than 25 mg/day, less than 30 a day (q.d.), twice a day (b.id.), or thrice a day (t.i.d.). In some mg/day, less than 35 mg/day, less than 40 mg/day, less than 45 embodiments, JNJ-26481585 is administered daily, once a mg/day, less than 50 mg/day, less than 60 mg/day, less than 70 week, twice a week, three times a week, four times a week, or mg/day, less than 80 mg/day, less than 90 mg/day, less than five times a week. 100 mg/day, less than 120 mg/day, less than 125 mg/day, less 0.115. In some embodiments, the HDAC inhibitor is than 140 mg/day, less than 150 mg/day, less than 160 mg/day, MGCD103. In certain embodiments, MGCD103 is adminis less than 175 mg/day, less than 180 mg/day, less than 200 tered at a dose of 45 mg/m/day. In some embodiments, mg/day, less than 225 mg/day, less than 250 mg/day, less than MGCD103 is administered at a dose of about 1 mg/m/day, 275 mg/day, or less than 300 mg/day. In some embodiments, about 2 mg/m/day, about 5 mg/m/day, about 10 mg/m/day, JNJ-16241 199/R3.06465 is administered at a dose of more about 15 mg/m/day, about 20 mg/m/day, about 25 mg/m/ than 1 mg/day, more than 2 mg/day, more than 5 mg/day, day, about 30 mg/m/day, about 35 mg/m/day, about 40 more than 10 mg/day, more than 15 mg/day, more than 20 mg/m2/day, about 45 mg/m/day, about 50 mg/m/day, about mg/day, more than 25 mg/day, more than 30 mg/day, more 60 mg/m/day, about 70 mg/m/day, about 80 mg/m/day, than 35 mg/day, more than 40 mg/day, more than 45 mg/day, about 90 mg/m/day, or about 100 mg/m/day. In certain more than 50 mg/day, more than 60 mg/day, more than 70 embodiments, MGCD103 is administered at a dose of less mg/day, more than 80 mg/day, more than 90 mg/day, more than 1 mg/m/day, less than 2 mg/m/day, less than 5 mg/m/ than 100 mg/day, more than 120 mg/day, more than 125 day, less than 10 mg/m/day, less than 15 mg/m/day, less mg/day, more than 140 mg/day, more than 150 mg/day, more than 20 mg/m/day, less than 25 mg/m/day, less than 30 than 160 mg/day, more than 175 mg/day, more than 180 mg/m/day, less than 35 mg/m/day, less than 40 mg/m/day, mg/day, more than 200 mg/day, more than 225 mg/day, more less than 45 mg/m/day, less than 50 mg/m/day, less than 60 than 250 mg/day, more than 275 mg/day, or more than 300 mg/m/day, less than 70 mg/m/day, less than 80 mg/m/day, mg/day. In certain embodiments, JNJ-16241 199/R3.06465 is less than 90 mg/m/day, or less than 100 mg/m/day. In some administered at a dose of more than 80 mg/day and less than embodiments, MGCD103 is administered at a dose of more 120 mg/day. In some embodiments, JNJ-16241 199/R306465 than 1 mg/m/day, more than 2 mg/m/day, more than 5 is administered at a dose of more than 40 mg/day and less than mg/m/day, more than 10 mg/m/day, more than 15 mg/m/ 120 mg/day. In certain embodiments, JNJ-16241 1997 day, more than 20 mg/m/day, more than 25 mg/m/day, more R306465 is administered at a dose of more than 50 mg/day than 30 mg/m/day, more than 35 mg/m/day, more than 40 and less than 240 mg/day. In some embodiments, JNJ mg/m/day, more than 45 mg/m/day, more than 50 mg/m/ 16241 199/R306465 is administered once a day (d.d.), twice a day, more than 60 mg/m/day, more than 70 mg/m/day, more day (b.id.), or thrice a day (t.i.d.). In some embodiments, than 80 mg/m/day, more than 90 mg/m/day, or more than JNJ-16241 199/R306465 is administered daily, once a week, 100 mg/m/day. In certain embodiments, MGCD103 is twice a week, three times a week, four times a week, or five administered at a dose of more than 30 mg/m/day and less times a week. than 80 mg/m/day. In some embodiments, MGCD103 is 0114. In some embodiments, the HDAC inhibitor is JNJ administered at a dose of more than 45 mg/m/day and less 26481585. In certain embodiments, JNJ-26481585 is admin than 60 mg/m/day. In certain embodiments, MGCD103 is istered at a dose of 10 mg/day. In some embodiments, JNJ administered once a day (q.d.), twice a day (b.id.), or thrice a 26481585 is administered at a dose of about 0.1 mg/day, day (t.i.d.). In some embodiments, MGCD103 is adminis about 0.2 mg/day, about 0.5 mg/day, about 1 mg/day, about 2 tered daily, once a week, twice a week, three times a week, mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, four times a week, or five times a week. about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 0116. In some embodiments, the HDAC inhibitor is mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, MS-275. In certain embodiments, MS-275 is administered at about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 a dose of 4 mg/m/day. In some embodiments, MS-275 is mg/day, or about 100 mg/day. In certain embodiments, JNJ administered at a dose of about 0.1 mg/m/day, of about 0.2 26481585 is administered at a dose of less than 0.1 mg/day, mg/m/day, of about 0.5 mg/m/day, of about 1 mg/m/day, of less than 0.2 mg/day, less than 0.5 mg/day, less than 1 mg/day, about 2 mg/m/day, of about 3 mg/m/day, of about 4 mg/m/ less than 2 mg/day, less than 5 mg/day, less than 10 mg/day, day, about 5 mg/m/day, of about 6 mg/m/day, of about 7 less than 15 mg/day, less than 20 mg/day, less than 25 mg/day, mg/m/day, of about 8 mg/m/day, of about 9 mg/m/day, less than 30 mg/day, less than 35 mg/day, less than 40 mg/day, about 10 mg/m/day, about 15 mg/m/day, about 20 mg/m/ less than 45 mg/day, less than 50 mg/day, less than 60 mg/day, day, about 25 mg/m/day, about 30 mg/m/day, about 35 less than 70 mg/day, less than 80 mg/day, less than 90 mg/day, mg/m/day, about 40 mg/m2/day, about 45 mg/m/day, about or less than 100 mg/day. In some embodiments, 50 mg/m/day, about 60 mg/m/day, about 70 mg/m/day, JNJ-26481585 is administered at a dose of more than 0.1 about 80 mg/m/day, about 90 mg/m/day, or about 100 mg/day, more than 0.2 mg/day, more than 0.5 mg/day, more mg/m/day. In certain embodiments, MS-275 is administered than 1 mg/day, more than 2 mg/day, more than 5 mg/day, at a dose of less than 0.1 mg/m/day, of less than 0.2 mg/m/ more than 10 mg/day, more than 15 mg/day, more than 20 day, of less than 0.5 mg/m/day, of less than 1 mg/m/day, of mg/day, more than 25 mg/day, more than 30 mg/day, more less than 2 mg/m/day, of less than 3 mg/m/day, of less than than 35 mg/day, more than 40 mg/day, more than 45 mg/day, 4 mg/m/day, less than 5 mg/m/day, of less than 6 mg/m/ more than 50 mg/day, more than 60 mg/day, more than 70 day, of less than 7 mg/m/day, of less than 8 mg/m/day, of mg/day, more than 80 mg/day, more than 90 mg/day, or more less than 9 mg/m/day, less than 10 mg/m/day, less than 15 than 100 mg/day. In certain embodiments, JNJ-26481585 is mg/m/day, less than 20 mg/m/day, less than 25 mg/m/day, administered at a dose of more than 2 mg/day and less than 20 less than 30 mg/m/day, less than 35 mg/m/day, less than 40 US 2013/0331313 A1 Dec. 12, 2013

mg/m2/day, less than 45 mg/m/day, less than 50 mg/m/day, thrice a day (t.i.d.). In some embodiments, SB939 is admin less than 60 mg/m/day, less than 70 mg/m/day, less than 80 istered daily, once a week, twice a week, three times a week, mg/m/day, less than 90 mg/m/day, or less than 100 mg/m/ four times a week, or five times a week. day. In some embodiments, MS-275 is administered at a dose 0118. In some embodiments, the HDAC inhibitor is of more than 0.1 mg/m/day, of more than 0.2 mg/m/day, of romidepsin. In certain embodiments, romidepsin is adminis more than 0.5 mg/m/day, of more than 1 mg/m/day, of more tered at a dose of 14 mg/m/day. In some embodiments, than 2 mg/m/day, of more than 3 mg/m/day, of more than 4 romidepsin is administered at a dose of about 0.1 mg/m/day, mg/m/day, more than 5 mg/m/day, of more than 6 mg/m/ of about 0.2 mg/m/day, of about 0.5 mg/m/day, of about 1 day, of more than 7 mg/m/day, of more than 8 mg/m/day, of mg/m/day, of about 2 mg/m/day, of about 3 mg/m/day, of more than 9 mg/m/day, more than 10 mg/m/day, more than about 4 mg/m/day, about 5 mg/m/day, of about 6 mg/m/ 15 mg/m/day, more than 20 mg/m/day, more than 25 day, of about 7 mg/m/day, of about 8 mg/m/day, of about 9 mg/m/day, more than 30 mg/m/day, more than 35 mg/m/ mg/m/day, about 10 mg/m/day, about 11 mg/m/day, about day, more than 40 mg/m2/day, more than 45 mg/m/day, more 12 mg/m/day, about 13 mg/m/day, about 14 mg/m/day, than 50 mg/m/day, more than 60 mg/m/day, more than 70 about 15 mg/m/day, about 16 mg/m/day, about 17 mg/m/ mg/m/day, more than 80 mg/m/day, more than 90 mg/m/ day, about 18 mg/m/day, about 19 mg/m/day, about 20 day, or more than 100 mg/m/day. In certain embodiments, mg/m/day, about 25 mg/m/day, about 30 mg/m/day, about MS-275 is administered at a dose of more than 2 mg/m/day 35 mg/m/day, about 40 mg/m2/day, about 45 mg/m/day, and less than 10 mg/m/day. In some embodiments, MS-275 about 50 mg/m/day, about 60 mg/m/day, about 70 mg/m/ is administered at a dose of more than 2 mg/m/day and less day, about 80 mg/m/day, about 90 mg/m/day, or about 100 than 40 mg/m/day. In certain embodiments, MS-275 is mg/m/day. In certain embodiments, romidepsin is adminis administered at a dose of more than 2 mg/m/day and less tered at a dose of less than 0.1 mg/m/day, of less than 0.2 than 6 mg/m/day. In some embodiments, MS-275 is admin mg/m/day, of less than 0.5 mg/m/day, of less than 1 mg/m/ istered at a dose of more than 6 mg/m/day and less than 8 day, of less than 2 mg/m/day, of less than 3 mg/m/day, of mg/m/day. In certain embodiments, MS-275 is administered less than 4 mg/m/day, less than 5 mg/m/day, of less than 6 once a day (q.d.), twice a day (b.id.), or thrice a day (t.i.d.). In mg/m/day, of less than 7 mg/m/day, of less than 8 mg/m/ some embodiments, MS-275 is administered daily, once a day, of less than 9 mg/m/day, less than 10 mg/m/day, less week, twice a week, three times a week, four times a week, or than 11 mg/m/day, less than 12 mg/m/day, less than 13 five times a week. mg/m/day, less than 14 mg/m/day, less than 15 mg/m/day, 0117. In some embodiments, the HDAC inhibitor is less than 16 mg/m/day, less than 17 mg/m/day, less than 18 SB939. In certain embodiments, SB939 is administered at a mg/m/day, less than 19 mg/m/day, less than 20 mg/m/day, dose of 60 mg/day. In some embodiments, SB939 is admin less than 25 mg/m/day, less than 30 mg/m/day, less than 35 istered at a dose of about 1 mg/day, about 2 mg/day, about 5 mg/m/day, less than 40 mg/m2/day, less than 45 mg/m/day, mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, less than 50 mg/m/day, less than 60 mg/m/day, less than 70 about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/m/day, less than 80 mg/m/day, less than 90 mg/m/day, mg/day, about 45 mg/day, about 50 mg/day, about 60 mg/day, or less than 100 mg/m/day. In some embodiments, about 70 mg/day, about 80 mg/day, about 90 mg/day, about romidepsin is administered at a dose of more than 0.1 mg/m/ 100 mg/day, about 120 mg/day, about 125 mg/day, about 140 day, of more than 0.2 mg/m/day, of more than 0.5 mg/m/ mg/day, about 150 mg/day, about 160 mg/day, about 175 day, of more than 1 mg/m/day, of more than 2 mg/m/day, of mg/day, about 180 mg/day, or about 200 mg/day. In certain more than 3 mg/m/day, of more than 4 mg/m/day, more than embodiments, SB939 is administered at a dose of less than 1 5 mg/m/day, of more than 6 mg/m/day, of more than 7 mg/day, less than 2 mg/day, less than 5 mg/day, less than 10 mg/m/day, of more than 8mg/m/day, of more than 9 mg/m/ mg/day, less than 15 mg/day, less than 20 mg/day, less than 25 day, more than 10 mg/m/day, more than 11 mg/m/day, more mg/day, less than 30 mg/day, less than 35 mg/day, less than 40 than 12 mg/m/day, more than 13 mg/m/day, more than 14 mg/day, less than 45 mg/day, less than 50 mg/day, less than 60 mg/m/day, more than 15 mg/m/day, more than 16 mg/m/ mg/day, less than 70 mg/day, less than 80 mg/day, less than 90 day, more than 17 mg/m/day, more than 18 mg/m/day, more mg/day, less than 100 mg/day, less than 120 mg/day, less than than 19 mg/m/day, more than 20 mg/m/day, more than 25 125 mg/day, less than 140 mg/day, less than 150 mg/day, less mg/m/day, more than 30 mg/m/day, more than 35 mg/m/ than 160 mg/day, less than 175 mg/day, less than 180 mg/day, day, more than 40 mg/m2/day, more than 45 mg/m/day, more or less than 200 mg/day. In some embodiments, SB939 is than 50 mg/m/day, more than 60 mg/m/day, more than 70 administered at a dose of more than 1 mg/day, more than 2 mg/m/day, more than 80 mg/m/day, more than 90 mg/m/ mg/day, more than 5 mg/day, more than 10 mg/day, more than day, or more than 100 mg/m/day. In certain embodiments, 15 mg/day, more than 20 mg/day, more than 25 mg/day, more romidepsin is administered at a dose of more than 13 mg/m/ than 30 mg/day, more than 35 mg/day, more than 40 mg/day, day and less than 18 mg/m/day. In some embodiments, more than 45 mg/day, more than 50 mg/day, more than 60 romidepsin is administered at a dose of more than 10 mg/m/ mg/day, more than 70 mg/day, more than 80 mg/day, more day and less than 20 mg/m/day. In certain embodiments, than 90 mg/day, more than 100 mg/day, more than 120 romidepsin is administered once a day (q.d.), twice a day mg/day, more than 125 mg/day, more than 140 mg/day, more (b.id.), or thrice a day (t.i.d.). In some embodiments, than 150 mg/day, more than 160 mg/day, more than 175 romidepsin is administered daily, once a week, twice a week, mg/day, more than 180 mg/day, or more than 200 mg/day. In three times a week, four times a week, or five times a week. certain embodiments, SB939 is administered at a dose of 0119. In some embodiments, the HDAC inhibitor is more than 30 mg/day and less than 70 mg/day. In some LBH589. In certain embodiments, LBH589 is administered embodiments, SB939 is administered at a dose of more than at a dose of 20 mg/day. In some embodiments, LBH589 is 10 mg/day and less than 90 mg/day. In certain embodiments, administered at a dose of about 1 mg/day, about 2 mg/day, SB939 is administered once a day (q.d.), twice a day (b.id.), or about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 US 2013/0331313 A1 Dec. 12, 2013 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, istered at a dose of more than 15 mg/m/day and less than about 40 mg/day, about 45 mg/day, about 50 mg/day, about 60 1000 mg/m/day. In certain embodiments, PXD101 is admin mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, istered once a day (q.d.), twice a day (b.id.), or thrice a day or about 100 mg/day. In certain embodiments, LBH589 is (t.i.d.). In some embodiments, PXD101 is administered daily, administered at a dose of less than 1 mg/day, less than 2 once a week, twice a week, three time a week, four times a mg/day, less than 5 mg/day, less than 10 mg/day, less than 15 week, or five times a week. mg/day, less than 20 mg/day, less than 25 mg/day, less than 30 0.121. In some embodiments, the HDAC inhibitor is vori mg/day, less than 35 mg/day, less than 40 mg/day, less than 45 nostat. In certain embodiments, Vorinostat is administered at mg/day, less than 50 mg/day, less than 60 mg/day, less than 70 a dose of 400 mg/day. In some embodiments, Vorinostat is mg/day, less than 80 mg/day, less than 90 mg/day, or less than administered at a dose of about 10 mg/day, about 20 mg/day, 100 mg/day. In some embodiments, LBH589 is administered about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60 at a dose of more than 1 mg/day, more than 2 mg/day, more mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, than 5 mg/day, more than 10 mg/day, more than 15 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, more than 20 mg/day, more than 25 mg/day, more than 30 about 175 mg/day, about 200 mg/day, about 225 mg/day, mg/day, more than 35 mg/day, more than 40 mg/day, more about 250 mg/day, about 275 mg/day, about 300 mg/day, than 45 mg/day, more than 50 mg/day, more than 60 mg/day, about 325 mg/day, about 350 mg/day, about 375 mg/day, more than 70 mg/day, more than 80 mg/day, more than 90 about 400 mg/day, about 450 mg/day, about 500 mg/day, mg/day, or more than 100 mg/day. In certain embodiments, about 550 mg/day, about 600 mg/day, about 650 mg/day, LBH589 is administered at a dose of more than 10 mg/day about 700 mg/day, about 750 mg/day, about 800 mg/day, and less than 20 mg/day. In some embodiments, LBH589 is about 900 mg/day, or about 1000 mg/day. In certain embodi administered at a dose of more than 5 mg/day and less than 30 ments, Vorinostat is administered at a dose of less than 10 mg/day. In certain embodiments, LBH589 is administered mg/day, less than 20 mg/day, less than 30 mg/day, less than 40 once a day (q.d.), twice a day (b.id.), or thrice a day (t.i.d.). In mg/day, less than 50 mg/day, less than 60 mg/day, less than 70 some embodiments, LBH589 is administered daily, once a mg/day, less than 80 mg/day, less than 90 mg/day, less than week, twice a week, three times a week, four times a week, or 100 mg/day, less than 125 mg/day, less than 150 mg/day, less five times a week. than 175 mg/day, less than 200 mg/day, less than 225 mg/day, 0120 In some embodiments, the HDAC inhibitor is less than 250 mg/day, less than 275 mg/day, less than 300 PXD101. In certain embodiments, PXD101 is administered mg/day, less than 325 mg/day, less than 350 mg/day, less than at a dose of 1000 mg/m/day. In some embodiments, PXD101 375 mg/day, less than 400 mg/day, less than 450 mg/day, less is administered at a dose of about 10 mg/m/day, about 15 than 500 mg/day, less than 550 mg/day, less than 600 mg/day, mg/m/day, about 20 mg/m/day, about 50 mg/m/day, about less than 650 mg/day, less than 700 mg/day, less than 750 75 mg/m/day, about 100 mg/m/day, about 150 mg/m/day, mg/day, less than 800 mg/day, less than 900 mg/day, or less about 200 mg/m/day, about 300 mg/m/day, about 400 than 1000 mg/day. In some embodiments, vorinostat is mg/m/day, about 500 mg/m/day, about 600 mg/m/day, administered at a dose of more than 10 mg/day, more than 20 about 700 mg/m/day, about 800 mg/m/day, about 900 mg/day, more than 30 mg/day, more than 40 mg/day, more mg/m/day, about 1000 mg/m/day, about 1100 mg/m/day, than 50 mg/day, more than 60 mg/day, more than 70 mg/day, about 1200 mg/m/day, about 1300 mg/m/day, about 1400 more than 80 mg/day, more than 90 mg/day, more than 100 mg/m/day, about 1500 mg/m/day, about 1750 mg/m/day, mg/day, more than 125 mg/day, more than 150 mg/day, more or about 2000 mg/m/day. In certain embodiments, PXD101 than 175 mg/day, more than 200 mg/day, more than 225 is administered at a dose of less than 10 mg/m/day, less than mg/day, more than 250 mg/day, more than 275 mg/day, more 15 mg/m/day, less than 20 mg/m/day, less than 50 mg/m/ than 300 mg/day, more than 325 mg/day, more than 350 day, less than 75 mg/m/day, less than 100 mg/m/day, less mg/day, more than 375 mg/day, more than 400 mg/day, more than 150 mg/m/day, less than 200 mg/m/day, less than 300 than 450 mg/day, more than 500 mg/day, more than 550 mg/m/day, less than 400 mg/m/day, less than 500 mg/m/ mg/day, more than 600 mg/day, more than 650 mg/day, more day, less than 600 mg/m/day, less than 700 mg/m/day, less than 700 mg/day, more than 750 mg/day, more than 800 than 800 mg/m/day, less than 900 mg/m/day, less than 1000 mg/day, more than 900 mg/day, or more than 1000 mg/day. In mg/m/day, less than 1100 mg/m/day, less than 1200 mg/m/ certain embodiments, Vorinostat is administered at a dose of day, less than 1300 mg/m/day, less than 1400 mg/m/day, more than 100 mg/day and less than 400 mg/day. In some less than 1500 mg/m/day, less than 1750 mg/m/day, or less embodiments, Vorinostat is administered at a dose of more than 2000 mg/m/day. In some embodiments, PXD101 is than 100 mg/day and less than 500 mg/day. In certain embodi administered at a dose of more than 10 mg/m/day, more than ments, Vorinostat is administered once a day (q.d.), twice a 15 mg/m/day, more than 20 mg/m/day, more than 50 day (b.id.), or thrice a day (t.i.d.). In some embodiments, mg/m/day, more than 75 mg/m/day, more than 100 mg/m/ Vorinostat is administered daily, once a week, twice a week, day, more than 150 mg/m/day, more than 200 mg/m/day, three times a week, four times a week, or five times a week. more than 300 mg/m/day, more than 400 mg/m/day, more 0.122. In some embodiments, an HDAC inhibitor inhibits than 500 mg/m/day, more than 600 mg/m/day, more than the growth of virus-positive cells. In certain embodiments, 700 mg/m/day, more than 800 mg/m/day, more than 900 the HDAC inhibitor inhibits the growths of EBV-positive mg/m/day, more than 1000 mg/m/day, more than 1100 lymphoma cells. In some embodiments, the HDAC inhibitor mg/m/day, more than 1200 mg/m/day, more than 1300 has growth inhibitory activity at a concentration of about 100 mg/m/day, more than 1400 mg/m/day, more than 1500 uM, about 90 uM, about 80 uM, about 75uM, about 70 uM, mg/m/day, more than 1750 mg/m/day, or more than 2000 about 60 uM, about 50 uM, about 40 uM, about 30 uM, about mg/m/day. In certain embodiments, PXD101 is adminis 25uM, about 20 uM, about 10 uM, about 5uM, about 2 uM, tered at a dose of more than 600 mg/m/day and less than about 1 uM, about 900 nM, about 800 nM, about 700 nM, 1000 mg/m/day. In some embodiments, PXD101 is admin about 600 nM, about 500 nM, about 400 nM, about 300 nM, US 2013/0331313 A1 Dec. 12, 2013

