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US 20170027944A9 (19) United States (10) Pub. No.: US 2017/0027944 A9 (12) Patent Application Publication (48) Pub. Date: Feb. 2, 2017 PERRINE et al. CORRECTED PUBLICATION

(54) METHODS FOR TREATING VIRAL continuation of application No. 12/890.042, filed on DSORDERS Sep. 24, 2010, now abandoned. (60) Provisional application No. 61/245,529, filed on Sep. (71) Applicant: TRUSTEES OF BOSTON 24, 2009, provisional application No. 61/295,663, UNIVERSITY, Boston, MA (US) filed on Jan. 15, 2010. (72) Inventors: Susan Park PERRINE, Weston, MA (US); Douglas FALLER, Weston, MA Publication Classification (US) (51) Int. Cl. A6II 3/522 (2006.01) (21) Appl. No.: 14/624,852 A63L/98 (2006.01) (52) U.S. Cl. (22) Filed: Feb. 18, 2015 CPC ...... A61 K3I/522 (2013.01); A61K 31/198 Prior Publication Data (2013.01) (15) Correction of US 2015/O157636A1 Jun. 11, 2015 (57) ABSTRACT See (60) Related U.S. Application Data. Disclosed are methods of treating viral disorders via the administration of an inducing agent and an anti-viral agent. (65) US 2015/O157636A1 Jun. 11, 2015 In one embodiment, the inducing agent and the anti-viral agent are administered for about five days, and the anti-viral Related U.S. Application Data agent is Subsequently administered without the inducing (63) Continuation of application No. 13/915,092, filed on agent for an additional period of about sixteen days for a Jun. 11, 2013, now Pat. No. 8,993,581, which is a total cycle of about 21 days. Patent Application Publication Feb. 2, 2017. Sheet 1 of 19 US 2017/0027944 A9

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METHODS FOR TREATINGVIRAL membrane proteins (LMP-1, LMP-2A, LMP-2B) and two DISORDERS small, non-poly(A) RNAs (EBER-1 and EBER-2) (Miller, G. et al. 1990 Epstein-Barr Virus: Biology, Pathogenesis CROSS-REFERENCE TO RELATED and Medical Aspects, Raven Press, N.Y.). In EBV (+) tumors APPLICATIONS Such as Burkitt's lymphoma, neoplastic genetic events have 0001. This application is a continuation application of often Superseded the requirement for viral immortalizing co-pending U.S. patent application Ser. No. 13/915,092 filed functions, and gene expression may be limited to EBNA-1 Jun. 11, 2013, which is a continuation application of U.S. (Rowe, M., et al. 1987 EMBO.J. 6:2743-51). Virus tropism patent application Ser. No. 12/890,042 filed on Sep. 24. is deteimined by complement receptor type 2 which medi 2010, which claims the benefit under 35 U.S.C. S 119(e) of ates attachment of the envelope protein gp350/2204 to Band U.S. Provisional Application No. 61/245,529, filed Sep. 24, some T lymphocytes, follicular dendritic cells and epithelial 2009, and U.S. Provisional Application No. 61/295,663, cells. filed Jan. 15, 2010, the contents of each of which are 0005 African Burkitt's lymphoma is characterized by incorporated herein by reference in their entireties. rapid growth of the tumor at non-lymphoid sites such as the jaw or the retroperitoneum. The tumor is of B cell origin and SEQUENCE LISTING is closely related to the small non-cleaved cells of normal lymphoid follicles. Biopsy specimens from African Burkitt's 0002 The instant application contains a Sequence Listing lymphoma invariably contain the EBV genome and are which has been submitted in ASCII format via EFS-Web and positive for EBNA (Magrath, I. 1986 Epstein-Barr Virus and is hereby incorporated by reference in its entirety. Said Associated Diseases, pp. 631-43, M. Ninjhoff Publishing, ASCII copy, created on Jun. 6, 2013, is named 701586 Boston). This contrasts with the non-African Burkitt's lym O69032 SL.txt and is 1,244 bytes in size. phoma, in which only 15% to 20% of the tumors contain the EBV genome. EBV has a worldwide distribution and infects BACKGROUND OF THE INVENTION most (more than 90%) individuals before adulthood. The 0003. A growing number of cellular disorders such as clustering of Burkitt's lymphoma in the equatorial belt of neoplastic malignancies have been found to contain viral East Africa remains unexplained. It has been hypothesized genetic sequences or virus particles in the anomalous cells. that alterations of the immune system, possibly due to For a large number of these disorders, the presence of the hyperstimulation by endemic malaria, may play an impor virus is believed to be a causative or at least contributory tant role in the outcome of an EBV infection to individuals instrument. Representative members of many of the known in this region (Moss, D. J., et al. 1983 Int. J. Cancer 31: families of viruses have been found in such cells including 727-32). Individuals from this region show impairment in members of the herpes family of viruses, the polyomavi virus-specific cytotoxic T-cell activity. Normally, it is the ruses, and the hepatitis viruses. Epstein-Barr virus (EBV), a T-cell response to EBV infection that limits B-cell prolif 172 kb herpes virus, is often found intimately associated eration, and this T-cell response is directly stimulated by with both mature and immature B cells. EBV is a common EBV (Zur Hausen, H., et al. 1970 Nature 228: 1056-58). It and worldwide pathogen. Childhood infection is asymptom has been postulated that the failure of the T-cell immune atic. About 50% of individuals with delayed exposure response to control this proliferation could lead to excessive develop a self-limited, lymphoproliferative syndrome B-cell proliferation and, as such, provide a suitable back referred to as infectious mononucleosis. EBV is also ground for further mutation, oncogenic transformation, and detected in 2 endemic tumors, African Burkitt's lymphoma lymphomagenesis. (BL) (Henle, G., et al. 1985 Proc. Natl. Acad. Sci. USA 0006. A scenario has been suggested for the involvement 58:94-101) and nasopharyngeal carcinoma (NPC) (Henle, of EBV in the etiology of African Burkitt's lymphoma W., et al. 1985 Adv. Viral Onco. 5:201-38), as well as gastric (Klein, G. 1979 Proc. Natl. Acad. Sci. USA 76:2442-46). carcinoma, breast cancers and sarcomas. Recently, some The first step involves the EBV-induced immortalization of T-cell and B-cell lymphomas, as well as about 50% of B lymphocytes in a primary infection. The second step Hodgkin’s lymphomas, have been found to contain EBV involves the stimulated proliferation of EB V(+) B cells. (Weiss, L. M., et al. 1989 N. Engl. JMed. 320:502). This step is facilitated in the geographic areas where 0004 EBV undergoes lytic replication after initial infec Burkitt's lymphoma is endemic (presumably because of the tion of oropharyngeal epithelia. The linear form genome is presence of malaria), through B-cell triggering and the duplicated, packaged into the viral capsid, and extruded suppression of T-cells involved in the control of the prolif from the cell by budding or lysis. One hundred viral proteins eration of EBV-infected cells. This pool of cells becomes are synthesized during this lytic stage of the virus life cycle. increased in size as a target cell population for random In contrast, normal B cells incubated with EBV in vitro are chromosomal rearrangements. The third and final step is the efficiently immortalized and develop into continuously reciprocal translocation involving a chromosomal locus with growing lymphoblastoid cell lines (LCLs). The cellular an immunoglobulin gene and the c-myc gene on chromo events that regulate these distinct outcomes are as yet Some 8. This leads to the deregulation of the c-myc gene, to unclear. In immortalized cells, the genome circularizes, the development of the malignant clone, and to the appear amplifies, and replicates coordinate with, and dependent ance of a tumor mass (Klein, G., et al. 1985 Nature 315: upon, cell division. Because no viral particles are produced, 190). Alternative scenarios have been proposed, in which the infection is considered to be latent, and EBV persists in the order of the steps is rearranged such that the B-cell activa cells for life. Outgrowth of latently infected B cells is tion by malaria precedes the chromosomal translocation and prevented by T cell immune Surveillance. In immortalizing is followed by EBV infection. Regardless, the components latent infection, only 11 gene products are detected, includ of these two scenarios each account for the geographic ing 6 nuclear antigens (EBNA-1, -2, -LP, -3A, -3B, -3O), 3 distribution of Burkitt's lymphoma, the critical involvement US 2017/0027944 A9 Feb. 2, 2017

of EBV in lymphomagenesis, and the eventual selection and a given cell. Once the viral DNA is established inside the clonal outgrowth of a population of cells with the critical cell, it circularizes and reproduces itself to yield multiple translocation involving the deregulation of the c-myc gene identical copies of viral DNA (Hurley, E. A., et al. 1988 J. on chromosome 8. Exp. Med. 168:2059). In this way, tumors derived from 0007 For more than 20 years, a role for EBV in the infected cells can have multiple copies of EBV per cell, pathogenesis of Hodgkin’s disease (HD) was postulated while maintaining clonal viral DNA structure. The average based on epidemiologic evidence linking Hodgkin’s patients amount of clonal EBV DNA in Hodgkin’s disease tissues with EBV seropositivity and elevated EBV titers (Evans, A. varied from 0.5 to 5 copies per cell. Because RS cells S., et al. 1984 Int. J. Cancer 34: 149). A number of studies comprised only a small fraction (<1%) of all HD tissue cells, have found an increase (2-5 fold) in the incidence of HD the content of EBV DNA in each RS cell is estimated to be after infectious mononucleosis. However, some Hodgkin’s at least 100 times higher than the measured average copy patients were seronegative for EBV, and the association number per cell, or at least 50 copies of viral DNA per RS between EBV and Hodgkin’s disease remained speculative cell. This is comparable with, or greater than, the viral until 1987. In that year, molecular genetic analysis dem burden in infected non-Hodgkin’s lymphomas. The high onstrated that some Hodgkin’s tissues contained monoclonal copy number of EBV in RS cells may relate to the patho EBV DNA and that the virus was localized to Reed-Stern biology of this complex lymphomatous disorder. In agree berg (RS) cells (the malignant cells in HD). Subsequent ment with these studies, EBV DNA is abundant and mono immunohistochemical and serologic data Support an asso clonal in infected RS cells. The presence of EBV in RS cells ciation between EBV and Hodgkin’s disease and confirm the was strongly and independently linked to mixed cellularity localization of the virus to cytologically malignant-appear histology and Hispanic ethnicity. ing RS cells and variants (Jiwa, N. M., et al. 1992 Histo 0010 Clonally-integrated EBV is found in association pathology 21:51). EBV also infects variable numbers of with T-cell lymphomas, as well as B-cell lymphomas. Cur small Band T lymphocytes in the reactive inflammatory cell rently, three populations of tissue-restricted T lymphocytes infiltrate that composes the bulk of Hodgkin’s tissues have been recognized: mucosa-associated, cutaneous, and (Weiss, L. M., et al. 1991 Am. J. Path. 139: 1259). Clonal nodal T lymphocytes. T-cell lymphomas arising from dif and non-clonal EBV genomes are present in Hodgkin’s ferent sites, but with similar morphology, may show differ disease. Expression of the oncogene LMP (latent membrane ences in lymphomagenesis and in expression of oncogenes, protein) is seen in RS cells. In HD, the region of the (viral) adhesion molecules, presence of certain DNA/RNA viral BNLF1 oncogene coding for the amino terminal and trans sequences, and in clinical presentation and behavior. Pri membrane domains (associated with oncogenic function) of mary cutaneous CD30(+) large cell, T-cell lymphomas often LMP appears to be homogeneous, whereas the region coding remain localized to the skin for a long time, express a unique for the intracytoplasmic (carboxyl terminal) domain of LMP cutaneous lymphocyte antigen (CLA), known as the skin is heterogeneous. Cytological similarities between RS cells homing receptor, have been postulated to be associated with and immunoblasts of known EBV-induced infectious mono the presence of human T-cell leukemia/lymphoma virus type nucleosis and EBV-induced AIDS-related lymphomas are I (HTLV 1), and have a good clinical course (Beljaards, R. consistent with the hypothesis that the EBV-BNLFI onco C., et al. 1993 Cancer 71:2097). In contrast, morphologi gene is an inducer of morphological features of RS cells. cally similar T-cell lymphomas of nodal origin often behave Whether chromosomal integration of EBV DNA is an more aggressively, are CLA-negative, and have been asso important factor in activation of Such a transforming activity ciated with the presence of EBV (de Bruin, P. C., et al. 1993 remains to be elucidated. Therefore, the RS cells appear to Histopathology 23: 127). There was no relation between be derived from lymphocytes beyond the pre-B-cell or primary cutaneous T-cell lymphoma and EBV. common thymocyte stage, which may or may not Subse (0011 Infection of T cells by EBV most likely occurs via quently become infected by EBV. CR2 or CR2-like receptors (Tsoukas, C. D., et al. 1993 0008. The high prevalence of EBV in Hodgkin’s disease Immunol. Today 14:56). The close contact between T cells implies an etiologic role for the virus in some cases of and the upper respiratory tract epithelium, known for its Hodgkin’s tumorigenesis. This pathogenetic theory is Sup reservoir function for EBV, probably make T cells in this ported by the monoclonality of EBV DNA in these tumors region