about 200 nM, about 100 nM, about 75 nM, about 50 nM, tion. Each of these activities is directly related to gene expres about 20 nM, or about 10 nM. In certain embodiments, the Sion, and increased expression can sensitize infected cells to HDAC inhibitor has growth inhibitory activity at a concen a specific anti-viral agent. tration of less than 100 uM, less than 90 uM, less than 80 LM, 0.125. In some embodiments, inducing agents include less than 75 uM, less than 70 uM, less than 60 uM, less than arginine butyrate and/or other histone deacetylase inhibitors. 50M, less than 40 uM, less than 30 uM, less than 25uM, less Arginine butyrate induces EBV-TK activity in EBV-immor than 20 uM, less than 10 uM, less than 5uM, less than 2 LM, talized B-cells and patient-derived tumor cells. As latently less than 1 uM, less than 900 nM, less than 800 nM, less than infected B-cells do not express TK, exposure of these cells to 700 nM, less than 600 nM, less than 500 nM, less than 400 agents like arginine butyrate and/or other HDAC inhibitors nM, less than 300 nM, less than 200 nM, less than 100 nM, results in a induction of lytic replication and TK expression. less than 75 nM, less than 50 nM, less than 20 nM, or less than This expression of a viral gene can be used as a point for 10 nM. In some embodiments, the HDAC inhibitor has attack by anti-viral agents, allowing for treatment of latent growth inhibitory activity at a concentration of more than 100 infections. uM, more than 90 uM, more than 80 uM, more than 75 uM, more than 70 uM, more than 60 uM, more than 50 uM, more 0.126 In other embodiments, inducing agents include than 40 uM, more than 30 uM, more than 25uM, more than 20 HDAC inhibitors that induce EBV-PK activity (also known uM, more than 10 uM, more than 5uM, more than 2 uM, more BGLF4) in EBV infected tumors. Expression of EBV-PK/ than 1 uM, more than 900 nM, more than 800 nM, more than BGLF4 sensitizes a cell to an antiviral agent. In certain 700 nM, more than 600 nM, more than 500 nM, more than instances, HDAC inhibitors induce EBV-PK. In some 400 nM, more than 300 nM, more than 200 nM, more than instances, HDAC inhibitors induce EBV-TKand/or EBV-PK. 100 nM, more than 75 nM, more than 50 nM, more than 20 I0127 Preliminary in vitro studies according to the inven nM, or more than 10 nM. In certain embodiments, the HDAC tion demonstrate that induction of EBV-TK activity in EBV inhibitor has growth inhibitory activity at more than 50 nM immortalized B-cells and patient-derived tumor cells using and less than 100 nM. In some embodiments, the HDAC these drugs is possible, and that these previously resistant inhibitor has growth inhibitory activity at more than 200 nM cells are rendered susceptible to ganciclovir therapy. Treat and less than 500 nM. In certain embodiments, the HDAC ment of patients with viral-associated tumors such as EBV inhibitor has growth inhibitory activity at more than 100 nM with inducing agents such as arginine butyrate, to induce the and less than 200 nM. expression of EBV-TK/EBV-PK, and GCV, to eliminate EBV-TK/EBV-PK expressing tumor cells, is an effective, Induced Genes Including Viral-Associated Genes non-toxic therapy. This therapeutic regimen does not depend 0123 Inducing agents (agents that induce expression) on the associated viral genome being the cause of the tumor. may act directly on the viral genome or indirectly through a Without wishing to be bound by theory, it is believed that just cellular factor required for viral expression. For example, the presence of the EBV genome in latent form would make viral gene expression can be regulated through the regulation the tumor Susceptible to this combination protocol. of the expression of viral transcription factors such as ZTA, I0128 Butyrate-associated induction of genes has been RTA, tat, and tax, cellular transcription factors such as AP-1, characterized for various cell types, and the genes are consis AP-2, Sp1, NF-kB, and other transcriptional activators and/or tently in the class of differentiation markers of a cell. For repressors (factors), co-activators and co-repressors, histone example, in colon cancer cell lines, morphologic changes acetylators and deacetylators, DNA methylases and demethy observed in the presence of butyrate correlate with increased lases, oncogenes or proto-oncogenes, or protein kinase C. expression of alkaline phosphatase, plasminogen activator, These proteins act to regulate and thereby control expression and CEA, all markers of differentiation. Hepatoma cell lines of specific viral and/or other cellular genetic elements. increase expression of alpha fetoprotein. Breast cancer cell According to the methods of the invention, control over their lines express milk-related glycoproteins, epithelial mem expression can lead to control over the infection. Other gene brane antigens, and increased lipid deposition. Sodium products, both viral and cellular in origin, whose expression butyrate can also induce expression of cellular proteins asso can be regulated with inducing agents include proteases, ciated with converting basal keratinacytes into committed polymerases, reverse transcriptases, cell-surface receptors, epithelial cells. major histocompatibility antigens, growth factors, and com I0129. Alteration of expression of certain transcription fac bination of these products. tors may affect regulation of gene expression and regulation 0124. Additional genes whose expression or transcrip of the cell cycle. In the breast cancer cell line MCF-7, butyrate tional regulation are altered in the presence of butyric acid induces a block in cellular proliferation that is associated with include the oncogenes myc, ras, my b, abland Src. The activi decreased expression of estrogen and prolactin hormone ties of these gene products, as well as the activities of other receptor mRNA expression, thus blocking the potential oncogenes, are described in Slamon, J. D., et al. 1984 Science growth stimulation by estrogen and prolactin. These effects 224:256-62. Anti-proliferative activity also includes the abil are associated with increased expression of the EGF receptor. ity to repress tumor angiogenesis through the blockade of Butyrate also has been shown to induce down-regulation of angiogenesis factor activity, production or release, transcrip c-myc and p53 mRNA and to up-regulate expression of the tional regulation, or the ability to modulate transcription of c-fos transcription factor. In mouse fibroblasts, butyrate will genes under angiogenesis or growth factor or holinonal con block the cell cycle in the G phase. When these cells are trol. Either would be an effective therapy, particularly against stimulated to proliferate with serum, TPA, or insulin, the both prostatic neoplasia and breast carcinomas. Further immediate-early response transcription factors c-myc and activities that effect transcription and/or cellular differentia c-jun are unregulated. However, the late G1 phase down tion include increased intracellular cAMP levels, inhibition stream gene marker cdc-2 mRNA is not expressed, and cells of histone acetylation, and inhibition of genomic methyla are prevented from entering S phase. US 2013/0331313 A1 Dec. 12, 2013

0130. The particular combination of inducing agent with uM, less than 90 uM, less than 80 LM, less than 75uM, less anti-viral agent that is most effective against a specific disor than 70 uM, less than 60 uM, less than 50 uM, less than 40 der can be determined by one of ordinary skill in the art from uM, less than 30 uM, less than 25uM, less than 20 uM, less empirical testing and, preferably, from a knowledge of each than 10 uM, less than 5uM, less than 2 uM, less than 1 M. agent's mechanism of action. Three such examples are as less than 900 nM, less than 800 nM, less than 700 nM, less follows. First, many of the RNA viruses such as HIV and than 600 nM, less than 500 nM, less than 400 nM, less than other retroviruses require a reverse transcriptase to transcribe 300 nM, less than 200 nM, less than 100 nM, less than 75 nM, their genome into DNA. A few of the agents that induce less than 50 nM, less than 20 nM, or less than 10 nM. In expression or activity of retroviruses and their encoded genes, certain embodiments, an inducing agent is capable of induc Such as, for example, reverse transcriptase, are known to ing gene expression at a concentration of more than 100LM, those of ordinary skill in the art. Anti-viral agents such as more than 90 uM, more than 80 uM, more than 75 uM, more nucleoside analogs can be administered to the patient. Those than 70 uM, more than 60 uM, more than 50 uM, more than 40 Substrate analogs will be specifically recognized by the uM, more than 30 uM, more than 25 uM, more than 20 uM, reverse transcriptase that, when incorporated into the more than 10 uM, more than 5uM, more than 2 LM, more than infected-cell genome, prevent viral replication and may also 1 uM, more than 900 nM, more than 800 nM, more than 700 result in cell death. Second, many viruses require an active nM, more than 600 nM, more than 500 nM, more than 400 protease to assemble virus capsids to be packaged with viral nM, more than 300 nM, more than 200 nM, more than 100 genome. Protease inhibitors or proteases that alter cleavage nM, more than 75 nM, more than 50 nM, more than 20 nM, or patterns so that packaging cannot occur can be specifically more than 10 nM. In some embodiments, an inducing agent is targeted with an anti-viral agent that comprises an amino acid capable of inducing gene expression at a concentration more analog or toxic conjugate. Third, arginine butyrate and isobu than 50 nMandless than 100 nM. In certain embodiments, an tyramide enhance expression of viral thymidine kinase and inducing agent is capable of inducing gene expression at a other viral protein kinases in EBV-infected lymphocytes. concentration of more than 200 nM and less than 500 nM. In Ganciclovir or famcyclovir, in the presence of the viralthy Some embodiments, an inducing agent is capable of inducing midine kinase or other viral kinases, destroys the infected gene expression at more than 100 nM and less than 200 nM cell. Treatment of infected cells with both agents, according 0133. In some embodiments, an HDAC inhibitor induces to the invention, will selectively destroy EBV virus-infected viral gene expression after more than 1 handless than 6h. In cells. In another aspect, of infected cells with both agents, certain embodiments, an HDAC inhibitor induces viral gene according to the invention, will selectively disable or disrupt expression about 2 fold, about 3 fold, about 4 fold, about 5 the viral activity within the cells in vivo. fold, about 6 fold, about 7 fold, about 8 fold, about 9 fold, 0131. In some embodiments, an inducing agent induces about 10 fold, about 12 fold, about 15 fold, about 20 fold, viral gene expression by more than 4 fold after 24 h of treat about 25 fold, about 30 fold, about 35 fold, about 40 fold, ment. In certain embodiments, an HDAC inhibitor induces about 45 fold, or about 50 fold. In some embodiments, an TK or EBV-PK expression by more than 4 fold after 24 h of HDAC inhibitor induces viral gene expression less than 2 treatment. In some embodiments, an HDAC inhibitor induces fold, less than 3 fold, less than 4 fold, less than 5 fold, less than viral gene expression after about 48 h, about 36 h, about 24 h. 6 fold, less than 7 fold, less than 8 fold, less than 9 fold, less about 18 h, about 12 h, about 8 h, about 6 h, about 4 h, about than 10 fold, less than 12 fold, less than 15 fold, less than 20 3 h, about 2 h, about 1 h, or about 30 minutes. In certain fold, less than 25 fold, less than 30 fold, less than 35 fold, less embodiments, an HDAC inhibitor induces viral gene expres than 40 fold, less than 45 fold, or less than 50 fold. In certain sion in less than 48 h, less than 36 h, less than 24 h, less than embodiments, an HDAC inhibitor induces viral gene expres 18 h, less than 12 h, less than 8 h, less than 6 h, less than 4h, sion more than 2 fold, more than 3 fold, more than 4 fold, less than 3 h, less than 2 h, less than 1 h, or less than 30 more than 5 fold, more than 6 fold, more than 7 fold, more minutes. In some embodiments, an HDAC inhibitor induces than 8 fold, more than 9 fold, more than 10 fold, more than 12 viral gene expression in more than 48 h, more than 36 h, more fold, more than 15 fold, more than 20 fold, more than 25 fold, than 24h, more than 18h, more than 12h, more than 8h, more more than 30 fold, more than 35 fold, more than 40 fold, more than 6 h, more than 4h, more than 3 h, more than 2 h, more than 45 fold, or more than 50 fold. In some embodiments, an than 1 h, or more than 30 minutes. In certain embodiments, an HDAC inhibitor induces viral gene expression more than 2 HDAC inhibitor induces viral gene expression after more fold and less than 50 fold. In certain embodiments, an HDAC than 30 minutes and less than 24 h. inhibitor induces viral gene expression more than 5 fold and 0132. In certain embodiments, an inducing agent is less than 40 fold. capable of inducing gene expressionata concentration of less Antiviral Agents than 500 nM. In some embodiments, the inducing agent is an HDAC inhibitor. In certain embodiments, the inducing agent I0134) Anti-viral agents that can be used in the composi is capable of inducing TK or EBV-PK expression. In certain tions and methods of the provided invention can include, for embodiments, an inducing agent is capable of inducing gene example, Substrates and Substrate analogs, inhibitors and expression at a concentration of about 100 uM, about 90 uM, other agents that severely impair, debilitate or otherwise about 80 uM, about 75uM, about 70 uM, about 60 uM, about destroy virus-infected cells. Substrate analogs include amino 50 uM, about 40 uM, about 30 uM, about 25uM, about 20 acid and nucleoside analogs. Substrates can be conjugated uM, about 10 uM, about 5uM, about 2 uM, about 1 uM, about with toxins or other viricidal substances. Inhibitors include 900 nM, about 800 nM, about 700 nM, about 600 nM, about integrase inhibitors, protease inhibitors, polymerase inhibi 500 nM, about 400 nM, about 300 nM, about 200 nM, about tors and transcriptase inhibitors such as reverse transcriptase 100 nM, about 75 nM, about 50 nM, about 20 nM, or about 10 inhibitors. nM. In some embodiments, an inducing agent is capable of 0.135 Antiviral agents that can be used in the compositions inducing gene expression at a concentration of less than 100 and methods of the provided invention can include, for US 2013/0331313 A1 Dec. 12, 2013

example, ganciclovir, Valganciclovir, oseltamivir (Tami than 3750 mg/day, less than 4000 mg/day, less than 4250 fluTM), Zanamivir (RelenzaTM) abacavir, aciclovir, acyclovir, mg/day, less than 4500 mg/day, less than 4750 mg/day, or less adefovir, amantadine, amprenavir, ampligen, arbidol, ataza than 5000 mg/day. In some embodiments, the antiviral agent navir, atripla, boceprevir, cidofovir, combivir, darunavir, is administered at a dose of more than 10 mg/day, more than delavirdine, didanosine, docosanol, edoxudine, efavirenz, 20 mg/day, more than 50 mg/day, more than 100 mg/day, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, more than 150 mg/day, more than 200 mg/day, more than 250 foSamprenavir, foscarnet, foSfonet, fusion inhibitors (e.g., mg/day, more than 300 mg/day, more than 350 mg/day, more enfuvirtide), ibacitabine, immunovir, idoxuridine, imiqui than 400 mg/day, more than 450 mg/day, more than 500 mod, indinavir, inosine, integrase inhibitor, interferon type mg/day, more than 600 mg/day, more than 700 mg/day, more III, interferon type II, interferon type I, interferon, lamivu than 800 mg/day, more than 900 mg/day, more than 1000 dine, lopinavir, loviride, maraviroc, moroxydine, nelfinavir, mg/day, more than 1200 mg/day, more than 1250 mg/day, nevirapine, nexavir, nucleoside analogues, peginterferon more than 1400 mg/day, more than 1500 mg/day, more than alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, 1600 mg/day, more than 1750 mg/day, more than 1800 protease inhibitor, raltegravir, reverse transcriptase inhibitor, mg/day, more than 1900 mg/day, more than 2000 mg/day, ribavirin, rimantadine, ritonavir, pyrimidine antiviral, more than 2250 mg/day, more than 2500 mg/day, more than saquinavir, stavudine, Synergistic enhancer (antiretroviral), 2750 mg/day, more than 3000 mg/day, more than 3250 tenofovir, tenofovir disoproxil, tipranavir, trifluridine, triz mg/day, more than 3500 mg/day, more than 3750 mg/day, ivir, tromantadine, truvada, Valaciclovir (ValtrexTM), Vicrivi more than 4000 mg/day, more than 4250 mg/day, more than roc, Vidarabine, Viramidine, Zalcitabine, and Zidovudine. 4500 mg/day, more than 4750 mg/day, or more than 5000 0136. In a specific embodiment, the antiviral agent is acy mg/day. In certain embodiments, the antiviral agent is admin clovir, ganciclovir, or Valganciclovir. istered at a dose of more than 10 mg/day and less than 5000 0.137 In some embodiments, the antiviral agent is a mg/day. In some embodiments, the antiviral agent is admin nucleoside. Examples of nucleoside analogs include acyclo istered at a dose of more than 200 mg/day and less than 1000 vir (ACV), ganciclovir (GCV), Valganciclovir, famciclovir, mg/day. In certain embodiments, the antiviral agent is admin foscarnet, ribavirin, Zalcitabine (ddC). Zidovudine (AZT), istered once a day (q.d.), twice a day (b.id.), or thrice a day stavudine (D4T), lamivudine (3TC), didanosine (ddI), cytara (t.i.d.). In some embodiments, the antiviral agent is adminis bine, dideoxyadenosine, edoxudine, floXuridine, idoZuridine, tered daily, once a week, twice a week, three times a week, inosine pranobex, 2'-deoxy-5-(methylamino)uridine, trifluri four times a week, or five times a week. dine and Vidarabine. Examples of a few protease inhibitors 0.139. In certain embodiments, the antiviral agent is gan that show particular promise in human therapy include Saqui ciclovir. In some embodiments, ganciclovir is administered at nivir, ritonavir and indinavir. Other anti-viral agents include a total daily dose of 3000 mg/day. In certain embodiments, interferons (e.g. Cl-, 3-, y-interferon), cytokines such as tumor ganciclovir is administered at a dose of 1000 mg three times necrosis factor (TNF) or interleukins, cell receptors and a day. In some embodiments, ganciclovir is administered at a growth factor antagonists, which can be purified or recombi dose of about 100 mg/day, about 250 mg/day, about 500 nantly produced. mg/day, about 750 mg/day, about 1000 mg/day, about 1500 0.138. In some embodiments, the antiviral agent is admin mg/day, about 2000 mg/day, about 2500 mg/day, about 3000 istered at a dose of less than 3000 mg/day. In some embodi mg/day, about 3500 mg/day, or about 4000 mg/day. In certain ments, the antiviral agent is administered at a dose of about 10 embodiments, ganciclovir is administered at a dose of less mg/day, about 20 mg/day, about 50 mg/day, about 100 than 100 mg/day, less than 250 mg/day, less than 500 mg/day, mg/day, about 150 mg/day, about 200 mg/day, about 250 less than 750 mg/day, less than 1000 mg/day, less than 1500 mg/day, about 300 mg/day, about 350 mg/day, about 400 mg/day, less than 2000 mg/day, less than 2500 mg/day, less mg/day, about 450 mg/day, about 500 mg/day, about 600 than 3000 mg/day, less than 3500 mg/day, or less than 4000 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day. In some embodiments, ganciclovir is administered at mg/day, about 1000 mg/day, about 1200 mg/day, about 1250 a dose of more than 100 mg/day, more than 250 mg/day, more mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 than 500 mg/day, more than 750 mg/day, more than 1000 mg/day, about 1750 mg/day, about 1800 mg/day, about 1900 mg/day, more than 1500 mg/day, more than 2000 mg/day, mg/day, about 2000 mg/day, about 2250 mg/day, about 2500 more than 2500 mg/day, more than 3000 mg/day, more than mg/day, about 2750 mg/day, about 3000 mg/day, about 3250 3500 mg/day, or more than 4000 mg/day. In certain embodi mg/day, about 3500 mg/day, about 3750 mg/day, about 4000 ments, ganciclovir is administered at a dose of more than 500 mg/day, about 4250 mg/day, about 4500 mg/day, about 4750 mg/day and less 4000 mg/day. In some embodiments, ganci mg/day, or about 5000 mg/day. In certain embodiments, the clovir is administered at a dose of more than 1000 mg/day and antiviral agent is administered at a dose of less than 10 less than 3000 mg/day. In some embodiments, ganciclovir is mg/day, less than 20 mg/day, less than 50 mg/day, less than administered once a day, twice a day, or three times a day. In 100 mg/day, less than 150 mg/day, less than 200 mg/day, less certain embodiments, ganciclovir is administered once a than 250 mg/day, less than 300 mg/day, less than 350 mg/day, week, twice a week, three times a week, four times a week, less than 400 mg/day, less than 450 mg/day, less than 500 five times a week, or daily. mg/day, less than 600 mg/day, less than 700 mg/day, less than 0140. In some embodiments, the antiviral agent is Valgan 800 mg/day, less than 900 mg/day, less than 1000 mg/day, less ciclovir. In certain embodiments, Valganciclovir is adminis than 1200 mg/day, less than 1250 mg/day, less than 1400 tered at a total daily dose of 900 mg/day. In some embodi mg/day, less than 1500 mg/day, less than 1600 mg/day, less ments, Valganciclovir is administered at a dose of 900 mg than 1750 mg/day, less than 1800 mg/day, less than 1900 once a day. In certain embodiments, Valganciclovir is admin mg/day, less than 2000 mg/day, less than 2250 mg/day, less istered at a total daily dose of 1800 mg/day. In some embodi than 2500 mg/day, less than 2750 mg/day, less than 3000 ments, Valganciclovir is administered at a dose of 900 mg mg/day, less than 3250 mg/day, less than 3500 mg/day, less twice a day. US 2013/0331313 A1 Dec. 12, 2013

0141. In some embodiments, Valganciclovir is adminis agent, a vaccine, or an anticancer agent. For example, a Sub tered at a dose of about 100 mg/day, about 200 mg/day, about ject with multiple Sclerosis can be administered a viral induc 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 ing agent, an antiviral agent, and a vaccine, for example, a mg/day, about 700 mg/day, about 800 mg/day, about 900 vaccine comprising myelin basic protein. In another example, mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 a Subject with diabetes can be administered a viral inducing mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 agent, an antiviral agent, and a vaccine, for example, a vac mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 cine comprising an antigen. mg/day, about 1900 mg/day, or about 2000 mg/day. In certain embodiments, Valganciclovir is administered at a dose of less 0144. In some embodiments, an additional agent is a anti than 100 mg/day, less than 200 mg/day, less than 300 mg/day, cancer agent. In certain embodiments, the anticancer agent is less than 400 mg/day, less than 500 mg/day, less than 600 a chemotherapeutic anticancer agent. Examples of chemo mg/day, less than 700 mg/day, less than 800 mg/day, less than therapeutic anticancer agents include, but are not limited to, 900 mg/day, less than 1000 mg/day, less than 1100 mg/day, nitrogen mustards; alkyl Sulfonates; ethylene imines; less than 1200 mg/day, less than 1300 mg/day, less than 1400 nitrosoureas; epoxides; other alkylating agents; folic acid mg/day, less than 1500 mg/day, less than 1600 mg/day, less analogues; purine analogs; pyrimidine analogs; Vinca alka than 1700 mg/day, less than 1800 mg/day, less than 1900 loids; podophyllotoxin derivatives; colchicine derivatives: mg/day, or less than 2000 mg/day. In some embodiments, taxanes; other plant alkaloids and natural products; actino valganciclovir is administered at a dose of more than 100 mycines; antracyclines; other cytotoxic antibiotics; platinum mg/day, more than 200 mg/day, more than 300 mg/day, more compounds; methylhydrazines; sensitizers; protein kinase than 400 mg/day, more than 500 mg/day, more than 600 inhibitors; other antineoplastic agents; estrogens; progesto mg/day, more than 700 mg/day, more than 800 mg/day, more gens; gonadotropin releasing hormone analogs; anti-estro than 900 mg/day, more than 1000 mg/day, more than 1100 mg/day, more than 1200 mg/day, more than 1300 mg/day, gens; anti-androgens; enzyme inhibitors; other hormone more than 1400 mg/day, more than 1500 mg/day, more than antagonists; immunostimulants; immunosuppressants; cal 1600 mg/day, more than 1700 mg/day, more than 1800 cineurin inhibitors; and radiopharmaceuticals. In some mg/day, more than 1900 mg/day, or more than 2000 mg/day. embodiments, the anticancer agent is a toxin, e.g. diphtheria In certain embodiments, Valganciclovir is administered at a toxin. dose of more than 100 mg/day and less 2000 mg/day. In some 0145. In certain embodiments, an additional agent is a embodiments, Valganciclovir is administered at a dose of non-steroidal anti-inflammatory agent (NSAID). NSAID more than 500 mg/day and less than 1500 mg/day. In some include, for example, Aspirin (AnacinTM, AScriptinTM, embodiments, Valganciclovir is administered once a day, BayerTM., BufferinTM, EcotrinTM, ExcedrinTM), Choline and twice a day, or three times a day. In certain embodiments, magnesium salicylates (CMTTM, TricosalTM, TrilisateTM), Valganciclovir is administered once a week, twice a week, choline salicylate (ArthropanTM), celecoxib (CelebrexTM), three time a week, four times a week, five times a week, or diclofenac potassium (CataflamTM), diclofenac sodium daily. (VoltarenTM, Voltaren XRTM), diclofenac sodium with miso 0142. In a specific embodiment, the antiviral agent is not a prostol (ArthrotecTM), diflunisal (DolobidTM), etodolac (Lod heat shock protein inhibitor, an immunosuppressant, an anti ineTM, Lodine XLTM), fenoprofen calcium (NalfonTM), flur biotic, a glucocorticoid, a non-steroidal anti-inflammatory biprofen (Ansaid TM), ibuprofen (AdviltM, MotrinTM, Motrin drug, a Cox-2-specific inhibitor or a TNF-C. binding protein. IBTM, NuprinTM), indomethacin (IndocinTM Indocin SRTM), In a related embodiment, the antiviral agent is not a Hsp90 ketoprofen (ActronTM, OrudisTM, Orudis KTTM, OruvailTM), inhibitor, tacrolimus, cyclosporin, rapamycin (sirolimus), magnesium salicylate (ArthritabM, Bayer SelectTM, Doan's methotrexate, cyclophosphamide, azathioprine, mercaptopu PillsTM, MaganTM, MobidinTM, MobogesicTM), meclofe rine, mycophenolate, FTY720, levofloxacin, amoxycillin, namate sodium (MeclomenTM), mefenamic acid (PonstelTM), prednisone, cortisone acetate, prednisolone, methylpredniso meloxicam (MobicTM), nabumetone (RelafenTM) naproxen lone, dexamethasone, betamethasone, triamcinolone, (NaprosyntM, NaprelanTM), naproxen sodium (AleveTM, beclometaSone, fludrocortisone acetate, deoxycorticosterone AnaproxTM), oxaprozin (DayproTM), piroxicam (FeldeneTM), acetate, aldosterone, salicylates, arylalkanoic acids, a 2-aryl rofecoxib (VioxxTM), salsalate (AmigesicTM, Anaflex 750TM, propionic acid, a N-arylanthranilic acid, an oxicam, a coxib, Disalcid TM, MarthriticTM, Mono-GesicTM, SalflexTM, Sal a sulphonanilide, Valdecoxib, celecoxib, rofecoxib, lefluno sitabM), sodium salicylate (various generics), Sulindac (Cli mide, gold thioglucose, gold thiomalate, aurofin, Sulfasala norilTM), tolmetin sodium (TolectinTM), valdecoxib (Bex Zine, hydroxychloroquinine, minocycline, infliximab, etaner traTM). cept, adalimumab, abatacept, anakinra, interferon-B, interferon-Y, interleukin-2, an allergy vaccine, an antihista 0146 In some embodiments, an additional agent is a lipid mine, an antileukotriene, a beta-agonist, theophylline, or an lowering agent. In certain embodiments, the lipid lowering anticholinergic. agent is a statin. Examples of statins include, but are not limited to, Advicor(R) (niacin extended-release/lovastatin), Additional Agents Altoprev(R) (lovastatin extended-release), CaduetR) (amlo dipine and atorvastatin), Crestor(R) (rosuvastatin), LescolR) 0143. The methods of the provided invention can com (fluvastatin), Lescol XL (fluvastatin extended-release), Lipi prise administering to a subject a viral inducing agent, and tor(R) (atorvastatin), Mevacor R (lovastatin), PravacholR) antiviral agent, and one or more additional active agents. The (pravastatin), Simcor R (niacin extended-release? simvasta additional agent can be selected based on the type of viral, tin), VytorinR (ezetimibe/simvastatin), and Zocor R (simvas virally-induced, or inflammatory condition the Subject has or tatin). A lipid lowering agent can be administered to a subject is suspected of having. The additional agent can comprise, for that has or is Suspected of having atherosclerosis. For example, another antiviral agent, another viral inducing example, a Subject with cytomegalovirus induced atheroscle US 2013/0331313 A1 Dec. 12, 2013