more vulnerable for EBV infection. The finding that (Gulley, M. L., et al. 1994 Blood 83: 1595-602). In one EBV can be found in almost all tumor cells in most cases of series, monoclonal EBV DNA was detected in all 17 cases primary extra-nodal, and especially nasal, T-cell lymphoma, having EBNA1-positive RS cells. Because tumor-associated in contrast to primary nodal T-cell lymphoma, where the viral DNA is monoclonal, it is likely that virus infection number of EB V-infected neoplastic cells varies greatly preceded clonal expansion. This reinforces the hypothesis between the cases, argues for an etiologic role for EBV in that the virus is not an innocent bystander, but, rather, plays these cases. Moreover, these cases often express LMP-1, a role in the pathogenesis of the Hodgkin’s disease and the known for its transforming and oncogenic properties in vitro other tumor types in which it is found (Neri, A., et al. 1991 and are reported to be monoclonal for EBV (Su, I., et al. Blood 77: 1092). The observation of EBNA1 expression in 1991 Blood 77:799). Thus, there are site-restricted etiologic the RS cells of clonally-infected cases indicates that the differences between morphologically identical T-cell lym clonal virus is localized to these cells and Suggests that phomas, of which EBV might be one of many factors. Hodgkin’s disease results from the transformation of an 0012 EBV-induced lymphoproliferative disease or lym EBV-competent cell. Other studies suggest that this virus is phoma has an immunodeficiency incidence in U.S. of about a modulating rather than an etiologic agent in a considerable 10,000 B-cell, EBV (+) lymphoma patients per year. EBV is proportion of HD cases. very commonly associated with lymphomas in patients with 0009 Investigations into the biology of EBV infection acquired or congenital immunodeficiencies. These lympho have shown that only one viral particle successfully infects mas can be distinguished from the classical Burkitt's lym US 2017/0027944 A9 Feb. 2, 2017 phomas in that the tumors may be polyclonal. Tumors also metabolites into viral DNA, leading to premature termina do not demonstrate the characteristic chromosomal abnor tion of the nascent DNA. ACV is a purine nucleoside analog malities of Burkitt's lymphoma described earlier. The patho with a linear side chain replacing the cyclic Sugar of guanos genesis of these lymphomas involves a deficiency in the ine. GCV differs from ACV in the addition of a hydroxym effector mechanisms needed to control EBV- transformed ethyl group to the side chain. However, ACV and GCV differ cells. The prototypic model for this disease has been the in functional assays. Whereas HSVTK preferentially phos X-linked lymphoproliferative (XLP) syndrome (Purtilo, D. phorylates ACV. EBV-TK preferentially phosphorylates T. et al. 1982 Am. J. Med. 73:49-56). Patients with XLP who GCV. Furthermore, because GCV triphosphate accumulates develop acute infectious mononucleosis exhibit the usual to higher levels and persists for longer periods in infected atypical lymphocytosis and polyclonal elevation of serum cells than ACV, GCV produces more interference with immunoglobulins and increases in specific antibody to VCA cellular DNA synthesis than occurs with ACV. In one study, and to EA. During these infections, patients with XLP fail to selective toxicity of GCV for cells expressing HSV-TK was mount and sustain an anti-EBNA response after acute EBV utilized to promote tumor killing in the CNS. Rapidly infection. The unique Vulnerability of males with XLP to dividing murine glioma cells were infected in Vivo with an EBV infection is most likely due to an inherited immune amphotropic retrovirus containing HSV-TK. Animals were regulatory defect that results in the failure to govern the treated with GCV, which killed TK+ tumor cells, sparing cytotoxic T cells and NK cells required to cope with EBV. adjacent normal cells that replicated too slowly for efficient 0013 The herpes virus family members are capable of infection and viral TK expression. bypassing the butyrate-mediated block, which is probably 0016 EBV-induced lymphomas are associated with due to the role of viral early genes in DNA synthesis, such immunosuppression. Patients with iatrogenic immunodefi as the viral DNA polymerase, DNA-binding protein, and ciencies, such as organ transplant recipients, are also at an helicase genes (Shadan, F. F., et al. 1994.J. Virol. 68:4785 increased risk for lymphomas, and these lymphomas often 96). Butyrate treatment has been reported to result in the contain EBV DNA and EBNA. Also, patients with AIDS are induction of the major CMV major immediate-early protein at a higher risk for developing polyclonal lymphomas asso (IEP) by activating the IEI promoter via cellular factors in a ciated with EBV. EBV-associated lymphoproliferative dis human epithelial thyroid papilloma carcinoma cell line and ease (EBV-LPD) is characterized by actively proliferating in cultured endothelial cells under conditions that are con EBV (+) B-cells, frequently without overt malignant change. ducive to terminal differentiation (Villarreal, L. P. 1991 These immunoblastic lymphoma-like lesions have been Microbiol. Rev. 55.512-42). Similarly, EBV early antigen is identified in a variety of transplant patients, in patients with induced by butyrate in the P3HR-1 cell line, as well as in congenital immunodeficiency, and in patients infected with Raji and NC37 cell lines. These results indicate that butyrate HIV (Cohen, J. I. 1991 Medicine 70: 137-60). These so exerts some of its effects on viral growth at the level of gene called post-transplant lymphoproliferative disorders (PTLD) transcription. This conclusion is also supported by the are observed after all transplants, including kidney, bone observation that butyrate activates the long terminal repeat marrow, heart, liver, and lung transplantation. This increased directed expression of human immunodeficiency virus and incidence of EBV-LPD in this setting is likely due to the induces the Moloney murine sarcoma virus via a putative aggressive immunosuppression required after these trans butyrate response enhancer-promoter element (Bohan, C., et plants. al. 1987 Biochem. Biophys. Res. Commun. 148:899-907; 0017 Although there are case reports of administration of Tang, D.C., et al. 1992 Biochem. Biophys. Res. Commun. inducing agents such as butyrates to patients for the treat 189: 141-47; Yeivin, A., et al. 1992 Gene 116: 159-64). ment of malignancies (Novogrodsky, A., et al. 1983 Cancer Therefore, butyrate appears to be associated with a general 51:9-14; Miller, A. A., et al. 1987 Eur: J. Cancer Clin. induction of early viral proteins. Butyrate has been reported Oncol. 23: 1283-89), as well as of administration of anti to exert additional cytostatic effects such as G2/M blockage viral agents for the treatment of viral disorders, there are no and anti-viral activity against RNA viruses. treatments requiring the administration of both agents and 0014. Unlike other members of the herpes virus family, involving a short course regimen. EBV is resistant to the antiviral agent ganciclovir, because 0018 Thus, there remains a need for effective regimens of low levels of viral thymidine kinase. Acyclovir and for treatment of viral-associated disorders. ganciclovir have also been used to treat AIDS patients, many of whom had an active EBV infection. During treatment, SUMMARY OF THE INVENTION regression of hairy leukoplakia, an EBV disorder, was 0019. In one aspect, the invention is directed to a method inadvertently observed while latent EBV infection was for treating a viral disorder in a Subject, comprising provid unaffected. Additional studies demonstrated that even when ing said Subject with at least one cycle of therapy, said cycle virus production is minimal, expression of many EBV genes of therapy comprising: i) administering to the Subject over a active during the lytic cycle, such as thymidine kinase, can first period an inducing agent to induce expression of a viral be induced. Therefore, exposure of EBV-transformed gene product in a virus-infected cell of the Subject and an B-cells or tumor cells to arginine butyrate induces EBV-TK anti-viral agent whose anti-viral activity is directed to the and renders them sensitive to ganciclovir. viral gene product expressed, wherein said first period of 0015. Like herpes simplex virus (HSV) and varicella time is less than or equal to one-half of the length of the Zoster virus (VZV), EBV encodes a thymidine kinase cycle, and further wherein said inducing agent and said enzyme localized to the BamHI, X fragment of the genome. anti-viral agent are administered in the same or separate In a rate-limiting step, the TK converts nucleoside analogs compositions; and ii) administering said anti-viral agent to to their monophosphate form. Cellular enzymes complete the Subject for a second period, wherein said second period their conversion to biologically-active triphosphates. A viral is the remainder of the cycle. The first wherein period may DNA polymerase preferentially incorporates the toxic be less than or equal to about 5 days, and the second period US 2017/0027944 A9 Feb. 2, 2017

may be at least about 5 days and less than or equal to about therapy comprising: i) administering to the Subject over a 16 days. In various aspects, the method is a method for first period of time a pharmaceutical composition compris killing virus-infected cells in vivo. ing an inducing agent to induce expression of a viral gene 0020. In another embodiment of a method of the inven product in a virus-infected cell of the Subject and an anti tion, the Subject is provided less than or equal to about six viral agent whose anti-viral activity is directed to the viral cycles of therapy. In yet another embodiment of a method of gene product expressed, wherein said first period of time is the invention, the Subject is provided more than or equal to less than or equal to one-half of the length of the cycle; and six cycles of therapy. In still another embodiment of a ii) continuing the administration of the anti-viral agent to the method of the invention, the inducing agent is administered subject for the remainder of the cycle, thus killing the to the subject via continuous infusion over the first period of virus-infected cells in vivo. The administration periods may time, which, in another embodiment, is less than or equal to be about 5 days and about 16 days, for a cycle of about 21 about five days. In still another embodiment of a method of days, in various embodiments. the invention, the inducing agent is administered to the 0026. In another embodiment of a method of the inven subject via once daily infusion over the first period of time, tion, the virus-infected cells are lymphocytes. In still another which, in another embodiment, is less than or equal to about embodiment of a method of the invention, the virus-infected five days. In still another embodiment of a method of the cells contain an integrated or episomal latent virus. In still invention, the inducing agent is administered to the Subject another embodiment of a method of the invention, the at least once over the first period of time, which, in another virus-infected cells contain a herpes virus, a human T cell or embodiment, is less than or equal to about five days. B cell leukemia virus, an adenovirus, or a hepatitis virus. In 0021. In another embodiment of a method of the inven still another embodiment of a method of the invention, the tion, the anti-viral agent is administered intravenously to the herpes virus is an Epstein-Barr virus (EBV) or a Kaposi's- subject about one to about two times per day over the first associated human herpes virus. In still another embodiment period of time of the cycle and orally about one to about two of a method of the invention, the leukemia virus is a human times per day over the remainder of the cycle. In still another immunodeficiency virus (HIV) or a human T-cell leukemia/ embodiment of a method of the invention, the inducing lymphoma virus (HTLV). agent is administered at a dose of about 0.1 to about 2000 0027. In various embodiments, the viral disorder is a mg/kg/day or about 1 to about 100 mg/m/day. In still neoplasia associated with viral infection. Alternatively, the another embodiment of a method of the invention the neoplasia is selected from the group consisting of lym inducing agent is administered at a dose of about 1000 phoma, Hodgkin disease, Burkitts lymphoma, post-trans mg/kg/day. In still another embodiment of a method of the plantation lymphoproliferative disease, viral associated lym invention, the inducing agent is administered at a dose of phoproliferative disease, hemophagocytic syndrome, about 5 mg/m/wk. nasopharyngeal carcinoma, gastric carcinoma, or breast can 0022. In another embodiment of a method of the inven tion, the inducing agent is selected from the group consisting C. of a short-chain fatty acid, a short-chain fatty acid deriva 0028. In various embodiments, the viral disorder is a tive, a histone deacetylase (HDAC) inhibitor, a DNA meth non-malignant viral disorder. yltransferase inhibitor, a proteasome inhibitor, a phorbol 0029. In another embodiment of a method of the inven ester, an oxidized phorbol ester, ceramide, bryostatin, a tion, the viral gene product regulates viral gene expression. cytokine, and combinations thereof. In another aspect, the In yet another embodiment of a method of the invention, the inducing agent is selected from arginine butyrate, PMA viral gene product is a viral enzyme, an oncogene or (phorbol myristate