rosis can be administered an additional agent that can com nary artery condition associated with a cytomegalovirus or prise atorvastatin, rosuvastatin, lovastatin, simvastatin, or herpes simplex virus infection. The Subject can have autoim pravastatin. mune condition associated with Epstein-Barr virus infection. 0147 In certain embodiments, an additional agent is an The Subject can have a lymphoma or other cancer associated immunosuppressive drug. Immunosuppressive drug, for with Epstein-Barr virus infection. example, include glucocorticoids, antibodies, cytostatic 0152. In some embodiments, the viral or virally-induced agents, and drugs that act on immunophilins. Glucocorticoids condition is caused by a retrovirus, such as HIV, HTLV 1 and can include, for example, prednisolone, prednisone, or meth 2. In certain embodiments, the viral or virally-induced con ylprednisolone. A cytostatic agent can include, for example, dition is caused by a DNA virus, such as a herpesvirus. In an agent that interferes with nucleic acid synthesis, for Some embodiments, the herpesvirus is an Epstein-Barr virus, example, folic acid, pyrimidine analogs, and purine analogs. cytomegalovirus, Herpes type 1 (oral herpes), herpes type 2, A folic acid analog that can be used as an immunosuppressive Kaposi's sarcoma virus (human herpes virus 8), BK viruses, drug is methotrexate, which can bind dihydrofolate reductase or hepatitis virus. In certain embodiments, the virally-in and prevent the synthesis of tetrahydrofolate. Another cyto duced or virus-associated disease is a cancer. In some static agent is azathioprine, which can be cleaved noneZy embodiments, the virally-induced or virus-associated cancer matically to form mercaptopurine, which can act as a purine is alymphoma, chronic lyphocytic leukemia, nasopharyngeal analogue. A cytostatic agent can include, for example, an carcinoma, gastric cancer, or Kaposi's sarcoma. In other alkylating agent, including, for example, cyclophosphamide, embodiments, the virally-induced or virus-associated disease and a nitrosourea. A cytostatic agent can be a platinum com is an autoimmune disease. In certain embodiments, the pound. Other cytostatic agents include, for example, cyto autoimmune disease is rheumatoid arthritis, systemic lupus toxic antibiotics, including dactinomycin, anthracylcines, erythematosus, or multiple Sclerosis. mitomycin C, bleomycin, and mithramycin. Examples of antibodies that can be immunosuppressive agents include, for 0153. The methods and compositions described herein example, heterologous polyclonal antibodies, for example, can be used to treat and/or prevent infections caused by any from rabbit or horse. Other antibodies include monoclonal virus, including, for example, Abelson leukemia virus, Abel antibodies directed to specific antigens e.g., T-cell receptor son murine leukemia virus, Abelson's virus, Acute laryn directed antibodies (e.g., OKT3, muromonab, which targets gotracheobronchitis virus, Adelaide River virus, Adeno asso CD3), and IL-2 receptor directed antibodies (e.g., targeting ciated virus group, Adenovirus, African horse sickness virus, CD25). Drugs that can act on immunophilins include, for African Swine fever virus, AIDS virus, Aleutian mink condi example, cyclosporin, tacrolimus (Prograf), Sirolimus (rapa tion parvovirus, Alpharetrovirus, Alphavirus, ALV related mycin, Rapamune). Other drugs that can act as immunosup virus, Amapari virus, Aphthovirus, Aquareovirus, Arbovirus, pressive drugs include, for example, mycophenolate (myco Arbovirus C. arbovirus group A, arbovirus group B, Arenavi phenolic acid), interferons, opioids, TNF binding proteins, rus group, Argentine hemorrhagic fever virus, Argentine Fingolimod, myriocin, and ciclosporin. hemorrhagic fever virus, Arterivirus, Astrovirus, Ateline her 0148. The additional agent can be, for example, FK506, a pesvirus group, Aujezky's condition virus, Aura virus, Aus monoclonal antibody, an anti-T cell monoclonal antibody, an duk condition virus, Australian batlyssavirus, Aviadenovirus, anti-B cell monoclonal antibody, or a TNF inhibitor. The avian erythroblastosis virus, avian infectious bronchitis virus, monoclonal antibody can be an anti-B cell antibody. The avian leukemia virus, avian leukosis virus, avian lymphoma anti-B cellantibody can be anti-CD20. The TNF inhibitor can tosis virus, avian myeloblastosis virus, avian paramyxovirus, be infliximab (RemicadeTM), etanercept (EnbrelTM), adali avian pneumoencephalitis virus, avian reticuloendotheliosis mumab (HumiraTM), or an anti-IL-6 antibody. virus, avian sarcoma virus, avian type C retrovirus group, 0149. A subject with an autoimmune condition can be Avihepadnavirus, Avipoxvirus, B virus, B19 virus, Babanki administered a viral inducing agent, an antiviral agent, and an virus, baboon herpesvirus, baculovirus, Barmah Forest virus, additional agent, where the additional agent comprises Bebaru virus, Berrimah virus, Betaretrovirus, Birnavirus, cyclosporine, azathiorprine, methotrexate, cyclophospha Bittner virus, BK virus, Black Creek Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus, Boma condition mide, FK506, tacrolimus, a monoclonal antibody, an anti-T virus, border condition of sheep virus, borna virus, bovine cell monoclonal antibody, an anti-B cell monoclonal anti alphaherpesvirus 1, bovine alphaherpesvirus 2, bovine coro body, an IL-2 receptor antibody, or a TNF inhibitor. navirus, bovine ephemeral fever virus, bovine immunodefi 0150. The additional agent can be glatiramer (Copax ciency virus, bovine leukemia virus, bovine leukosis virus, oneTM), Natalizumab (TysabriTM), mitoxantrone (No bovine mammillitis virus, bovine papillomavirus, bovine VantroneTM), cladribine, or Campath antibody. For example, a papular stomatitis virus, bovine parvovirus, bovine syncytial Subject with multiple Sclerosis can be administered an addi virus, bovine type Concovirus, bovine viral diarrhea virus, tional agent that can comprise glatiramer, mitoxantrone, Buggy Creek virus, bullet shaped virus group, Bunyamwera natalizumab, cladribine, or Campath antibody. virus Supergroup, Bunyavirus, Burkitt's lymphoma virus, Bwamba Fever, CA virus, Calicivirus, California encephalitis Types of Viruses and Virally-Induced Conditions virus, camelpox virus, canarypox virus, canid herpesvirus, 0151. The methods and compositions provided herein can canine coronavirus, canine distemper virus, canine herpesvi be used to treat and/or prevent viral infections. The virus rus, canine minute virus, canine parvovirus, Cano Delgadito causing the infection can be a member of the herpes virus virus, caprine arthritis virus, caprine encephalitis virus, family, a human immunodeficiency virus, parvovirus, or cox Caprine Herpes Virus, Capripox virus, Cardiovirus, cavid sackie virus. A member of the herpes virus family can be herpesvirus 1, Cercopithecid herpesvirus 1, cercopithecine herpes simplex virus, herpes genitalis virus, varicella Zoster herpesvirus 1, Cercopithecine herpesvirus 2, Chandipura virus, Epstein-Barr virus, human herpes virus 6, human her virus, Changuinola virus, channel catfish virus, Charleville pes virus 8, or cytomegalovirus. The Subject can have coro virus, chickenpox virus, Chikungunyavirus, chimpanzee her US 2013/0331313 A1 Dec. 12, 2013 20 pesvirus, chub reovirus, chum salmon virus, Cocal virus, virus, human immunodeficiency virus 1, human immunode Coho Salmon reovirus, coital exanthema virus, Colorado tick ficiency virus 2, human papillomavirus, human T cell leuke fever virus, Coltivirus, Columbia SK virus, common cold mia virus, human T cell leukemia virus I, human T cell leu virus, contagious eethyma virus, contagious pustular derma kemia virus II, human T cell leukemia virus III, human T cell titis virus, Coronavirus, Corriparta virus, coryza virus, cow lymphoma virus I, human T cell lymphoma virus II, human T pox virus, coxsackie virus, CPV (cytoplasmic polyhedrosis cell lymphotropic virus type 1, human T cell lymphotropic virus), cricket paralysis virus, Crimean-Congo hemorrhagic virus type 2, human T lymphotropic virus I, human T lym fever virus, croup associated virus, Cryptovirus, Cypovirus, photropic virus II, human T lymphotropic virus III, Ichnovi Cytomegalovirus, cytomegalovirus group, cytoplasmic poly rus, infantile gastroenteritis virus, infectious bovine rhinotra hedrosis virus, deer papillomavirus, deltaretrovirus, dengue cheitis virus, infectious haematopoietic necrosis virus, virus, Densovirus, Dependovirus, Dhori virus, diploma virus, infectious pancreatic necrosis virus, influenza virus A, influ Drosophila C virus, duck hepatitis B virus, duck hepatitis enza virus B, influenza virus C, influenza virus D, influenza virus 1, duck hepatitis virus 2, duovirus, Duvenhage virus, virus pr8, insect iridescent virus, insect virus, iridovirus, Deformed wing virus DWV, eastern equine encephalitis Japanese B virus, Japanese encephalitis virus, JC virus, Junin virus, eastern equine encephalomyelitis virus, EB virus, virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo Ebola virus, Ebola-like virus, echo virus, echovirus, echovi virus, Kilham's rat virus, Klamath virus, Kolongo virus, rus 10, echovirus 28, echovirus 9, ectromelia virus, EEE Korean hemorrhagic fever virus, kumba virus, Kysanur forest virus, EIA virus, EIA virus, encephalitis virus, encepha condition virus, Kyzylagach virus, La Crosse virus, lactic lomyocarditis group virus, encephalomyocarditis virus, dehydrogenase elevating virus, lactic dehydrogenase virus, Enterovirus, enzyme elevating virus, enzyme elevating virus Lagos bat virus, Langur virus, lapine parvovirus, Lassa fever (LDH), epidemic hemorrhagic fever virus, epizootic hemor virus, Lassa virus, latent rat virus, LCM virus, Leaky virus, rhagic condition virus, Epstein-Barr virus, equid alphaherp Lentivirus, Leporipoxvirus, leukemia virus, leukovirus, esvirus 1, equid alphaherpesvirus 4, equid herpesvirus 2, lumpy skin condition virus, lymphadenopathy associated equine abortion virus, equine arteritis virus, equine encepha virus, Lymphocryptovirus, lymphocytic choriomeningitis losis virus, equine infectious anemia virus, equine morbillivi virus, lymphoproliferative virus group, Machupo virus, mad rus, equine rhinopneumonitis virus, equine rhinovirus, itch virus, mammalian type B oncovirus group, mammalian Eubenangu virus, European elk papillomavirus, European type B retroviruses, mammalian type C retrovirus group, swine fever virus, Everglades virus, Eyach virus, felid herp mammalian type D retroviruses, mammary tumor virus, esvirus 1, feline calicivirus, feline fibrosarcoma virus, feline Mapuera virus, Marburg virus, Marburg-like virus, Mason herpesvirus, feline immunodeficiency virus, feline infectious Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME peritonitis virus, feline leukemia/sarcoma virus, feline leuke virus, measles virus, Menangle virus, Mengo virus, Mengovi mia virus, feline panleukopenia virus, feline parvovirus, rus, Middelburg virus, milkers nodule virus, mink enteritis feline sarcoma virus, feline syncytial virus, Filovirus, virus, minute virus of mice, MLV related virus, MM virus, Flanders virus, Flavivirus, foot and mouth condition virus, Mokola virus, Molluscipoxvirus, Molluscum contagiosum Fort Morgan virus, Four Corners hantavirus, fowl adenovirus virus, monkey B virus, monkeypox virus, Mononegavirales, 1, fowlpox virus, Friend virus, Gammaretrovirus, GB hepa Morbillivirus, Mount Elgon bat virus, mouse cytomegalovi titis virus, GB virus, German measles virus, Getah virus, rus, mouse encephalomyelitis virus, mouse hepatitis virus, gibbon ape leukemia virus, glandular fever virus, goatpox mouse K virus, mouse leukemia virus, mouse mammary virus, golden shinner virus, Gonometa virus, goose parvovi tumor virus, mouse minute virus, mouse pneumonia virus, rus, granulosis virus, Gross virus, ground squirrel hepatitis B mouse poliomyelitis virus, mouse polyomavirus, mouse Sar virus, group Aarbovirus, Guanarito virus, guinea pig cytome coma virus, mousepox virus, Mozambique virus, Mucambo galovirus, guinea pig type C virus, Hantaan virus, Hantavirus, virus, mucosal condition virus, mumps virus, murid betaher hard clam reovirus, hare fibroma virus, HCMV (human pesvirus 1, murid cytomegalovirus 2, murine cytomegalovi cytomegalovirus), hemadsorption virus 2, hemagglutinating rus group, murine encephalomyelitis virus, murine hepatitis virus of Japan, hemorrhagic fever virus, hendra virus, Heni virus, murine leukemia virus, murine nodule inducing virus, paviruses, Hepadnavirus, hepatitis. A virus, hepatitis B virus murine polyomavirus, murine sarcoma virus, Muromegalovi group, hepatitis C virus, hepatitis D virus, hepatitis delta rus, Murray Valley encephalitis virus, myxoma virus, Myx virus, hepatitis E virus, hepatitis F virus, hepatitis G virus, ovirus, Myxovirus multiforme, Myxovirus parotitidis, hepatitis nonA nonB virus, hepatitis virus, hepatitis virus Nairobi sheep condition virus, Nairovirus, Nanirnavirus, (nonhuman), hepatoencephalomyelitis reovirus 3, Hepatovi Nariva virus, Ndumo virus, Neethling virus, Nelson Bay rus, heron hepatitis B virus, herpes B virus, herpes simplex virus, neurotropic virus, New World Arenavirus, newborn virus, herpes simplex virus 1, herpes simplex virus 2, herp pneumonitis virus, Newcastle condition virus, Nipah virus, esvirus, herpesvirus 7. Herpesvirusateles, Herpesvirus homi noncytopathogenic virus, Norwalk virus, nuclear polyhedro nis, Herpesvirus infection, Herpesvirus saimiri, Herpesvirus sis virus (NPV), nipple neck virus, Onyongnyong virus, suis, Herpesvirus varicellae, Highlands J virus, Hirame rhab Ockelbo virus, oncogenic virus, oncogenic viruslike particle, dovirus, hog cholera virus, human adenovirus 2, human oncornavirus, Orbivirus, Orf virus, Oropouche virus, Ortho alphaherpesvirus 1, human alphaherpesvirus 2, human alpha hepadnavirus, Orthomyxovirus, Orthopoxvirus, Orthoreovi herpesvirus 3, human B lymphotropic virus, human betaher rus, Orungo, Ovine papillomavirus, Ovine catarrhal fever pesvirus 5, human coronavirus, human cytomegalovirus virus, owl monkey herpesvirus, Palyam virus, Papillomavi group, human foamy virus, human gammaherpesvirus 4. rus, Papillomavirus Sylvilagi, Papovavirus, parainfluenza human gammaherpesvirus 6, human hepatitis A virus, human virus, parainfluenza virus type 1, parainfluenza virus type 2, herpesvirus 1 group, human herpesvirus 2 group, human her parainfluenza virus type 3, parainfluenza virus type 4. pesvirus 3 group, human herpesvirus 4 group, human herp Paramyxovirus, Parapoxvirus, paravaccinia virus, Parvovi esvirus 6, human herpesvirus 8, human immunodeficiency rus, Parvovirus B19, parvovirus group, Pestivirus, Phlebovi US 2013/0331313 A1 Dec. 12, 2013 rus, phocine distemper virus, Picodnavirus, Picornavirus, pig virus, Yaba monkey tumor virus, Yaba virus, Yatapoxvirus, cytomegalovirus—pigeonpox virus, Piry virus, Pixuna virus, yellow fever virus, and the Yug Bogdanovac virus. pneumonia virus of mice, Pneumovirus, poliomyelitis virus, poliovirus, Polydnavirus, polyhedral virus, polyoma virus, Inflammatory Conditions Polyomavirus, Polyomavirus bovis, Polyomavirus cercopith 0154) Inflammatory conditions that can be treated and/or eci, Polyomavirus hominis 2, Polyomavirus maccacae 1, prevented using the methods and compositions provided Polyomavirus muris 1, Polyomavirus muris 2, Polyomavirus herein include, for example, autoimmune condition. Autoim papionis 1, Polyomavirus papionis 2, Polyomavirus Sylvilagi, mune conditions include, for example, rheumatoid arthritis, Pongine herpesvirus 1, porcine epidemic diarrhea virus, por multiple Sclerosis, Sjogren's syndrome, systemic lupus cine hemagglutinating encephalomyelitis virus, porcine par erythematosus, autoimmune hepatitis, autoimmune thyroidi vovirus, porcine transmissible gastroenteritis virus, porcine tis, hemophagocytic syndrome (hemophagocytic lymphohis type C virus, pox virus, poxvirus, poxvirus variolae, Prospect tiocytosis), diabetes mellitus type 1, Crohn's condition, ulcer Hill virus, Provirus, pseudocowpox virus, pseudorabies ative colitis, psoriasis, psoriatic arthritis, idiopathic virus, psittacinepox virus, quailpox virus, rabbit fibroma thrombocytonpenic pupura, polymyositis, dermatomyositis, virus, rabbit kidney Vaculolating virus, rabbit papillomavirus, myasthenia gravis, autoimmune thyroiditis, Evan's Syn rabies virus, raccoon parvovirus, raccoonpox virus, Ranikhet drome, autoimmune hemolytic anemia, aplastic anemia, virus, rat cytomegalovirus, rat parvovirus, rat virus, Raus autoimmune neutropenia, Scleroderma, Reiter's syndrome, cher's virus, recombinant vaccinia virus, recombinant virus, ankylosing spondylitis, pemphinigus, pemphigoid or autoim reovirus, reovirus 1, reovirus 2, reovirus 3, reptilian type C mune hepatitis, Behcet’s condition, Celiac condition, Chagas virus, respiratory infection virus, respiratory syncytial virus, condition, acute disseminated encephalomyelitis, Addison's respiratory virus, reticuloendotheliosis virus, Rhabdovirus, condition, antiphospholipid antibody syndrome, autoim Rhabdovirus carpia, Rhadinovirus, Rhinovirus, Rhizidiovi mune inner ear condition, bullous pemphigoid, Chronic rus, Rift Valley fever virus, Riley's virus, rinderpest virus, obstructive pulmonary condition, Goodpasture’s syndrome, RNA tumor virus, Ross River virus, Rotavirus, rougeole Graves condition, Guillain-Barré syndrome, Hashimoto's virus, Rous sarcoma virus, rubella virus, rubeola virus, thyroditis, Hidradenitis Suppurativa, Interstitial cystitis, neu RubiVirus, Russian autumn encephalitis virus, SA 11 simian romyotonia, pemphigus Vulgaris, pernicious anemia, primary virus, SA2 virus, Sabia virus, Sagiyama virus, Saimirine her biliary cirrhosis, and vasculitis syndromes. pesvirus 1, salivary gland virus, Sandfly fever virus group, 0.155. Other inflammatory conditions that can be treated Sandjimba virus, SARS virus, SDAV (sialodacryoadenitis and/or prevented using the methods and compositions of the virus), sealpox virus, Semliki Forest Virus, Seoul virus, provided invention include, for example, an allergic condition sheeppox virus, Shope fibroma virus, Shope papilloma virus, (e.g., allergic rhinitis, asthma, atopic eczema), a skin condi simian foamy virus, simian hepatitis. A virus, simian human tion, coronary artery condition, peripheral artery condition, immunodeficiency virus, simian immunodeficiency virus, atherosclerosis, retinitis, pancreatitis, cardiomyopathy, peri simian parainfluenza virus, simian T cell lymphotrophic carditis, colitis, glomerulonephritis, lung inflammation, virus, simian virus, simian virus 40, Simplexvirus, Sin Nom esophagitis, gastritis, duodenitis, ileitis, meningitis, encepha bre virus, Sindbis virus, smallpox virus, South American litis, encephalomyelitis, transverse myelitis, cystitis, urethri hemorrhagic fever viruses, sparrowpox virus, Spumavirus, tis, mucositis, lymphadenitis, dermatitis, hepatitis, osteomy squirrel fibroma virus, squirrel monkey retrovirus, SSV 1 elitis, or herpes Zoster. virus group, STLV (simian T lymphotropic virus) type I, STLV (simian T lymphotropic virus) type II, STLV (simian T Formulations, Routes of Administration, and Effective Doses lymphotropic virus) type III, stomatitis papulosa virus, Sub maxillary virus, Suid alphaherpesvirus 1, Suid herpesvirus 2, 0156 Another aspect of the present invention relates to Suipoxvirus, Swamp fever virus, Swinepox virus, Swiss formulations, routes of administration and effective doses for mouse leukemia virus, TAC virus, Tacaribe complex virus, pharmaceutical compositions comprising an agent or combi Tacaribe virus, Tanapox virus, Taterapox virus, Tench reoVi nation of agents. Such pharmaceutical compositions can be rus. Theiler's encephalomyelitis virus. Theiler's virus, used to treat a virus-induced inflammatory condition as Thogoto virus, Thottapalayam virus, Tick borne encephalitis described above. A pharmaceutical composition can com virus, Tioman virus, Togavirus, Torovirus, tumor virus, prise a viral inducing agent. A pharmaceutical composition Tupaia virus, turkey rhinotracheitis virus, turkeypox virus, can comprise a viral inducing agent and one or more addi type C retroviruses, type D oncovirus, type D retrovirus tional agents. A pharmaceutical composition can comprise an group, ulcerative condition rhabdovirus, Una virus, Uukuni antiviral agent. A pharmaceutical composition can comprise emi virus group, Vaccinia virus, vacuolating virus, varicella an antiviral agent and one or more additional agents. A phar Zoster virus, Varicellovirus, Varicola virus, variola major maceutical composition can comprise a viral inducing agent virus, variola virus, Vasin Gishu condition virus, VEE virus, and an antiviral agent. A pharmaceutical composition can Venezuelan equine encephalitis virus, Venezuelan equine comprise a viral inducing agent, an antiviral agent, and one or encephalomyelitis virus, Venezuelan hemorrhagic fever more additional agents. virus, vesicular stomatitis virus, Vesiculovirus, Vilyuisk 0157. The agents or their pharmaceutically acceptable virus, Viper retrovirus, viral haemorrhagic septicemia virus, salts can be provided alone or in combination with one or Visna Maedi virus, Visna virus, volepox virus, VSV (vesicu more other agents or with one or more other forms. For lar stomatitis virus), Wallal virus, Warrego virus, wart virus, example, a formulation can comprise one or more agents in WEE virus, West Nile virus, western equine encephalitis particular proportions, depending on the relative potencies of virus, western equine encephalomyelitis virus, Whataroa each agent and the intended indication. For example, in com virus, Winter Vomiting Virus, woodchuck hepatitis B virus, positions for targeting two different targets and where poten woolly monkey sarcoma virus, wound tumor virus, WRSV cies are similar, about a 1:1 ratio of agents can be used. The US 2013/0331313 A1 Dec. 12, 2013 22 two forms can beformulated together, in the same dosage unit about 99:1 to about 1:99 of a viral inducing agent to the other e.g. in one cream, Suppository, tablet, capsule, enteric coated active agent can be used; molar ratios of about 99:1 to about tablet or capsule, aerosol spray, or packet of powder to be 1:99 of an antiviral agent to the other active agent can be used; dissolved in a beverage; or each form may be formulated in a molar ratios of about 99:1 to about 1:99 of a viral inducing separate unit, e.g., two creams, two Suppositories, two tablets, agent and antiviral agent can be used. The range of molar two capsules, a tablet and a liquid for dissolving the tablet, ratios of viral inducing agent:other active agent can be two aerosol sprays, or a packet of powder and a liquid for selected from about 80:20 to about 20:80; about 75:25 to dissolving the powder, etc. about 25:75, about 70:30 to about 30:70, about 66:33 to about 0158. A “pharmaceutically acceptable salt can be a salt 33:66, about 60:40 to about 40:60; about 50:50; and about that retains the biological effectiveness and properties of one 90:10 to about 10:90. The range of molar ratios of an antiviral or more agents, and which are not biologically or otherwise agent:other active agent can be selected from about 80:20 to undesirable. For example, a pharmaceutically acceptable salt about 20:80; about 75:25 to about 25:75, about 70:30 to about does not interfere with the beneficial effect of a viral inducing 30:70, about 66:33 to about 33:66, about 60:40 to about agent or an antiviral agent. 40:60; about 50:50; and about 90:10 to about 10:90. The 0159 Salts can include those of the inorganic ions, for molar ratio may of a viral inducing agent: other active agent example, sodium, potassium, calcium, magnesium ions, and can be about 1:9 or about 1:1. The molar ratio may of an the like. Salts can include salts with inorganic or organic antiviral agent: other active agent can be about 1:9 or about acids, for example, hydrochloric acid, hydrobromic acid, 1:1. Two or more agents, forms and/or compounds can be phosphoric acid, nitric acid, Sulfuric acid, methanesulfonic formulated together, in the same dosage unit, e.g., in one acid, p-toluenesulfonic acid, acetic acid, fumaric acid, suc cream, Suppository, tablet, capsule, enteric coated capsule or cinic acid, lactic acid, mandelic acid, malic acid, citric acid, tablet, or packet of powder to be dissolved in a beverage; or tartaric acid or maleic acid. If one or more agents contain a each agent, form, and/or compound can be formulated in carboxy group or other acidic group, it can be converted into separate units, e.g., two creams, Suppositories, tablets, two a pharmaceutically acceptable addition salt with inorganic or capsules, enteric coated capsules or tablets, a tablet and a organic bases. Examples of Suitable bases include Sodium liquid for dissolving the tablet, an aerosol spray a packet of hydroxide, potassium hydroxide, ammonia, cyclohexy powder and a liquid for dissolving the powder, etc. lamine, dicyclohexyl-amine, ethanolamine, diethanolamine, triethanolamine, and the like. 0163 A viral inducing agent, for example a HDAC inhibi 0160 A pharmaceutically acceptable ester or amide can tor, can be administered in combination with an antiviral be an ester or amide that retains biological effectiveness and agent. Pharmaceutical compositions comprising a combina properties of one or more agents, and which are not biologi tion of a viral inducing agent and an antiviral agent can be cally or otherwise undesirable. For example, the ester or formulated to comprise certain mg per dose. For example, a amide does not interfere with the beneficial effect of a viral viral inducing agent can be administered at 0.01, 0.05, 0.1, inducing agent, an antiviral agent, or an additional agent. 0.5, 1, 2, 5, 10, 20, 25, 50, 100, 250, 500, 1000 mg/kg per Esters can include, for example, ethyl, methyl, isobutyl, eth dose. A HDAC inhibitor can be administered at 0.01-0.1, ylene glycol, and the like. Amides include can include, for 0.05-0.5, 1-2, 1-5, 5-10, 10-20, 10-25, 10-50, 100-500, or example, unsubstituted amides, alkylamides, dialkylamides, 500-1000 mg/kg per dose. A single dose of an oral formula and the like. tion of a viral inducing agent can contain 0.01, 0.05, 0.1, 0.5, 0161 A viral inducing agent, for example a HDAC inhibi 1, 2, 5, 10, 20, 25, 50, 100, 250, 500, 1000 mg. In one tor, can be administered in combination with an antiviral embodiment, the HDAC inhibitor is administered at 0.01, agent. Pharmaceutical compositions comprising a combina 0.05, 0.1, 0.5, 1, 2, 5, 10, 20, 25, 50, 100, 250, 500, 1000 tion of a viral inducing agent and an antiviral agent can be mg/kg perdose. In a related embodiment, the HDAC inhibitor formulated to comprise certain molar ratios. For example, is administered orally. In a specific embodiment, the total molar ratios of about 99:1 to about 1:99 of a viral inducing daily oral dose of a HDAC inhibitor is no more than 1, 2, 5, 10. agent to the antiviral agent can be used. The range of molar 20, 25, 40, 50, 100, 250, or 500 mg. In another related ratios of viral inducing agent: the antiviral agent can be embodiment, the HDAC inhibitor is administered 1,2,3,4, or selected from about 80:20 to about 20:80; about 75:25 to 5 times a day orally. In other embodiments, a single daily dose about 25:75, about 70:30 to about 30:70, about 66:33 to about of a HDAC inhibitor is provided whereas oral valganciclovir 33:66, about 60:40 to about 40:60; about 50:50; and about is provided at 900 mgs/dose, two times a day. 90:10 to about 10:90. The viral inducing agent and the anti (0164. An oral formulation of an HDAC inhibitor can be viral agent can be co-formulated, in the same dosage unit, co-formulated with an antiviral agent, such as Valganciclovir. e.g., in one cream, Suppository, tablet, capsule, enteric coated In a specific embodiment when an HDAC inhibitor and val capsule or tablet, or packet of powder to be dissolved in a ganciclovir are co-formulated for a single daily dose, the beverage; or each agent, form, and/or compound can be for Valganciclovir is present in a slow release or timed release mulated in separate units, e.g., two creams, suppositories, form. In certain embodiments, the HDAC inhibitor and val tablets, two capsules, enteric coated capsules or tablets, a ganciclovir or other antiviral agent are co-formulated Such tablet and a liquid for dissolving the tablet, an aerosol spray a that the HDAC inhibitor is present at no more than 100 mg per packet of powder and a liquid for dissolving the powder, etc. dose, and the antiviral agent is present at no more than 1000 0162 An agent can be administered in combination with mg per dose. In some embodiments, the HDAC inhibitor and one or more other compounds, forms, and/or agents, e.g., as Valganciclovir or other antiviral agent are co-formulated Such described above. Pharmaceutical compositions comprising that the HDAC inhibitor is present at no more than 80 mg per combinations of a viral inducing agent and/or antiviral agent dose, and the antiviral agent is present at no more than 500 mg with one or more other active agents can be formulated to per dose. In certain embodiments, the HDAC inhibitor and comprise certain molar ratios. For example, molar ratios of Valganciclovir or other antiviral agent are co-formulated Such US 2013/0331313 A1 Dec. 12, 2013