acetate), TSA (trichostatin A), 2,2-dim proto-oncogene, a transcription factor, a protease, a poly ethylbutyrate, panobinostat (LHB589), apicidin, MS-275, merase, a reverse transcriptase, a cell Surface receptor, a and largazole. In yet another embodiment of a method of the structural protein, a major histocompatibility antigen, a invention, the inducing agent is arginine butyrate. growth factor, or a combination thereof. In yet another 0023. In another embodiment of a method of the inven embodiment of a method of the invention, the viral enzyme tion, the anti-viral agent is selected from the group consist is a thymidine or protein kinase. In yet another embodiment ing of an interferon, an amino acid analog, a nucleoside of a method of the invention, the gene product expressed analog, an integrase inhibitor, a protease inhibitor, a poly sensitizes the infected-cells to the anti-viral agent. In various merase inhibitor, and a transcriptase inhibitor. In still another embodiments, induction of gene products that target the cell embodiment of a method of the invention, the anti-viral for destruction by the immune system are excluded such that agent is acyclovir (ACV), ganciclovir (GCV), famcyclovir, the therapeutic action is essentially through the activity of penciclovir, foscarnet, ribavirin, Zalcitabine (ddC), zidovu the anti-viral agent. dine (AZT), stavudine (D4T), larnivudine (3TC), didanosine 0030. In another aspect, the invention provides a method (ddl), cytarabine, dideoxyadenosine, edoxudine, floXuridine, for treating a cellular disorder resulting from and/or asso idoZuridine, inosine pranobex, 2'-deoxy-5-(methylamino) ciated with viral infection in a Subject, comprising providing uridine, trifluridine or Vidarabine. In still another embodi said Subject with at least one cycle of therapy, said cycle of ment of a method of the invention, the anti-viral agent is therapy comprising: i) administering to the Subject over a ganciclovir. first period of time a pharmaceutical composition compris 0024. In another embodiment of a method of the inven ing an activator and an anti-viral agent, wherein the activator tion, the inducing agent and the anti-viral agent are admin is administered in an amount Sufficient to activate expression istered separately. of a latent virus episomal or integrated into proliferating 0025. In another aspect, the invention provides a method cells of the subject, wherein said first period of time is less for killing virus-infected cells in Vivo, comprising providing than or equal to one-half of the length of the cycle; and ii) a subject with at least one cycle of therapy, said cycle of continuing the administration of the anti-viral agent to the US 2017/0027944 A9 Feb. 2, 2017

subject for the remainder of the cycle, thus treating the FIGS. 12A, 12B, 12C, 12D and 12E show cell count results cellular disorder resulting from and/or associated with viral after using various largazole compounds. FIG. 12F shows infection in the subject. fold of TK expression induced from various largazole com 0031. In another aspect, the invention provides a method pounds. for treating an HIV-associated disorder in a Subject, com 004.5 FIG. 13 illustrates results from treatment of an prising providing said Subject with at least one cycle of HIV-1-infected monocyte cell line with combination therapy, said cycle of therapy comprising: i) administering to therapy. Viral release (p24 release) was measured through the Subject over a first period of time: a) an anti-viral agent, optical density (OD) measurement. and b) an inducing agent in an amount Sufficient to induce 0046 FIG. 14 illustrates results from treatment of an expression of a viral gene product selected from the group HIV-1-infected monocyte cell line with combination consisting of EBV-thymidine kinase and HIV reverse tran therapy. Viral release (p24 release) was measured through Scriptase; and ii) continuing the administration of the anti optical density (OD) measurement and then converted into viral agent to the subject for the remainder of the cycle. pg of protein. 0032. Other objects and advantages of the invention are set forth in part in the description of the invention that DETAILED DESCRIPTION OF THE follows and, in part, will be apparent from this description INVENTION or may be learned from the practice of the invention. 0047. As embodied and broadly described herein, the present invention is directed to methods for the treatment BRIEF DESCRIPTION OF THE DRAWINGS and prevention of viral diseases and disorders. It has now 0033 FIGS. 1A-1B illustrate CT scans of tumor reduc been found that the relevant effect of an inducing agent lasts tion after treatment with arginine butyrate (AB) and GCV. long after it has been administered and, even after the FIGS. 1A and 1B show pre- and post-treatment, respectively. inducing agent is no longer detectable in the Subjects 0034 FIGS. 2A-2B illustrate results from toxicity assays plasma. In the currently described treatment regimen, one with anti-herpesvirus drugs ganciclovir (GCV) and penci contemplated dose is 1000 mg/kg/day for 5 days (i.e., 5000 clovir (PCV). FIGS. 2A and 2B show results from various mg/kg) of inducing agent. It is Surprising, for example, in concentrations of GCV and PCV. FIGS. 2C and 2D show virus-associated neoplastic disorders, that the dose of drug results from GCV and PCV used in combination with NaB. and the time span of its administration can be cut down 0035 FIGS. 3A-3B illustrate the results from analysis of dramatically—both the total amount of inducing agent efficacy of anti-virals using short chain fatty acids as induc administered, and the time span over which it is given. ing agents. FIG. 3A shows cell count results after using NaB. 0048. In one aspect, the invention provides methods for FIG. 3B shows results from VA. FIG. 3C shows fold of TK treating virus-associated disorders. The methods comprise expression induced. providing a Subject with at least one cycle of therapy 0036 FIGS. 4A-4B illustrate results from analysis of comprising administering over a first period of time a efficacy of anti-virals using hydroxamic acids as inducing therapeutic agent, such as an anti-viral agent, and an induc agents. FIG. 4A shows cell count results after using scrip ing agent that stimulates the expression of a specific gene, taid. FIG. 4B shows fold of TK expression induced. Such as a virus-associated gene, that renders the infected cell 0037 FIGS. 5A-5B illustrate results from analysis of susceptible to further therapeutic treatment via a therapeutic efficacy of anti-virals using SAHA (Vorinostat) as an induc agent such as an anti-viral agent, and Subsequently, continu ing agent. FIG. 5A shows cell count results after using ing to administer the therapeutic agent for the remainder of SAHA. FIG. 5B shows fold of TK expression induced. the cycle. The inducing agent is administered in a short 0038 FIGS. 6A-6B illustrate results from analysis of course regimen (i.e., over the first period of time less than or efficacy of anti-virals using LHB589 (Panobinostat) as an equal to one half of the length of the cycle of therapy over inducing agent. FIG. 6A shows cell count results after using which the therapeutic agent is given). LHB589. FIG. 6B shows fold of TK expression induced. 