that the HDAC inhibitor is present at not greater than 80 mg 450 mg, less than 400 mg, less than 350 mg, less than 300 mg. per dose, and the antiviral agent is present at not greater than less than 250 mg, less than 200 mg, less than 150 mg, less than 1500 mg per dose. 140 mg, less than 130 mg, less than 120 mg, less than 110 mg. 0.165. In some embodiments, a co-formulation comprising less than 100 mg, less than 90 mg, less than 80 mg, less than an HDAC inhibitor and an antiviral agent comprises less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less 500 mg, less than 400 mg, less than 300 mg, less than 200 mg. than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg. less than 100 mg, less than 90 mg, less than 80 mg, less than less than 2 mg. or less than 1 mg of the antiviral agent. In some 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less embodiments, the unit dose comprises more than 2000 mg. than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg. more than 1900 mg, more than 1800 mg, more than 1700 mg. less than 2 mg, or less than 1 mg of the HDAC inhibitor. In more than 1600 mg, comprises more than 1500 mg, more than other embodiments, a co-formulation comprising an HDAC 1400 mg, more than 1300 mg, more than 1200 mg, more than inhibitor and an antiviral agent comprises less than 1500 mg. 1100 mg, more than 1000 mg, more than 900 mg, more than less than 1400 mg, less than 1300 mg, less than 1200 mg, less 800 mg, more than 750 mg, more than 700 mg, more than 650 than 1100 mg, less than 1000 mg, less than 900 mg, less than mg, more than 600 mg, more than 550 mg, more than 500 mg. 800 mg, less than 700 mg, less than 600 mg, less than 500 mg. more than 450 mg, more than 400 mg, more than 350 mg. less than 400 mg, less than 300 mg, less than 200 mg, less than more than 300 mg, more than 250 mg, more than 200 mg. 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less more than 150 mg, more than 140 mg, more than 130 mg. than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg. more than 120 mg, more than 110 mg, more than 100 mg. less than 20 mg, less than 10 mg, less than 5 mg, less than 2 more than 90 mg, more than 80 mg, more than 70 mg, more mg, or less than 1 mg of the antiviral agent. than 60 mg, more than 50 mg, more than 40 mg, more than 30 0166 In certain embodiments, a unit dose of a co-formu mg, more than 20 mg, more than 10 mg, more than 5 mg, more lated HDAC inhibitor and antiviral agent comprises between than 2 mg, or more than 1 mg of the antiviral agent. In certain about 1 mg and about 500 mg of the HDAC inhibitor and embodiments, the unit dose comprises more than 50 mg and between 1 mg and 1500 mg of the antiviral agent. In some less than 1500 mg of the antiviral agent. In some embodi embodiments, the unit dose comprises about 500 mg, about ments, the unit dose comprises more than 100 mg and less 400 mg, about 300 mg, about 200 mg, about 100 mg, about 90 than 500 mg of the antiviral agent. In certain embodiments, mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg. the antiviral agent is formulated as slow release. about 40 mg, about 30 mg, about 20 mg, about 10 mg, about (0168. In some embodiments, the co-formulated HDAC 5 mg, about 2 mg, or about 1 mg of the HDAC inhibitor. In inhibitor and antiviral agent are administered once a day. In certain embodiments, the unit dose comprises less than 500 certain embodiments, the co-formulated HDAC inhibitor and mg, less than 400 mg, less than 300 mg, less than 200 mg, less antiviral agent are administered twice a day. In other embodi than 100 mg, less than 90 mg, less than 80 mg, less than 70 ments, the co-formulated HDAC inhibitor and antiviral agent mg, less than 60 mg, less than 50 mg, less than 40 mg, less are administered thrice a day. In some embodiments, the than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg. co-formulated HDAC inhibitor and antiviral agent are admin less than 2 mg, or less than 1 mg of an HDAC inhibitor. In istered once a day, twice a day, or thrice a day, and a further some embodiments, the unit dose comprises more than 500 dose of the HDAC inhibitor is administered once, twice, or mg, more than 400 mg, more than 300 mg, more than 200 mg. thrice a day. In certain embodiments, the co-formulated more than 100 mg, more than 90 mg, more than 80 mg, more HDAC inhibitor and antiviral agent are administered once a than 70 mg, more than 60 mg, more than 50 mg, more than 40 day, twice a day, or thrice a day, and a further dose of the mg, more than 30 mg, more than 20 mg, more than 10 mg. antiviral agent is administered once, twice, or thrice a day. more than 5 mg, more than 2 mg, or more than 1 mg of an (0169. In certain embodiments, one unit dose of the co HDAC inhibitor. In certain embodiments, the unit dose com formulated HDAC inhibitor and antiviral agent are adminis prises more than 2 mg and less than 500 mg of an HDAC tered per day. In some embodiments, two unit doses of the inhibitor. In some embodiments, the unit dose comprises co-formulated HDAC inhibitor and antiviral agent are admin more than 10 mg and less than 50 mg of an HDAC inhibitor. istered per day. In certain embodiments, three unit doses of 0167. In some embodiments, the unit dose comprises the co-formulated HDAC inhibitor and antiviral agent are about 2000 mg, about 1900 mg, about 1800 mg, about 1700 administered per day. In some embodiments, four unit doses mg, about 1600 mg, comprises about 1500 mg, about 1400 of the co-formulated HDAC inhibitor and antiviral agent are mg, about 1300 mg, about 1200 mg, about 1100 mg, about administered per day. In certain embodiments, the one, two, 1000 mg, about 900 mg, about 800 mg, about 750 mg, about three, or four unit doses are administered daily, once a week, 700 mg, about 650 mg, about 600 mg, about 550 mg, about twice a week, three times a week, four times a week, or five 500 mg, about 450 mg, about 400 mg, about 350 mg, about times a week. 300 mg, about 250 mg, about 200 mg, about 150 mg, about (0170. In some embodiments, one or more unit doses of the 140 mg, about 130 mg, about 120 mg, about 110 mg, about co-formulated HDAC inhibitor and antiviral agent are admin 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg. istered in combination with other treatments, such as antibod about 50 mg, about 40 mg, about 30 mg, about 20 mg, about ies, chemotherapy drugs, and radiation therapy. 10 mg, about 5 mg, about 2 mg, or about 1 mg of the antiviral 0171 One or more agents and/or combinations of agents agent. In certain embodiments, the unit dose comprises less can be administered with still other agents. The choice of than 2000 mg, less than 1900 mg, less than 1800 mg, less than agents that can be co-administered with the agents and/or 1700 mg, less than 1600 mg, comprises less than 1500 mg. combinations of agents can depend, at least in part, on the less than 1400 mg, less than 1300 mg, less than 1200 mg, less condition being treated. Agents of particular use in the for than 1100 mg, less than 1000 mg, less than 900 mg, less than mulations of the present invention include, for example, any 800 mg, less than 750 mg, less than 700 mg, less than 650 mg. agent having a therapeutic effect for a virus-induced inflam less than 600mg, less than 550 mg, less than 500 mg, less than matory condition, including, e.g., drugs used to treat inflam US 2013/0331313 A1 Dec. 12, 2013 24 matory conditions. For example, formulations of the instant agent (e.g., lecithin, lysolecithin and/or a long-chain fatty invention can additionally contain one or more conventional alcohol), as well as coloring agents, preservatives, flavoring anti-inflammatory drugs, such as an NSAID, e.g. ibuprofen, agents, and the like. naproxen, acetominophen, ketoprofen, or aspirin. In some 0.175. Oils or non-aqueous solvents can be required to alternative embodiments for the treatment of a virus-induced bring one or more agents into Solution, due to, for example, inflammatory condition can additionally contain one or more the presence of large lipophilic moieties. Alternatively, emul conventional influenza antiviral agents, such as amantadine, sions, Suspensions, or other preparations, for example, lipo rimantadine, Zanamivir, and oseltamivir. In treatments for Somal preparations, can be used. With respect to liposomal retroviral infections, such as HIV, formulations of the instant preparations, any known methods for preparing liposomes for invention may additionally contain one or more conventional treatment of a condition can be used. See, for example, Bang antiviral drug, such as protease inhibitors (lopinavir/ritonavir ham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., {KaletraTM}, indinavir CrixivanTM, ritonavir NorvirTM}, Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), incorpo nelfinavir Viracept TM}, saquinavir hard gel capsules Invi rated herein by reference. Ligands can also be attached to the raseTM, atazanavir ReyatazTM, amprenavir Agen liposomes to direct these compositions to particular sites of eraseTM, fosamprenavir TelzirTM tipranavir Apti action. One or more agents can also be integrated into food vusTM), reverse transcriptase inhibitors, including non stuffs, e.g., cream cheese, butter, salad dressing, or ice cream Nucleoside and Nucleoside/nucleotide inhibitors (AZT to facilitate solubilization, administration, and/or compliance {zidovudine, RetrovirTM}, dd I didanosine, VidexTM, 3TC in certain patient populations. {lamivudine, EpivirTM}, d4T stavudine, ZeritTM, abacavir 0176 Pharmaceutical preparations for oral use can be {ZiagenTM, FTC emitricitabine, EmtrivaTM}, tenofovir obtained as a solid excipient, optionally grinding a resulting {VireadTM), efavirenz SustivaTM} and nevirapine Vira mixture, and processing the mixture of granules, after adding muneTM), fusion inhibitors T20 enfuvirtide, FuzeonTM, suitable auxiliaries, if desired, to obtain tablets or dragee integrase inhibitors (MK-0518 and GS-9137), and matura cores. Suitable excipients are, in particular, fillers such as tion inhibitors (PA-457 BevirimattM}). As another example, Sugars, including lactose, Sucrose, mannitol, or Sorbitol; fla formulations can additionally contain one or more Supple Voring elements, cellulose preparations such as, for example, ments, such as vitamin C, E or other anti-oxidants. maize starch, wheat starch, rice starch, potato starch, gelatin, 0172. One or more agents (or pharmaceutically acceptable gum tragacanth, methyl cellulose, hydroxypropylmethyl-cel salts, esters or amides thereof) can be administered perse or lulose, Sodium carboxymethylcellulose, and/or polyvinyl in the form of a pharmaceutical composition wherein the one pyrrolidone (PVP). Disintegrating agents can be added, for or more active agent(s) is in an admixture or mixture with one example, the cross-linked polyvinyl pyrrolidone, agar, or alg or more pharmaceutically acceptable carriers. A pharmaceu inic acid or a salt thereof Such as Sodium alginate. One or tical composition, as used herein, can be any composition more agents can also be formulated as a Sustained release prepared for administration to a subject. Pharmaceutical preparation. compositions can be formulated in conventional manner 0177 Dragee cores can be provided with suitable coat using one or more physiologically acceptable carriers, com ings. For this purpose, concentrated Sugar Solutions may be prising excipients, diluents, and/or auxiliaries, e.g., that used, which may optionally contain gum arabic, talc, polyvi facilitate processing of the active agents into preparations that nyl pyrrolidone, carbopol gel, polyethylene glycol, and/or can be administered. Proper formulation can depend at least titanium dioxide, lacquer Solutions, and Suitable organic Sol in part upon the route of administration chosen. One or more vents or solvent mixtures. Dyestuffs or pigments can be added agents, or pharmaceutically acceptable salts, esters, or to the tablets or dragee coatings for identification or to char amides thereof, can be delivered to a patient using a number acterize different combinations of one or more active agents. of routes or modes of administration, including oral, buccal, 0.178 Pharmaceutical preparations that can be used orally topical, rectal, transdermal, transmucosal, Subcutaneous, include push-fit capsules made of gelatin, as well as Soft, intravenous, and intramuscular applications, as well as by sealed capsules made of gelatin and a plasticizer, Such as inhalation. glycerol or Sorbitol. The push-fit capsules can contain the 0173 For oral administration, one or more agents can be active ingredients in admixture with filler Such as lactose, formulated readily by combining the one or more active binders such as starches, and/or lubricants such as talc or agents with pharmaceutically acceptable carriers well known magnesium Stearate and, optionally, stabilizers. In soft cap in the art. Such carriers can enable the one or more agents to Sules, the active agents can be dissolved or Suspended in be formulated as tablets, including chewable tablets, pills, Suitable liquids, such as fatty oils, liquid paraffin, or liquid dragees, capsules, lozenges, hard candy, liquids, gels, syrups, polyethylene glycols. In addition, stabilizers can be added. slurries, powders, Suspensions, elixirs, wafers, and the like, All formulations for oral administration can be in dosages for oral ingestion by a patient to be treated. Such formulations suitable for administration. can comprise pharmaceutically acceptable carriers including 0179 For injection, one or more agents can be formulated Solid diluents or fillers, Sterile aqueous media and various in aqueous Solutions, including but not limited to physiologi non-toxic organic solvents. Generally, the agents of the inven cally compatible buffers such as Hank's solution, Ringer's tion can be included at concentration levels ranging from Solution, or physiological Saline buffer. Such compositions about 0.5%, about 5%, about 10%, about 20%, or about 30% can also include one or more excipients, for example, preser to about 50%, about 60%, about 70%, about 80% or about vatives, solubilizers, fillers, lubricants, stabilizers, albumin, 90% by weight of the total composition of oral dosage forms, and the like. Methods of formulation are known in the art, for in an amount Sufficient to provide a desired unit of dosage. example, as disclosed in Remington's Pharmaceutical Sci 0174 Aqueous Suspensions for oral use can contain one or ences, latest edition, Mack Publishing Co., Easton P. more agents with pharmaceutically acceptable excipients, 0180. One or more agents can also be formulated as a Such as a Suspending agent (e.g., methyl cellulose), a wetting depot preparation. Such long acting formulations can be US 2013/0331313 A1 Dec. 12, 2013

administered by implantation or transcutaneous delivery (for 0185. Ocular viral infections can be effectively treated example Subcutaneously or intramuscularly), intramuscular with ophthalmic Solutions, Suspensions, ointments or inserts injection or use of a transdermal patch. Thus, for example, comprising an agent or combination of agents of the present one or more agents can beformulated with Suitable polymeric invention. or hydrophobic materials (for example as an emulsion in an 0186. In some embodiments, viral infections of the ear can acceptable oil) or ion exchange resins, or as sparingly soluble be effectively treated with otic solutions, suspensions, oint derivatives, for example, as a sparingly soluble salt. ments or inserts comprising an agent or combination of 0181 Pharmaceutical compositions comprising one or agents of the present invention. more agents can exert local and regional effects when admin 0187. One or more agents can be delivered in soluble istered topically or injected at or near particular sites of infec rather than Suspension form, which can allow for more rapid tion. Direct topical application, e.g., of a viscous liquid, gel. and quantitative absorption to the sites of action. In general, jelly, cream, lotion, ointment, Suppository, foam, or aerosol formulations such as jellies, creams, lotions, Suppositories spray, can be used for local administration, to produce, for and ointments can provide an area with more extended expo example local and/or regional effects. Pharmaceutically Sure to the agents of the present invention, while formulations appropriate vehicles for such formulation include, for in solution, e.g., sprays, provide more immediate, short-term example, lower aliphatic alcohols, polyglycols (e.g., glycerol exposure. or polyethylene glycol), esters of fatty acids, oils, fats, sili 0188 Relating to topical/local application, a pharmaceu cones, and the like. Such preparations may also include pre tical composition can include one or more penetration servatives (e.g., p-hydroxybenzoic acid esters) and/or anti enhancers. For example, the formulations can comprise Suit oxidants (e.g., ascorbic acid and tocopherol). See also able solid or gel phase carriers or excipients that increase Dermatological Formulations: Percutaneous absorption, penetration or help delivery of agents or combinations of Barry (Ed.), Marcel Dekker Incl. 1983. In some embodi agents of the invention across a permeability barrier, e.g., the ments, local/topical formulations comprising a viral inducing skin. Many of these penetration-enhancing compounds are agent and or antiviral agent are used to treat epidermal or known in the art of topical formulation, and include, e.g., mucosal viral-induced inflammatory condition. water, alcohols (e.g., terpenes like methanol, ethanol, 2-pro 0182 Pharmaceutical compositions can contain a cos panol), Sulfoxides (e.g., dimethylsulfoxide, decylmethyl Sul metically or dermatologically acceptable carrier. Such carri foxide, tetradecylmethyl sulfoxide), pyrrolidones (e.g., ers can be compatible with skin, nails, mucous membranes, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl) tissues and/or hair, and can include any conventionally used pyrrolidone), laurocapram, acetone, dimethylacetamide, cosmetic or dermatological carrier meeting these require dimethylformamide, tetrahydrofurfuryl alcohol, L-O-amino ments. Such carriers can be readily selected by one of ordi acids, anionic, cationic, amphoteric or nonionic Surfactants nary skill in the art. Informulating skin ointments, an agent or (e.g., isopropyl myristate and Sodium lauryl Sulfate), fatty combination of agents can be formulated in an oleaginous acids, fatty alcohols (e.g., oleic acid), amines, amides, hydrocarbon base, an anhydrous absorption base, a water-in clofibric acid amides, hexamethylene lauramide, proteolytic oil absorption base, an oil-in-water water-removable base enzymes, C.-bisabolol, d-limonene, urea and N,N-diethyl-m- and/or a water-soluble base. toluamide, and the like. Additional examples include humec 0183 The compositions according to the present inven tants (e.g., urea), glycols (e.g., propylene glycol and polyeth tion can be in any form Suitable for topical application, ylene glycol), glycerol monolaurate, alkanes, alkanols, including aqueous, aqueous-alcoholic or oily Solutions, ORGELASE, calcium carbonate, calcium phosphate, various lotion or serum dispersions, aqueous, anhydrous or oily gels, Sugars, starches, cellulose derivatives, gelatin, and/or other emulsions obtained by dispersion of a fatty phase in an aque polymers. A pharmaceutical composition can include one or ous phase (O/W or oil in water) or, conversely, (W/O or water more such penetration enhancers. in oil), microemulsions or alternatively microcapsules, 0189 A pharmaceutical composition for local/topical microparticles or lipid vesicle dispersions of ionic and/or application can include one or more antimicrobial preserva nonionic type. These compositions can be prepared according tives, for example, quaternary ammonium compounds, to conventional methods. The amounts of the various con organic mercurials, p-hydroxybenzoates, aromatic alcohols, stituents of the compositions according to the invention can chlorobutanol, and the like. be those conventionally used in the art. These compositions 0190. Gastrointestinal viral infections can be effectively constitute protection, treatment or care creams, milks, treated with orally- or rectally delivered solutions, suspen lotions, gels or foams for the face, for the hands, for the body sions, ointments, enemas and/or Suppositories comprising an and/or for the mucous membranes, or for cleansing the skin. agent or combination of agents of the present invention. The compositions can also consist of Solid preparations con 0191 Respiratory viral infections can be effectively stituting soaps or cleansing bars. treated with aerosol Solutions, Suspensions or dry powders 0184. A pharmaceutical composition can also contain comprising an agent or combination of agents of the present adjuvants common to the cosmetic and dermatological fields, invention. Administration by inhalation is particularly useful for example, hydrophilic or lipophilic gelling agents, hydro in treating viral infections of the lung, Such as influenza. The philic or lipophilic active agents, preserving agents, antioxi aerosol can be administered through the respiratory system or dants, solvents, fragrances, fillers, Sunscreens, odor-absorb nasal passages. For example, one skilled in the art will rec ers and dyestuffs. The amounts of these various adjuvants can ognize that a composition of the present invention can be be those conventionally used in the fields considered and, for Suspended or dissolved in an appropriate carrier, e.g., a phar example, are from about 0.01% to about 20% of the total maceutically acceptable propellant, and administered weight of the composition. Depending on their nature, these directly into the lungs using a nasal spray or inhalant. For adjuvants can be introduced into the fatty phase, into the example, an aerosol formulation comprising a viral inducing aqueous phase and/or into the lipid vesicles. agent and/or antiviral agent can be dissolved, Suspended or US 2013/0331313 A1 Dec. 12, 2013 26 emulsified in a propellant or a mixture of Solvent and propel pellant. Solvents useful in the invention include, for example, lant, e.g., for administration as a nasal spray or inhalant. water, ethanol and glycols. Any combination of Suitable sol Aerosol formulations may contain any acceptable propellant vents can be used, optionally combined with preservatives, underpressure. Such as a cosmetically or dermatologically or antioxidants, and/or other aerosol components. pharmaceutically acceptable propellant, as conventionally 0.197 An aerosol formulation can also be a dispersion or used in the art. Suspension. A Suspension aerosol formulation may comprise 0192 An aerosol formulation for nasal administration is a suspension of an agent or combination of agents of the generally an aqueous solution designed to be administered to instant invention, e.g., a viral inducing agent and/or antiviral the nasal passages in drops or sprayS. Nasal Solutions can be agent, and a dispersing agent. Dispersing agents useful in the similar to nasal Secretions in that they are generally isotonic invention include, for example, Sorbitan trioleate, oleyl alco and slightly buffered to maintain a pH of about 5.5 to about hol, oleic acid, lecithin and corn oil. A Suspension aerosol 6.5, although pH values outside of this range can additionally formulation can also include lubricants, preservatives, anti be used. Antimicrobial agents or preservatives can also be oxidant, and/or other aerosol components. included in the formulation. 0198 An aerosol formulation can be formulated as an 0193 An aerosol formulation for inhalations and inhal emulsion. An emulsion aerosol formulation can include, for ants can be designed so that an agent or combination of agents example, an alcohol Such as ethanol, a Surfactant, water and a can be carried into the respiratory tree of the subject when propellant, as well as an agent or combination of agents, e.g., administered by the nasal or oral respiratory route. Inhalation a viral inducing agent and/oran antiviral agent. The Surfactant Solutions can be administered, for example, by a nebulizer. used can be nonionic, anionic or cationic. One example of an Inhalations or insufflations, comprising finely powdered or emulsion aerosol formulation comprises, for example, etha liquid drugs, can be delivered to the respiratory system as a nol, Surfactant, water and propellant. Another example of an pharmaceutical aerosol of a solution or Suspension of the emulsion aerosol formulation comprises, for example, Veg agent or combination of agents in a propellant, e.g., to aid in etable oil, glyceryl monostearate and propane. disbursement. Propellants can be liquefied gases, including 0199 Pharmaceutical compositions suitable for use in the halocarbons, for example, fluorocarbons such as fluorinated present invention can include compositions wherein the chlorinated hydrocarbons, hydrochlorofluorocarbons, and active ingredients are presentin an effective amount, i.e., in an hydrochlorocarbons, as well as hydrocarbons and hydrocar amount effective to achieve therapeutic and/or prophylactic bon ethers. benefit in a host with at least one virus-induced inflammatory 0194 Halocarbon propellants can include fluorocarbon condition. The actual amount effective for a particular appli propellants in which all hydrogens are replaced with fluorine, cation will depend on the condition or conditions being chlorofluorocarbon propellants in which all hydrogens are treated, the condition of the subject, the formulation, and the replaced with chlorine and at least one fluorine, hydrogen route of administration, as well as other factors known to containing fluorocarbon propellants, and hydrogen-contain those of skill in the art. Determination of an effective amount ing chlorofluorocarbon propellants. Halocarbon propellants of a viral inducing agent and/or antiviral agent is well within are described in Johnson, U.S. Pat. No. 5,376,359, issued the capabilities of those skilled in the art, in light of the Dec. 27, 1994: Byronet al., U.S. Pat. No. 5,190,029, issued disclosure herein, and can be determined using routine opti Mar. 2, 1993; and Purewal et al., U.S. Pat. No. 5,776,434, mization techniques. issued Jul. 7, 1998. Hydrocarbon propellants useful in the invention include, for example, propane, isobutane, n-butane, 0200. An effective amount for use in humans can be deter pentane, isopentane and neopentane. A blend of hydrocar mined from animal models. For example, a dose for humans bons can also be used as a propellant. Ether propellants can be formulated to achieve circulating, liver, topical and/or include, for example, dimethyl ether as well as the ethers. An gastrointestinal concentrations that have been found to be aerosol formulation of the invention can also comprise more effective in animals. One skilled in the art can determine the than one propellant. For example, an aerosol formulation can effective amount for human use, especially in light of the comprise more than one propellant from the same class. Such animal model experimental data described herein. Based on as two or more fluorocarbons; or more than one, more than animal data, and other types of similar data, those skilled in two, more than three propellants from different classes. Such the art can determine an effective amount of a composition as a fluorohydrocarbon and a hydrocarbon. Pharmaceutical appropriate for humans. compositions of the present invention can also be dispensed 0201 An effective amount when referring to an agent or with a compressed gas, e.g., an inert gas Such as carbon combination of agents of the invention can generally mean dioxide, nitrous oxide or nitrogen. the dose ranges, modes of administration, formulations, etc., 0195 Aerosol formulations can also include other com that have been recommended or approved by any of the vari ponents, for example, ethanol, isopropanol, propylene glycol, ous regulatory or advisory organizations in the medical or as well as Surfactants or other components such as oils and pharmaceutical arts (e.g., FDA, AMA) or by the manufacturer detergents. These components can serve to stabilize the for or Supplier. mulation and/or lubricate valve components. 0202 Further, appropriate doses for a viral inducing agent 0196. The aerosol formulation can be packaged under and/or antiviral agent can be determined based on in vitro pressure and can be formulated as an aerosol using Solutions, experimental results. Suspensions, emulsions, powders and semisolid preparations. 0203 A person of skill in the art would be able to monitor For example, a solution aerosol formulation can comprise a in a patient the effect of administration of a particular agent. Solution of an agent, Such as a viral inducing agent and/or For example, HIV or EBV viral load levels can be determined antiviral agent in (Substantially) pure propellant or as a mix by techniques standard in the art, Such as measuring CD4 cell ture of propellant and solvent. The solvent can be used to counts, and/or viral levels as detected by PCR. Other tech dissolve the agent and/or retard the evaporation of the pro niques would be apparent to one of skill in the art. US 2013/0331313 A1 Dec. 12, 2013 27

Administration Schedule infusion or other forms of delivery to the patient are disclosed in U.S. Pat. Nos. 4,747,825; 4,723,958; 4,948,592: 4,965,251 0204 Administration of one or more agents (e.g., a viral and 5,403,590. inducing agent and/or an antiviral) can be intermittent; for 0210. In certain embodiments, the co-formulated unit example, administration can be once every two days, every dose comprising an HDAC inhibitor and an antiviral agent is three days, every five days, once a week, once or twice a administered daily. In further embodiments, administration is month, and the like. The amount, forms, and/or amounts of continuous. In some embodiments, the administration of the the different forms can be varied at different times of admin co-formulated unit dose is by pulsed administration. In cer istration. tain embodiments, pulsed administration comprises admin 0205 Pulsed administration of one or more pharmaceuti istering pulses of the co-formulated unit dose for about 1 day, cal compositions can be used for the treatment or prevention about 2 days, about 3 days, about 4 days, about 5 days, about of a viral-induced inflammatory condition. Pulsed adminis 6 days, about 7 days, about 10 days, about 2 weeks, about 3 tration can be more effective than continuous treatment as weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 pulsed doses can be lower than would be expected from weeks, about 8 weeks, about 2 months, about 3 months, about continuous administration of the same composition. Each 4 months, about 5 months, about 6 months, about 9 months, pulse dose can be reduced and the total amount of drug about 12 months. In some embodiments, pulsed administra administered over the course of treatment to the patient can be tion comprises intervals of not administering the co-formu minimized. lated unit dose of about 1 day, about 2 days, about 3 days, 0206 With pulse therapy, in vivo levels of an agent can about 4 days, about 5 days, about 6 days, about 7 days, about drop below that level required for effective continuous treat 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about ment. Pulsed administration can reduce the amount of the 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about composition administered to the patient per dose or per total 2 months, about 3 months, about 4 months, about 5 months, treatment regimen with an increased effectiveness. Pulsed about 6 months, about 9 months, about 12 months. administration can provide a saving in time, effort and 0211. In some embodiments, the administration of the co expense and a lower effective dose can lessen the number and formulated unit dose is by pulsed administration. In certain severity of complications that can be experienced by a Sub embodiments, the pulsed administration comprises adminis ject. As such, pulsing can be more effective than continuous tering the co-formulated unit dose for about 8 weeks, fol administration of the same composition. lowed by not administering the co-formulated unit dose for 0207 Individual pulses can be delivered to a subject con about 4 weeks. In some embodiments, the pulsed administra tinuously over a period of several hours, such as about 2, 4, 6, tion comprises administering the co-formulated unit dose for 8, 10, 12, 14 or 16 hours, or several days, such as 2, 3, 4, 5, 6, about 6 weeks, followed by not administering the co-formu or 7 days, or from about 1 hour to about 24 hours or from lated unit dose for about 2 weeks. In certain embodiments, the about 3 hours to about 9 hours. Alternatively, periodic doses pulsed administration comprises administering the co-formu can be administered in a single bolus or a small number of lated unit dose for about 4 weeks, followed by not adminis injections of the composition over a short period of time, for tering the co-formulated unit dose for about 2 weeks. In some example, less than 1 or 2 hours. For example, arginine embodiments, the pulsed administration comprises adminis butyrate can be administered over a period of 4 days with tering the co-formulated unit dose for about 2 weeks, fol infusions for about 8 hours per day or overnight, followed by lowed by not administering the co-formulated unit dose for a period of 7 days of no treatment. about 2 weeks. In some embodiments, pulsed administration comprises pulses of administering the co-formulated unit 0208. The interval between pulses or the interval of no dose for about 1 day, about 2 days, about 3 days, about 4 days, delivery can be greater than 24 hours or can be greater than 48 about 5 days, about 6 days, about 7 days, about 10 days, about hours, and can be for even longer such as for 3, 4, 5, 6, 7, 8, 9 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about or 10 days, two, three or four weeks or even longer. The 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about interval between pulses can be determined by one of ordinary 3 months, about 4 months, about 5 months, about 6 months, skill in the art. The interval between pulses can be calculated about 9 months, about 12 months. In certain embodiments, by administering another dose of the composition when the pulsed administration comprises intervals of not administer composition or the active component of the composition is no ing the co-formulated unit dose of about 1 day, about 2 days, longer detectable in the patient prior to delivery of the next about 3 days, about 4 days, about 5 days, about 6 days, about pulse. Intervals can also be calculated from the in vivo half 7 days, about 10 days, about 2 weeks, about 3 weeks, about 4 life of the composition. Intervals can be calculated as greater weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 than the in vivo half-life, or 2, 3, 4, 5 and even 10 times greater weeks, about 2 months, about 3 months, about 4 months, than the composition half-life. Intervals can be 25, 50, 100, about 5 months, about 6 months, about 9 months, about 12 150, 200, 250 300 and even 500 times the half life of the months. In some embodiments, administration is continuous. chemical composition. In certain embodiments, administration is for the lifetime of 0209. The number of pulses in a single therapeutic regi the subject. In other embodiments, administration is for about men can be as little as two, but can be from about 5 to 10, 10 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about to 20, 15 to 30 or more. Subjects (e.g., patients) can receive 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about one or more agents (e.g., drugs) for life according to the 2 months, about 3 months, about 4 months, about 5 months, methods of this invention. Compositions can be administered about 6 months, about 9 months, or about 12 months. In some by most any means, and can be delivered to the patient as an embodiments, an antiviral agent is administered during inter injection (e.g. intravenous, Subcutaneous, intraarterial), infu vals of not administering the co-formulated unit dose. In sion or instillation, and more preferably by oral ingestion. certain embodiments, an antiviral agent is administered in Various methods and apparatus for pulsing compositions by addition to the co-formulated unit dose. In some embodi US 2013/0331313 A1 Dec. 12, 2013 28 ments, an antiviral agent is administered simultaneously with neoplasms that were EBV+, were treated with AB and GCV. the co-formulated unit dose. In other embodiments, an anti Prior therapies (varying in different subjects) included ritux viral agent is administered separate from the co-formulated imab, chemotherapy, chemoradiotherapy and bone marrow unit dose. 0212 A pharmaceutical composition comprising a viral transplant. GCV was administered at a rate of 5 mg/kg intra inducing agent can be administered to a Subject before a venously (IV) over 1 hour twice per day, and continued pharmaceutical composition comprising an antiviral agent is throughout the cycle. AB was continuously infused at a start administered to the Subject. A pharmaceutical composition ing dose of 500 mg/kg/day. Dose escalation was continued as comprising a viral inducing agent can be co-administered to a follows until MTD was established: Subject with a pharmaceutical composition comprising an antiviral agent. A pharmaceutical composition comprising a Level 1: 500 mg/kg/day IV for 2 days viral inducing agent can be co-administered with a pharma Level 2: 1000 mg/kg/day IV for 2 days ceutical composition comprising an antiviral agent and a pharmaceutical composition comprising one or more addi Level 3: 1500 mg/kg/day IV for 2 days tion agents. The pharmaceutical compositions can be pro Level 4: 2000 mg/kg/day IV until day 21 vided by pulsed administration. For example, a pharmaceu tical composition comprising a viral inducing agent can be 0214. A total of 15 patients were evaluated for anti-tumor administered to a subject, followed by administration of a response (Table 1). A complete response (CR) was defined as pharmaceutical composition comprising an antiviral agent to disappearance of detectable malignant disease on imaging or the subject after an interval of time has passed, and this order of administration the same or similar time interval can be physical examination (e.g., for skin lesions or tonsillar repeated, for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or masses). A partial response (PR) was defined as a 50% more times. decrease in tumor size (the Sum of the product of the largest perpendicular diameters) or measurable lesions chosen for EXAMPLES analysis prior to beginning of treatment. For lesions which Example 1 could only be measured in 1 dimension, Such as skin (cuta Phase 1 Study of AB Plus Ganciclovir in Patients neous T cell lymphoma), a greater than 50% decrease in the with EBV Associated Lymphoid Malignancies largest dimension qualified as a PR. For the 3 patients who 0213 Fifteen patients with EBV-associated lymphoid died from co-morbidities, anti-tumor responses were con malignancies, who had histologically confirmed lymphoid firmed pathologically at autopsy. TABLE 1. Treatment Courses in Patients with EBV Associated Lymphoid Malignancies Treated with AB and GCV