0049. The inducing agents may induce expression of 0039 FIG. 7 illustrates results from analysis of efficacy certain viral gene products. Gene products that can be of anti-virals using PXD 101 which induced a high level of induced by agents of the invention include, but are not TK expression at the 5 uM concentration. limited to, viral proteins such as viral thymidine kinase and 0040 FIG. 8 illustrates results from analysis of efficacy the BGLF4 protein kinase of EBV-infected cells. Expression of anti-virals using oXamflatin as an inducing agent. FIG. 8 of these products can be used in the treatment and prevention shows cell count results after using oXamflatin. of viral disorders. 0041 FIG. 9 illustrates results from analysis of efficacy 0050. The therapeutic agents may comprise anti-viral of anti-virals using a cyclic tetrapeptide as an inducing agents that, for example, in combination with certain induc agent. FIG. 9 shows cell count results after using apicidin. ing agents, destroy virus-infected cells. Effective anti-viral 0042 FIGS. 10A-10C illustrate results from analysis of agents that can be used include Substrate analogs such as efficacy of anti-virals using a benzamide (MS-275) as an nucleoside analogs, polymerase inhibitors, and transcriptase inducing agent. FIG. 10A shows cell count results after inhibitors. Cells that demonstrate induced expression or using MS-275. FIG. 10B shows fold of TK expression proliferation are targeted and destroyed. induced. FIG. 10C shows cell count results after treating 0051. Another embodiment of the invention is directed to cells in combination for shorter time periods. a method for destroying, killing or otherwise severely crip 0043 FIGS. 11A-11B illustrate chemical structures of pling virus-infected cells by treating said cells with an largazole compounds used. Shown in both FIGS. 11A and inducing agent, to induce the activity of a gene product, and 11B. an anti-viral agent whose anti-viral activity is directed to the 0044 FIGS. 12A-12F illustrate results from analysis of activity of the gene product induced, over a first period of efficacy of anti-virals using largaZoles as an inducing agent. time less than or equal to one half of the duration of a cycle US 2017/0027944 A9 Feb. 2, 2017 of therapy, followed by treatment with the anti-viral agent acid, Viscous paraffin, perfume oil, fatty acid monoglycer alone over the remainder of the cycle of therapy. The ides and diglycerides, petroethral fatty acid esters, combination portion of the treatment course is, thus, a short hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The course regimen. pharmaceutical compositions of the invention can also be 0052 Preferably, the gene product is a viral enzyme that sterilized and, if desired, mixed with auxiliary agents, e.g., relates to a basic and necessary process of the virus such as lubricants, preservatives, stabilizers, wetting agents, emul virus adsorption, cell penetration, fusion, uncoating, reverse sifiers, salts for influencing osmotic pressure, buffers, col transcription, integration, DNA replication, viral interfer orings, flavorings and/or aromatic Substances and the like, ence, viral transcription, the Switch from early to late which do not deleteriously react with the active compounds expression, the latent or lytic phases, the Switch from a latent of the invention. to lytic phase, defective-interfering particle production, 0057 The term “subject” as used herein refers to a virus assembly, capsid packaging, the generation of virus vertebrate, preferably a mammal, more preferably a primate, specific membrane, virus budding and virus secretion. The still more preferably a human. Mammals include, without activity of one or more of these processes may be enhanced limitation, humans, primates, wild animals, feral animals, by one or more of the inducing agents, and the enhanced farm animals, sports animals, and pets. activity is then targeted by one or more anti-viral agents. The 0058. The term “obtaining” as in “obtaining the compo combination treatment as part of the cycle of therapy is more sition' is intended to include purchasing, synthesizing, or effective than conventional treatment with anti-viral agents otherwise acquiring the composition (or agent(s) of the alone or simply allows for the administration of therapeu composition). tically effective amounts of the anti-viral agent that are less 0059. The terms “comprises”, “comprising, are intended than what would be considered effective with conventional to have the broad meaning ascribed to them and can mean treatment regimens. “includes”, “including and the like. 0053 Another embodiment of the invention is directed to 0060. The invention can be understood more fully by a method for treating a viral disorder in a patient comprised reference to the following detailed description and illustra of administering an activator and an anti-viral agent to the tive examples, which are intended to exemplify non-limiting patient, wherein the activator is administered in an amount embodiments of the invention. Sufficient to activate expression of a latent virus integrated into proliferating cells of the patient. The treatment regimen B. VIRUSES AND VIRAL (INCLUDING is as described above for the methods of the invention. VIRUS-ASSOCIATED) DISORDERS Useful activators include phorbol ester, an oxidized phorbol ester, ceramide, bryostatin, an inducing agent, or a combi 0061 The methods and compositions of the provided nation thereof. The activator should be administered in an invention can be used to treat and/or prevent viral infections. The virus causing the infection can be a member of the amount Sufficient to activate, for example, protein kinase C, herpes virus family, a human immunodeficiency virus, par an oncogene, a thymidine kinase or other viral kinases, vovirus, or coxsackie virus. A member of the herpes virus AP-1, AP-2, Sp-1 or NF-KB. family can be herpes simplex virus, herpes genitalis virus, varicella Zoster virus, Epstein-Barr virus, human herpesvirus A. DEFINITIONS 6, or cytomegalovirus. 0054. The terms “viral and “virus-associated with ref 0062. The methods and compositions described herein erence to disorders are used interchangeably throughout the can be used to treat and/or prevent infections caused by any instant specification. virus, including, for example, Abelson leukemia virus, Abel 0055. The term “treating, as used herein, refers to alter son murine leukemia virus, Abelson's virus, Acute laryn ing the disease course of the Subject being treated. Thera gotracheobronchitis virus, Adelaide River virus, Adeno peutic effects of treatment include, without limitation, pre associated virus group, Adenovirus, African horse sickness venting occurrence or recurrence of disease, alleviation of virus, African swine fever virus, AIDS virus, Aleutian mink symptom(s), diminishment of direct or indirect pathological disease parvovirus, Alpharetrovirus, Alphavirus, ALV consequences of the disease, decreasing the rate of disease related virus, Amapari virus, Aphthovirus, Aquareovirus, progression, amelioration or palliation of the disease state, Arbovirus, Arbovirus C. arbovirus group A, arbovirus group and remission or improved prognosis. B, Arenavirus group, Argentine hemorrhagic fever virus, 0056. The term “pharmaceutically acceptable excipient', Argentine hemorrhagic fever virus, Arterivirus, Astrovirus, as used herein, refers to carriers and vehicles that are Ateline herpesvirus group, Aujezky's disease virus, Aura compatible with the active ingredient (for example, a com virus, Ausduk disease virus, Australian bat lyssavirus, Avia pound of the invention) of a pharmaceutical composition of denovirus, avian erythroblastosis virus, avian infectious the invention (and preferably capable of stabilizing it) and bronchitis virus, avian leukemia virus, avian leukosis virus, not deleterious to the subject to be treated. For example, avian lymphomatosis virus, avian myeloblastosis virus, solubilizing agents that form specific, more soluble com avian paramyxovirus, avian pneumoencephalitis virus, avian plexes with the compounds of the invention can be utilized reticuloendotheliosis virus, avian sarcoma virus, avian type as pharmaceutical excipients for delivery of the compounds. C retrovirus group, Avihepadnavirus, Avipoxvirus, B virus, Suitable carriers and vehicles are known to those of extraor B 19 virus, Babanki virus, baboon herpesvirus, baculovirus, dinary skill in the art. The term “excipient’ as used herein Barmah Forest virus, Bebaru virus, Berrimah virus, Betaret will encompass all Such carriers, adjuvants, diluents, Sol rovirus, Birnavirus, Bittner virus, BK virus, Black Creek vents, or other inactive additives. Suitable pharmaceutically Canal virus, bluetongue virus, Bolivian hemorrhagic fever acceptable excipients include, but are not limited to, water, virus, Boma disease virus, border disease of sheep virus, salt Solutions, alcohol, vegetable oils, polyethylene glycols, borna virus, bovine alphaherpesvirus 1, bovine alphaherpes gelatin, lactose, amylose, magnesium Stearate, talc, silicic virus 2, bovine coronavirus, bovine ephemeral fever virus, US 2017/0027944 A9 Feb. 2, 2017 bovine immunodeficiency virus, bovine leukemia virus, D virus, hepatitis delta virus, hepatitis E virus, hepatitis F bovine leukosis virus, bovine mammillitis virus, bovine virus, hepatitis G. virus, hepatitis nonA nonB virus, hepatitis papillomavirus, bovine papular stomatitis virus, bovine par virus, hepatitis virus (nonhuman), hepatoencephalomyelitis vovirus, bovine syncytial virus, bovine type C oncovirus, reovirus 3, Hepatovirus, heron hepatitis B virus, herpes B bovine viral diarrhea virus, Buggy Creek virus, bullet virus, herpes simplex virus, herpes simplex virus 1, herpes shaped virus group, Bunyamwera virus Supergroup, Bunya simplex virus 2, herpesvirus, herpesvirus 7. Herpesvirus virus, Burkitt's lymphoma virus, Bwamba Fever, CA virus, ateles, Herpesvirus hominis, Herpesvirus infection, Herpes Calicivirus, California encephalitis virus, camelpox virus, virus Saimiri. Herpesvirus Suis, Herpesvirus varicellae, canarypox virus, canid herpesvirus, canine coronavirus, Highlands J virus, Hirame rhabdovirus, hog cholera virus, canine distemper virus, canine herpesvirus, canine minute human adenovirus 2, human alphaherpesvirus 1, human virus, canine parvovirus, Cano Delgadito virus, caprine alphaherpesvirus 2, human alphaherpesvirus 3, human B arthritis virus, caprine encephalitis virus, Caprine Herpes lymphotropic virus, human betaherpesvirus 5, human coro Virus, Capripox virus, Cardiovirus, cavid herpesvirus 1, navirus, human cytomegalovirus group, human foamy virus, Cercopithecid herpesvirus 1, cercopithecine herpesvirus 1. human gammaherpesvirus 4, human gammaherpesvirus 6. Cercopithecine herpesvirus 2, Chandipura virus, human hepatitis A virus, human herpesvirus 1 group, human Changuinola virus, channel catfish virus, Charleville virus, herpesvirus 2 group, human herpesvirus 3 group, human chickenpox virus, Chikungunya virus, chimpanzee herpes herpesvirus 4 group, human herpesvirus 6, human herpes virus, chub reovirus, chum salmon virus, Cocal virus, Coho virus 8, human immunodeficiency virus, human immuno salmon reovirus, coital exanthema virus, Colorado tick fever deficiency virus 1, human immunodeficiency virus 2, human virus, Coltivirus, Columbia SK virus, common cold virus, papillomavirus, human T cell leukemia virus, human T cell contagious ecthyma virus, contagious pustular dermatitis leukemia virus I, human T cell leukemia virus II, human T virus, Coronavirus, Corriparta virus, coryza virus, cowpox cell leukemia virus III, human T cell lymphoma virus I, virus, coxsackie virus, CPV (cytoplasmic polyhedrosis human T cell lymphoma virus II, human T cell lymphotropic virus), cricket paralysis virus, Crimean-Congo hemorrhagic virus type 1, human T cell lymphotropic virus type 2, human fever virus, croup associated virus, Cryptovirus, Cypovirus, T lymphotropic virus I, human T lymphotropic virus II, Cytomegalovirus, cytomegalovirus group, cytoplasmic human T lymphotropic virus III, Ichnovirus, infantile gas polyhedrosis virus, deer papillomavirus, deltaretrovirus, troenteritis virus, infectious bovine rhinotracheitis virus, dengue virus, Densovirus, Dependovirus, Dhori virus, infectious haematopoietic necrosis virus, infectious pancre diploma virus, Drosophila C virus, duck hepatitis B virus, atic necrosis virus, influenza virus A, influenza virus B, duck hepatitis virus 1, duck hepatitis virus 2, duovirus, influenza virus C, influenza virus D, influenza virus pr8, Duvenhage virus, Deformed wing virus DWV, eastern insect iridescent virus, insect virus, iridovirus, Japanese B equine encephalitis virus, eastern equine encephalomyelitis virus, Japanese encephalitis virus, JC virus, Junin virus, virus, EB virus, Ebola virus, Ebola-like virus, echo virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo virus, echovirus, echovirus 10, echovirus 28, echovirus 9, ectrome Kilham's rat virus, Klamath virus, Kolongo virus, Korean lia virus, EEE virus, EIA virus, EIA virus, encephalitis