Patient HD/HTD' Outcome, Number No. Cycles (mg/kg/day) 1 cycle Adverse Events 1 <1, 15 d 500 CR confusion; diarrhea, emesis; rejection of lung transplant* 2 <1, 16 d 1800 CR confusion; mucositis; headache; nausea, vomiting: abdominal pain 3 <1, 19d 2OOO PR confusion; mucositis; headache; nausea/vomiting: tumor regression preceding bowel perforation 2OOO PR confusion: nausea/vomiting; anorexia 5 2OOO NR confusion; restlessness; somnolence; nausea; vomiting; abdominal pain; vision change; orthostasis Headache; nausea/vomiting; abdominal pain; thrombocytopenia 2OOO1500 CR Lethargy stuport confusion; hypotonia hypoesthesia: fungal infection mucositis; tumor lysis leading to hemorrhage 1SOO.1OOO PR Acoustic hallucinations; somnolence; hypokalemia; sepsis: Deep Vein Thrombosis 2OOO,2OOO CR Confusion; fatigue; elevated BUN; tumor lysis leading to pancreatitis/hepatitis 10 1OOO.800 NR Elevated BUN, encephalopathy 11 <1, 8 d 1SOO.1SOO PR Diarrhea: hepatomegaly 12 2OOO,2OOO NR Nausea; pneumonia; port infection 13 3 938,938 PR Nausea; anorexia; weight loss; anemia; thrombocytopenia; lethargy; insomnia; hypokalemia 14 <1, 19d 12SO.12SO NR Sinus, throat, back pain; thrombocytopenia; hypokalemia; lethargy 15 <1, 5 d 1OOO,1OOO PR Lethargy; increased dyspnea; polymicrobial pneumonia acute respiratory distress syndrome

*fatal AE; DHTD-highest dose highest tolerated dose. US 2013/0331313 A1 Dec. 12, 2013 29

0215 Four patients were classified as achieving CRs, and HH6 viral load became undetectable. These findings including 2 with PTLD, 1 with extranodal NK/T cell lym indicate that a shorter, more patient-accessible regimen of the phoma and 1 with peripheral T-cell lymphoma. Three of these virus-target therapeutic strategy is more efficacious. Also, patients died after completing therapy as a result of co-morbid there remains a continuous need for an oral as opposed to an conditions and complications presumed related to tumor intravenous HDAC inhibitor. Therefore, the present invention regression. Autopsy examination of 2 subjects revealed contemplated oral HDAC inhibitors having increased apparent complete disappearance of tumor, while the third potency as compared to AB. patient demonstrated significant necrosis of residual lym phoma at autopsy. TABLE 2 0216 Six patients were classified as partial responses (PRs), including 3 with PTLD, 1 with diffuse large-cell B-cell Quantification of tumor response evaluated by CT Scan. lymphoma, 1 with extranodal NK/T-cell lymphoma and 1 Tumor dimensions in cm. with Subcutaneous panniculitis-like T-cell lymphoma. Pre-Treatment Post-Treatment 0217. The remaining 5 patients were classified as non responders (NR). Location Dimension 1 Dimension 2 Dimension 1 Dimension 2 0218. In summary 10 out of 15 patients showed a degree of R. Upper lobe 0.7 0.7 None None response to treatment of AB in combination with the antiviral R. Mid Lobe 1.1 1.1 None None ganciclovir. R. Lower Lobe 1.4 O.8 O.8 O.6 L. Upper Lobe O.9 O.8 None None L. Lower Lobe O.9 O6 O6 O.S Example 2 Lingular O.9 0.7 None None Hepatic Seg. 6 1.1 1.1 None None Phase II Trial of Low-Close Arginine Butyrate and Hepatic Seg. 8 1.O 0.7 None None L. Ant. Abd. 1.1 1.9 None None Ganciclovir/Valganciclovir in EBV (+) Lymphoid Wall Malignancies R. Ant. Abd. O.9 O.S O.9 O.S 0219. It has previously been found that continuous infu Wall sion of inducing agent, for example, arginine butyrate, may not be necessary to maintain viral thymidine kinase expres sion and sensitization to anti-viral agents in EBV-associated Example 3 tumors, but that, in fact, cells that survived initial exposure to the inducing agent plus the anti-viral agent remained Suscep Analysis of Efficacy of the Herpes Anti-Virals tible to further cycles of combination treatment (Ghosh, S.K., et al. 2007 Blood Cells, Molecules, and Diseases 38:57-65, 0222. There are 12 mammalian HDACs, and any one of incorporated herein in its entirety). However, it was neither which might be required for repression of the TK or EBV-PK anticipated nor expected that after some first period of treat gene during latency in tumors. HDAC isozyme-specific siR ment with inducing agent and anti-viral agent, one could NAs were used to knockdown individual HDACs in tumor continue the anti-viral treatment effectively within a cycle of lines expressing latent EBV to determine which one of them therapy without continued administration of the inducing induces reactivation of TK from latency, rendering it suscep agent (continued administration including continued periods tible to anti-virals. of pulsing throughout). 0220. A clinical trial was instituted utilizing a 5-day infu 0223. The EBV-positive B lymphoma cell line P3HR1 sion of arginine butyrate and 21 days of ganciclovir/valgan was used throughout these assays. The P3HR1 cell line was ciclovir for EBV+ lymphomas and Post-transplant Lymphop originally derived from Burkitt's lymphoma patient. EBV roliferative Disorder (PTLD). The first patient enrolled in the maintains a latent state of replication in this cell line. Cells protocol (with Rituximab-refractory PTLD following a cord were maintained in RPMI 1640 with 10% fetal bovine serum stem cell transplantation for Hodgkin Disease) tolerated the containing 100 U penicillin per ml and 100 ug streptomycin treatment regimen well, with resolution of cough within three per ml. The HDAC inhibitors used were from five different days and a decrease in LDH levels. classes: a) short chain fatty acids, b) hydroxamic acids, c) 0221 Treatment with arginine butyrate (AB) was admin benzamides, d) cyclic tetrapeptides, and e) largaZoles. istered in a hospital/inpatient basis. The subject was a 32 year 0224. To measure the relative level of TK mRNA in vari old with EBV-related post-transplant lymphoma who had ous total RNA preparations, reverse transcription and quan failed multiple therapies (chemotherapy, Rituxan). The sub titative PCR using real time PCR technology was used. Five ject received AB 1,000 mg/kg/dose intravenously for 5 days micrograms of total RNA was reverse-transcribed using ran (day 1-5). The dose was given continuously over 24 hours. dom hexamer primers and Superscript III cDNA synthesis kit AB was given through a long IV line or port due to hyperto (Invitrogen). The cDNA was diluted to a final volume of 60 ul nicity. Ganciclovir at 5 mg/kg IV over 1 hour was given twice with sterile water, 8 ul of which was then used in each real a day for five days (day 1-5). Valganciclovir 900 mg was given time PCR reaction in an ABI 7500 Sequencher using SYBR orally twice per day for 16 days (day 6-21). At the end of the Green technology. Primers used for the amplification of TK 21-day cycle, imaging studies were done to determine were EBV-TK1-F: 5'-AGATGACGACGGCCTCTACCA-3' response and revealed elimination of nearly all tumor masses (SEQ ID NO: 1); EBV-TK1-R: 5'-CCTCCTTCTGTGCAC (FIG. 1). Four of six target lesions resolved completely, and GAAGT3' (SEQ ID NO: 2). The B-actin mRNA levels in two additional lesions decreased in size. (Table 2) The sub those samples were determined similarly using B-actin-spe jects symptoms of fever and cough resolved for first time in cific primers Actin/hu-F: 5'-GCTCGTCGTCGACAACG 9 weeks. Measure of the tumor marker serum LDH was GCTC-3' (SEQ ID NO: 3); Actin/hu-R: 5'-CAAACAT reduced from 899 to 328 (normal). Additionally, EBV, CMV, GATCTGGGTCATCTTCTC-3' (SEQ ID NO: 4). The US 2013/0331313 A1 Dec. 12, 2013 30 relative level of TK expression in a sample was calculated 0231 Healthy, actively-growing P3HR1 cells were har following normalization of B-actin expression level. vested and resuspended in fresh growth media. Cells were 0225. Toxicity assays with two anti-herpesvirus drugs, seeded in wells. Appropriate dilutions of HDAC inhibitors Gancicovir (GCV) and Penciclovir (PCV), treated to P3HR1 were added to certain wells, some of which received an anti cells alone was conducted as a control. A total of 3x10 viral drug (such as GCV at 50 LM concentration). At 72 hrs, P3HR1 cells were incubated with various concentrations of 800 ul of culture fluid was removed from each well. Wells GCV or PCV and incubated for 6 days. Viable cell counts were then refed with 1.0 ml fresh growth media without were measured and toxicity was expressed as percentage of HDAC inhibitors. Fresh GCV solution was added to the wells cell growth compared to untreated cells. As shown in FIG. 2A that originally received GCV at the same initial concentra and FIG. 2B, PCV was less toxic to the cells compared to tion. On day 6, cell morphology was observed under micro GCV. The effect of 40 uM GCV and PCV in combination scope and viable cell counts in each individual wells were treatment approach with 1.0 mMNa-butyrate in P3HR1 cells determined by trypan blue dye exclusion method using an was compared (FIG. 2C). Inhibition of cell growth with 40 automated cell counter (Countess, Invitrogen). uMPCV (76%) was much less than with 40 uMGCV (38%). This lower level of inhibition of cell growth with PCV did not Thymidine Kinase Expression Assay change significantly when the drug was used at higher con centrations (FIG. 2D). 0232 A Thymidine Kinase (TK) was used to determine if HDAC inhibitors induced TK expression in EBV-infected Example 4 lymphoma cells. 0233 P3HR1 cells were seeded in 60 mm plates contain Analysis of Efficacy of HDAC Inhibitors ing 3x106 cells in 3 ml of fresh growth media. Appropriate 0226. The induction of lytic phase was assayed in EBV concentrations of HDAC inhibitors were added to the plate positive lymphoma cell lines exposed to different HDAC and cells were incubated in the presence of HDAC inhibitors inhibitors (HDACi) for 24-48 hrs, then the expression of EBV for 6 h, 24 h, 48 h, or as needed. Cells were harvested by TK and other EBV transcripts by RT-PCR analysis was quan centrifugation and washed once in cold PBS. Total cellular tified. To determine tumor cytotoxic activity of the combina RNA was then extracted. To measure the relative level of TK tion of HDACi and GCV. EBV+ lymphoma cells were mRNA in various total RNA preparations, reverse transcrip exposed to a range of concentrations of HDAC inhibitors and tion and quantitative PCR using real time PCR analysis were ganciclovir (GCV) for 3 days and then to GCV alone for used. See, Ghosh, S. K., Forman, L. W., Akinsheye, I., Per another 3 days. Efficacy of a particular HDAC inhibitor in the rine, S. P. Faller, D. V.: Short discontinuous sodium butyrate combination treatment approach was then determined by exposure efficiently sensitizes latently EBV infected cells enumerating living cells. A general experimental protocol is towards nucleoside analogue-mediated growth inhibition, Blood Cells Mol. Diseases (2007), 38:57-65. The relative described below. level of TK expression in a sample was calculated following Cells normalization of B-actin expression level. 0227. The EBV-positive B lymphoma cell line P3HR1 Results was used in the study. The P3HR1 cell line was originally derived from Burkitt's lymphoma patient. EBV maintains a 0234. The HDAC inhibitors had varying levels of syner latent state of replication in this cell line. These cells were gistic activity with anti-viral agents in killing EBV+ lym maintained in RPMI 1640 with 10% fetal bovine serum con phoma cells. The hydroxamic acid LBH589, the benzamide taining 100 U penicillin per ml and 100 ug streptomycin per MS275, and synthetic largazole derivatives were 10 to 10 ml. times more potent in killing EBV+ lymphoma cells in the presence of GCV, compared to sodium butyrate. The effective Study Agent concentration of LBH589 was in the range of 50-100 nM, MS275 at 200-500 nM, and Largazole derivatives at 100-200 0228. Various HDAC inhibitors were evaluated in this nM. At these concentrations, the drugs as single agents pro study. As a positive control, the Short Chain Fatty Acid duced no significant growth inhibitory activity in the tumor butyrate, an established inducer of EBV-TK was used. Gan cells. LBH589, MS275 and Largazole derivatives also ciclovir (GCV) was used as the anti-viral drug. strongly induced EBV-TK expression in the tumor cells. In certain instances, the effectiveness of these HDACi com Titration of HDAC Inhibitors on P3HR1Cells: pounds at Such low concentrations makes them potentially 0229 Concentrations of HDAC inhibitors, which do not applicable as sensitizers to anti-viral therapeutics for the significantly affect the viability or proliferation of P3HR1 treatment of EBV-associated lymphomas and other viral or cells in culture were established. virally-induced conditions. In some embodiments of the invention, these HDAC inhibitors are used as an alternative Drug Sensitivity Assay therapeutic option, in combination with antivirals, for the treatment of EBV-associated tumors and other viral or 0230. To test the sensitivity of EBV-positive lymphoma virally-induced conditions. cells towards HDAC inhibitors, P3HR1 cells were treated with HDAC inhibitors in the presence of one anti-viral drug. A. Short Chain Fatty Acids At the end of the assay, the efficacy of the HDAC inhibitors was assessed by measuring the inhibition of cell growth com 0235. Two SCFA HDAC inhibitors, Na-butyrate (NaB) pared to untreated cells. and valproic acid (VA) were tested. US 2013/0331313 A1 Dec. 12, 2013

0236 Sodium Butyrate (NaB): 0249. Oxamflatin: 0237. In a combination treatment approach, NaB+GCV 0250 Oxamflatin showed synergistic activity with GCV reduced growth of EBV-positive P3HR1 cells significantly towards reducing cell growth. At a 200 nM concentration, the (up to 50% more) compared to cells treated with NaB or GCV activity level (growth suppression) was more than what typi alone (FIG. 3A). The optimal concentration of NaB for this cally seen with 1.0 mM NaB (FIG. 8). purpose was found to be 1.0 mM. Responses from 1.0 mM 0251. As shown in the data, hydroxamic acid HDAC NaB was used as a control for interpreting results in this inhibitors synergistically with GCV reduce cell growth of experiment. At a higher concentration, NaB alone reduces P3HR1 cells. Furthermore, hydroxamic acid HDAC inhibi cell growth to a significant degree, and the Synergistic effects tors induce EBV kinase expression by at least 2-, 5-, 10-, 20 of GCV are lost at those concentrations of NaB. or 30-fold. In addition, hydroxamic acid HDAC inhibitors in 0238 Valproic Acid (VA): combination with antiviral agents reduce the cell count of 0239. The other HDACiused in this experiment, VA, also EBV infected cells to less than 70%, 60%, 50%, 40%, 30%, had very similar activity (FIG. 3B). Analysis of TK mRNA 20%, or 10% of cells treated without the HDAC inhibitor or level by RT and real-time PCR however showed that VA was antiviral treatment. less efficient than NaB in inducing TK expression (FIG. 3C). C. Cyclic Tetrapeptide B. Hydroxamic Acids (0252 Apicidin: 0253) The cyclic tetrapeptide group of HDACi examined 0240. A total of five different HDAC inhibitors from the was apicidin. A toxicity assay with apicidin alone showed that hydroxamic acid group were examined as combination thera concentrations of apicidin higher than 200 nM was quite toxic pies. These inhibitors include scriptaid, SAHA, panobin to the cells. The combination treatment assay (FIG.9) showed ostat-LHB589, belinostat-PXD101, and oxamflatin. All of that at 100 nM and 200 nM concentrations, apicidin reduced these HDAC inhibitors can be administered orally via an oral cell growth by 40-50% over cells treated with apicidin alone. formulation. However, the 200 nM concentration cell growth was signifi 0241 Scriptaid: cantly retarded without any GCV and a 500 nM concentration 0242 Scriptaid showed strong synergistic effect with was very toxic to the cells. GCV in reducing cell growth of P3HR1 cells, especially at 500 nM and 1 uM concentrations (FIG. 4A). As shown in the D. Benzamide data, in preferred embodiments, an HDAC inhibitor of the 0254 MS-275: invention combined with an antiviral agent can reduce the cell 0255 Experiments show that the benzamide class of count of EBV infected cells to less than 70%, 60%, 50%, HDAC inhibitors were extremely potent in sensitizing 40%, 30%, 20%, or 10% of cells treated without the HDAC P3HR1 cells to GCV-mediated effects. As shown below (FIG. inhibitor orantiviral treatment, or by at least 60%, 50%, 40%, 10A) a 500 nM concentration of MS-275 was as efficient as 30%, or 20% from cells treated with an antiviral agent alone. 1.0 mMNaB. Higher concentrations were extremely toxic to 0243 SAHA-Vorinostat: the cells. Interestingly, MS-275 also strongly induced TK 0244. The combination treatment experiment with SAHA expression at 500 nM and higher concentrations (FIG. 10B). showed that it could induce TK expression at a higher level TK expression was also induced at only 6 hr post treatment. than that seen with efficient concentrations of butyrate (1.0 Based on these results, an even shorter exposure to MS-275 mM) (FIG. 5B). As such, the present invention contemplates was examined to see if it would be sufficient to sensitize using an HDAC inhibitor (preferably an oral HDAC inhibitor) P3HR1 cells to GCV-mediated killing. Cells with were to induce EBV kinase expression by at least 2-, 4-, 6-, 8-, or treated with MS-275 and GCV for shorter time periods of 24 10-fold, wherein the HDAC inhibitor is administered at a hr or 48 hr (as opposed to 72 hr) and then further incubated in concentration of less than 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 presence of GCV for up to 6 days, at which time the viable cell mg/kg, 6 mg/kg, 8 mg/kg, or 10 mg/kg. counts were enumerated. As shown in FIG. 10C, even at just 24 hr exposure to MS-275 sensitized the cells to GCV-medi 0245 LHB589-Panobinostat: ated effects as efficiently as a 72 hr continuous treatment. This 0246 The growth inhibitory activity of LHB589 at a 50 further demonstrates that MS-275 is very effective sensitizing nM concentration was comparable to that of NaB at 1.0 mM agent for combination treatment studies. (FIG. 6A). When the cells were treated for 3 days or longer, LHB589 was extremely toxic to the cells at any concentra E. Largazole tions 100 nM or above. Although when treated for 24 h only, 0256 Largazole Derivatives: cells survived well even at a concentration of 5 uM. TK 0257 Largazole is a member of macrocyclic depsipeptide expression level in presence of LHB589 was quite high com that was originally isolated from coral reef cyanobacteria. pared to optimum concentration of NaB (2.5 mM) (FIG. 6B). Largazole is a potent HDAC inhibitor with specificity towards Thus, in some embodiments, the present invention contem HDAC class 1 and 2 only. Additionally, largazole has very low plates a short administration of an oral HDAC inhibitor (e.g., IC 50 and HDAC isozyme specificity. 16 different analogs of less than 4 days, 3 days, 2 days, 36 h, 24 h, 12 h, or 6 h) in the largazole were tested (abó-113b, ab6-113a, abó-123a, combination with or followed by an antiviral treatment. ab6-123b, abó-164b, ab6-156b, 232a, 233a, 238a, 233b, 0247 PXD101-Belinostat: 234b, 235b, 234a, 235a, 237a, 212b, TLN1 357, TNL2 380, 0248 PXD101 induced high level of TK expression at the ARTO1) for synergistic cell killing activity in combination 5 LM concentration. (FIG. 7). Thus, the present invention with GCV (FIGS. 12A, B, C, D, and E). In some embodi contemplates using an HDAC inhibitor (preferably an oral ments, the HDAC inhibitor and antiviral treatment reduces HDAC inhibitor) to induce EBV kinase expression by at least the number of EBVTK induced cells by at least 10%, 20%, 5-, 10-, 15- 20-, 25-, 30-, or 35-fold. 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to US 2013/0331313 A1 Dec. 12, 2013 32 untreated cells or cells treated with the antiviral agent only. 13 Prophetic Example 2 largazole derivatives were tested both in combination treat ment approach and also for their ability to induce EBV TK Treatment of Atherosclerosis (FIG. 12F). Several of the largazoles showed potent cell kill ing activity in combination with GCV. Thus, in some embodi 0260 To treat a coronary artery condition patient sus ments, an HDAC inhibitor of the invention is one that can pected of having cytomegalovirus-induced atherosclerosis, a induce EBVTK by at least 2-, 4-, 6-, 8-,10-, 12-, or 14-fold health care professional administers a dose of a pharmaceu as compared to cells not treated with an HDAC inhibitor. In tical composition comprising a viral inducing agent, JNJ any of the embodiments herein, the HDAC inhibitor is pref 26481585. A week later, a health care professional adminis erably suitable for oral formulation. ters to the Subject a dose of a pharmaceutical composition comprising Valganciclovir. A cycle of administration is car Example 5 ried out for a period of a month. During the period of admin istration of the viral inducing agent and the antiviral agent, the Analysis of Efficacy of Combination Treatment with Subject is also administered rosuvastatin to treat the athero HIV-Infected Cells Sclerosis. 0258 Virus production (p24 release) was examined in an Prophetic Example 3 HIV-1-infected monocyte line. Cells were treated or not treated with HDAC-inhibitors and other compounds. P24 0261) A patient either diagnosed with or suspected of hav release expressed as optical density (“OD) (FIG. 13), and ing an Epstein Barr Virus (EBV)-associated malignancy Such then converted to pg of protein (FIG. 14). Arginine butyrate, as nasopharyngeal carcinoma, Hodgkin’s disease, Burkitt's phorbol myristate acetate (PMA), trichostatin A (TSA), lymphoma, post-transplantation lymphoproliferative dis LHB589, apicidin (API) and largazole (LARG) are shown to ease, or gastric carcinoma can be treated. A health care pro be active, whereas 2,2-dimethyl butyrate (ST20) and fessional administers a dose of a pharmaceutical composition 2-(duinazolin-4-ylamino)butanoic acid (RB3) increased viral comprising JNJ-26481585 and valganciclovir co-formulated production at levels similar to the control of vehicle alone. for oral administration. The patient is administered a single DMSO was vehicle for some of the compounds tested. daily dose in tablet form, where the tablet contains 5 mg of JNJ-26481585 and 1500 mg of timed-release or slow-release Prophetic Example 1 Valganciclovir. A cycle of administration is carried out for a period of 28 days. During the period of administration, the Treatment of Multiple Sclerosis Subject can optionally also be administered an additional 0259. To treat a subject suspected of having Epstein-Barr chemotherapeutic agent to treat the malignancy. virus-induced multiple Sclerosis, a health care professional 0262. While preferred embodiments of the present inven administers to the Subject a dose of a pharmaceutical compo tion have been shown and described herein, it will be obvious sition comprising a viral inducing agent, the HDAC inhibitor to those skilled in the art that such embodiments are provided JNJ-26481585. A week later, a health care professional by way of example only. Numerous variations, changes, and administers to the Subject a dose of a pharmaceutical compo substitutions will now occur to those skilled in the art without sition comprising an antiviral agent, Valganciclovir. A cycle departing from the invention. It should be understood that of administration is carried out for a period of a month (FIG. various alternatives to the embodiments of the invention 15). During the period of administration of the viral inducing described herein may be employed in practicing the inven agent and the antiviral agent, the Subject is also administered tion. It is intended that the following claims define the scope mitoxantrone to treat the multiple sclerosis. A cycle of HDAC of the invention and that methods and structures within the inhibitor and antiviral treatment may be repeated at least 2, 4, Scope of these claims and their equivalents be covered 6, 8, 10, or 12 times as needed. thereby.

SEQUENCE LISTING

<16 Os NUMBER OF SEO ID NOS: 4

<21 Os SEQ ID NO 1 &211s LENGTH: 21 &212s. TYPE: DNA <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer

<4 OOs SEQUENCE: 1

agatgacgac ggcct ct acc a 21

<21 Os SEQ ID NO 2 &211s LENGTH: 2O &212s. TYPE: DNA US 2013/0331313 A1 Dec. 12, 2013

- Continued <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer

<4 OOs, SEQUENCE: 2 cctic cttctg togcacgaagt

<210s, SEQ ID NO 3 &211s LENGTH: 21 &212s. TYPE: DNA <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer

<4 OOs, SEQUENCE: 3 gct citcgt.c gacaacggct c 21

<210s, SEQ ID NO 4 &211s LENGTH: 25 &212s. TYPE: DNA <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic primer

<4 OOs, SEQUENCE: 4 caaacatgat Ctgggtcatc ttcto 25

What is claimed is: 5. The method of claim 1, wherein the virally-induced 1. A method for treating and/or preventing a viral or virally condition is a lymphoma, chronic lymphocytic leukemia, induced condition comprising administering a HDAC inhibi nasopharyngeal carcinoma, gastric cancer, Kaposi's Sar tor and an antiviral agent wherein the viral or virally-induced coma, rheumatoid arthritis, systemic lupus erythematosus, or condition is caused by a DNA virus and the HDAC inhibitor multiple Sclerosis. is administered at dose of less than 2 mg/kg per dose. 6. A method for treating and/or preventing a viral or virally 2. The method of claim 1, wherein the HDAC inhibitor is Vorinostat/suberoylanilide hydroxamic acid, JNJ-26481585 induced condition comprising administering a HDAC inhibi (N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)methyl) tor and an antiviral agent wherein the viral or virally-induced amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide), condition is caused by a retrovirus and the HDAC inhibitor is R306465/JNJ-16241199 (N-hydroxy-5-(4-(naphthalen-2-yl administered at dose of less than 2 mg/kg per dose. Sulfonyl)piperazin-1-yl)pyrimidine-2-carboxamide), 7. The method of claim 6, wherein the HDAC inhibitor is CHR-3996 (2-(6-(6-Fluoroquinolin-2-yl)methylamino Vorinostat/suberoylanilide hydroxamic acid, JNJ-26481585 3-azabicyclo[3.1.0 hex-3-yl)-N-hydroxypyrimidine-5-car (N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)methyl) boxamide), Belinostat/PXD101, Panobinostat/LBH-589, tri amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide), chostatin A/TSA (7-4-(dimethylamino)phenyl-N-hydroxy R306465/JNJ-16241199 (N-hydroxy-5-(4-(naphthalen-2-yl 4,6-dimethyl-7-oxohepta-2,4-dienamide), ITF2357, CBHA, Sulfonyl)piperazin-1-yl)pyrimidine-2-carboxamide), Givinostat/ITF2357, romidepsin, PCI-24781, depsipeptide CHR-3996 (2-(6-(6-Fluoroquinolin-2-yl)methylamino (FR901228 or FK228), butyrate, phenylbutyrate, valproic 3-azabicyclo[3.1.0 hex-3-yl)-N-hydroxypyrimidine-5-car acid, AN-9, CI-994, Entinostat/MS-275, SNDX-275, moce boxamide), Belinostat/PXD101, Panobinostat/LBH-589, tri tinostat/MGCD0103 (N-(2-aminophenyl)-4-((4-pyridin-3- chostatin A/TSA (7-4-(dimethylamino)phenyl-N-hydroxy ylpyrimidin-2-ylamino)methyl)benzamide), m-carboxycin 4,6-dimethyl-7-oxohepta-2,4-dienamide), ITF2357, CBHA, namic acid, bishydroxamic acid, Suberic bishydroxamic acid, Givinostat/ITF2357, romidepsin, PCI-24781, depsipeptide oxamflatin, ABHA, SB-55629, SB939, pyroxamide, prope (FR901228 or FK228), butyrate, phenylbutyrate, valproic namides, aroyl pyrrolyl hydroxamides, or LAQ824 (((E)-N- acid, AN-9, CI-994, Entinostat/MS-275, SNDX-275, moce hydroxy-3-4-2-hydroxyethyl-2-(1H-indol-3-yl)ethyl tinostat/MGCD0103 (N-(2-aminophenyl)-4-((4-pyridin-3- aminomethylphenylprop-2-enamide). ylpyrimidin-2-ylamino)methyl)benzamide), m-carboxycin 3. The method of claim 1, wherein the DNA virus is a namic acid, bishydroxamic acid, Suberic bishydroxamic acid, herpesvirus, an Epstein-Barr virus, a parvovirus, a BK virus, oxamflatin, ABHA, SB-55629, SB939, pyroxamide, prope or a hepatitis B virus. namides, aroyl pyrrolyl hydroxamides, or LAQ824 (((E)-N- 4. The method of claim 1, wherein the virally-induced hydroxy-3-4-2-hydroxyethyl-2-(1H-indol-3-yl)ethyl condition is a cancerous condition, an inflammatory condi aminomethylphenylprop-2-enamide). tion, apathology of the immune system, an allergic condition, 8. The method of claim 6, wherein the retrovirus is HIV, or a skin condition. HTLV 1 or HTLV2. US 2013/0331313 A1 Dec. 12, 2013 34

9. A method for treating and/or preventing a viral condi oxamflatin, ABHA, SB-55629, SB939, pyroxamide, prope tion, a virally-induced condition, or an inflammatory condi namides, aroyl pyrrolyl hydroxamides, or LAQ824 (((E)-N- tion comprising administering a HDAC inhibitor and an anti hydroxy-3-4-2-hydroxyethyl-2-(1H-indol-3-yl)ethyl viral agent wherein the MW of the HDAC inhibitor is greater aminomethylphenylprop-2-enamide). than 275 g/mol. 14. The method of claim 13, wherein the viral condition or 10. The method of claim 9, wherein the viral condition or virally-induced condition is caused by a human immunode virally-induced condition is caused by a DNA virus, a herpes ficiency virus, a herpes virus, an Epstein-Barr virus, a par virus, an Epstein-Barr virus, a retrovirus, HIV. HTLV1, or vovirus, a coxsackie virus, a Human T-lymphotropic virus, a HTLV2. BK virus, or a hepatitis virus. 11. The method of claim 9, wherein the virally-induced 15. A composition comprising a (i) HDAC inhibitor and (ii) condition is a cancerous condition, an inflammatory condi tion, apathology of the immune system, an allergic condition, an antiviral agent. or a skin condition. 16. The composition of claim 15, wherein the HDAC 12. The method of claim 9, wherein the antiviral agent is a inhibitor is Vorinostat/suberoyl anilide hydroxamic acid, HIV drug, a Herpes drug, a CMV drug, or a hepatitis drug. JNJ-26481585 (N-hydroxy-2-(4-((((1-methyl-1H-indol-3- 13. A method for treating and/or preventing a viral condi yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-car tion, a virally-induced condition, or an inflammatory condi boxamide), R306465/JNJ-16241199 (N-hydroxy-5-(4- tion comprising administering a HDAC inhibitor and an anti (naphthalen-2-ylsulfonyl)piperazin-1-yl)pyrimidine-2- viral agent, wherein HDAC inhibitor is Vorinostat/suberoyl carboxamide), CHR-3996 (2-(6-(6-Fluoroquinolin-2-yl) anilide hydroxamic acid, JNJ-26481585 (N-hydroxy-2-(4- methylamino-3-azabicyclo[3.1.0 hex-3-yl)-N- ((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)piperi hydroxypyrimidine-5-carb oxamide), Belinostat/PXD101, din-1-yl)pyrimidine-5-carboxamide), R306465/JNJ Panobinostat/LBH-589, trichostatin A/TSA (7-4-(dimethy 1624 11.99 (N-hydroxy-5-(4-(naphthalen-2-ylsulfonyl) lamino)phenyl-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4- piperazin-1-yl)pyrimidine-2-carboxamide), CHR-3996 (2- dienamide), ITF2357, CBHA, Givinostat/ITF2357, (6-(6-Fluoroquinolin-2-yl)methylamino-3-azabicyclo romidepsin, PCI-24781, depsipeptide(FR901228 or FK228), 3.1.0 hex-3-yl)-N-hydroxypyrimidine-5-carb oxamide), butyrate, phenylbutyrate, valproic acid, AN-9, CI-994, Enti Belinostat/PXD101, Panobinostat/LBH-589, trichostatin nostat/MS-275, SNDX-275, mocetinostat/MGCD0103 (N- A/TSA (7-4-(dimethylamino)phenyl-N-hydroxy-4,6-dim (2-aminophenyl)-4-((4-pyridin-3-ylpyrimidin-2-ylamino) ethyl-7-oxohepta-2,4-dienamide), ITF2357, CBHA, Givi methyl)benzamide), m-carboxycinnamic acid, nostat/ITF2357, romidepsin, PCI-24781, depsipeptide bishydroxamic acid, suberic bishydroxamic acid, oxamflatin, (FR901228 or FK228), butyrate, phenylbutyrate, valproic ABHA, SB-55629, SB939, pyroxamide, propenamides, acid, AN-9, CI-994, Entinostat/MS-275, SNDX-275, moce aroyl pyrrolyl hydroxamides, or LAQ824 (((E)-N-hydroxy tinostat/MGCD0103 (N-(2-aminophenyl)-4-((4-pyridin-3- 3-4-2-hydroxyethyl-2-(1H-indol-3-yl)ethylaminome ylpyrimidin-2-ylamino)methyl)benzamide), m-carboxycin thylphenylprop-2-enamide). namic acid, bishydroxamic acid, Suberic bishydroxamic acid, k k k k k