virus, hemorrhagic fever virus, kumba virus, Kysanur forest dis encephalomyocarditis group virus, encephalomyocarditis ease virus, Kyzylagach virus, La Crosse virus, lactic dehy virus, Enterovirus, enzyme elevating virus, enzyme elevat drogenase elevating virus, lactic dehydrogenase virus, ing virus (LDH), epidemic hemorrhagic fever virus, Lagos bat virus, Langur virus, lapine parvovirus, Lassa fever epizootic hemorrhagic disease virus, Epstein-Barr virus, virus, Lassa virus, latent rat virus, LCM virus, Leaky virus, equid alphaherpesvirus 1, equid alphaherpesvirus 4, equid Lentivirus, Leporipoxvirus, leukemia virus, leukovirus, herpesvirus 2, equine abortion virus, equine arteritis virus, lumpy skin disease virus, lymphadenopathy associated equine encephalosis virus, equine infectious anemia virus, virus, Lymphocryptovirus, lymphocytic choriomeningitis equine morbillivirus, equine rhinopneumonitis virus, equine virus, lymphoproliferative virus group, Machupo virus, mad rhinovirus, Eubenangu virus, European elk papillomavirus, itch virus, mammalian type B oncovirus group, mammalian European Swine fever virus, Everglades virus, Eyach virus, type B retroviruses, mammalian type C retrovirus group, felid herpesvirus 1, feline calicivirus, feline fibrosarcoma mammalian type D retroviruses, mammary tumor virus, virus, feline herpesvirus, feline immunodeficiency virus, Mapuera virus, Marburg virus, Marburg-like virus, Mason feline infectious peritonitis virus, feline leukemia/sarcoma Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME virus, feline leukemia virus, feline panleukopenia virus, virus, measles virus, Menangle virus, Mengo virus, Men feline parvovirus, feline sarcoma virus, feline syncytial govirus, Middelburg virus, milkers nodule virus, mink virus, Filovirus, Flanders virus, Flavivirus, foot and mouth enteritis virus, minute virus of mice, MLV related virus, MM disease virus, Fort Morgan virus, Four Corners hantavirus, virus, Mokola virus, Molluscipoxvirus, Molluscum conta fowl adenovirus 1, fowlpox virus, Friend virus, Gammaret giosum virus, monkey B virus, monkeypox virus, Monon rovirus, GB hepatitis virus, GB virus, German measles virus, egavirales, Morbillivirus, Mount Elgon bat virus, mouse Getah virus, gibbon ape leukemia virus, glandular fever cytomegalovirus, mouse encephalomyelitis virus, mouse virus, goatpox virus, golden shinner virus, Gonometa virus, hepatitis virus, mouse K virus, mouse leukemia virus, mouse goose parvovirus, granulosis virus, Gross virus, ground mammary tumor virus, mouse minute virus, mouse pneu squirrel hepatitis B virus, group A arbovirus, Guanarito monia virus, mouse poliomyelitis virus, mouse polyomavi Virus, guinea pig cytomegalovirus, guinea pig type C virus, rus, mouse sarcoma virus, mousepox virus, Mozambique Hantaan virus, Hantavirus, hard clam reovirus, hare fibroma virus, Mucambo virus, mucosal disease virus, mumps virus, virus, HCMV (human cytomegalovirus), hemadsorption murid betaherpesvirus 1, murid cytomegalovirus 2, murine virus 2, hemagglutinating virus of Japan, hemorrhagic fever cytomegalovirus group, murine encephalomyelitis virus, virus, hendra virus, Henipaviruses, Hepadnavirus, hepatitis murine hepatitis virus, murine leukemia virus, murine nod A virus, hepatitis B virus group, hepatitis C virus, hepatitis ule inducing virus, murine polyomavirus, murine sarcoma US 2017/0027944 A9 Feb. 2, 2017 virus, Muromegalovirus, Murray Valley encephalitis virus, virus, Tench reovirus, Theiler's encephalomyelitis virus, myxoma virus, Myxovirus, Myxovirus multiforme, Myxo Theiler's virus, Thogoto virus, Thottapalayam virus, Tick virus parotitidis, Nairobi sheep disease virus, Nairovirus, borne encephalitis virus, Tioman virus, Togavirus, Torovi Nanirnavirus, Nariva virus, Ndumo virus, Neethling virus, rus, tumor virus, Tupaia virus, turkey rhinotracheitis virus, Nelson Bay virus, neurotropic virus, New World Arenavirus, turkeypox virus, type C retroviruses, type D oncovirus, type newborn pneumonitis virus, Newcastle disease virus, Nipah D retrovirus group, ulcerative disease rhabdovirus, Una virus, noncytopathogenic virus, Norwalk virus, nuclear virus, Uukuniemi virus group, Vaccinia virus, vacuolating polyhedrosis virus (NPV), nipple neck virus, virus, varicella Zoster virus, Varicellovirus, Varicola virus, Onyongnyong virus, Ockelbo virus, oncogenic virus, variola major virus, variola virus, Vasin Gishu disease virus, oncogenic viruslike particle, oncornavirus, Orbivirus, Orf VEE virus, Venezuelan equine encephalitis virus, Venezu virus, Oropouche virus, Orthohepadnavirus, Orthomyxovii elan equine encephalomyelitis virus, Venezuelan hemor rus, Orthopoxvirus, Orthoreovirus, Orungo, ovine papillo rhagic fever virus, Vesicular stomatitis virus, Vesiculovirus, mavirus, Ovine catarrhal fever virus, owl monkey herpesvi Vilyuisk virus, Viper retrovirus, viral haemorrhagic septice rus, Palyam virus, Papillomavirus, Papillomavirus Sylvilagi, mia virus, Visna Maedi virus, Visna virus, volepox virus, Papovavirus, parainfluenza virus, parainfluenza virus type 1, VSV (vesicular stomatitis virus), Wallal virus, Warrego parainfluenza virus type 2, parainfluenza virus type 3. virus, wart virus, WEE virus, West Nile virus, western parainfluenza virus type 4, Paramyxovirus, Parapoxvirus, equine encephalitis virus, western equine encephalomyelitis paravaccinia virus, Parvovirus, Parvovirus B19, parvovirus virus, Whataroa virus, Winter Vomiting Virus, woodchuck group, Pestivirus, Phlebovirus, phocine distemper virus, hepatitis B virus, woolly monkey sarcoma virus, wound Picodnavirus, Picornavirus, pig cytomegalovirus-pigeonpox tumor virus, WRSV virus, Yaba monkey tumor virus, Yaba virus, Piry virus, Pixuna virus, pneumonia virus of mice, virus, Yatapoxvirus, yellow fever virus, and the Yug Bog Pneumovirus, poliomyelitis virus, poliovirus, Polydnavirus, danovac virus. polyhedral virus, polyoma virus, Polyomavirus, Polyoma 0063 Types of virus infections and related disorders that virus bovis, Polyomavirus cercopitheci, Polyomavirus can be treated include, for example, infections due to the hominis 2, Polyomavirus maccacae 1, Polyomavirus muris herpes family of viruses such as EBV, CMV, HSV I, HSV II, 1, Polyomavirus muris 2, Polyomavirus papionis 1, Polyo VZV and Kaposis-associated human herpes virus (type 8), mavirus papionis 2, Polyomavirus Sylvilagi, Pongine her human T cell or B cell leukemia and lymphoma viruses, pesvirus 1, porcine epidemic diarrhea virus, porcine hemag adenovirus infections, hepatitis virus infections, pox virus glutinating encephalomyelitis virus, porcine parvovirus, infections, papilloma virus infections, polyoma virus infec porcine transmissible gastroenteritis virus, porcine type C tions, infections due to retroviruses such as the HTLV and virus, pox virus, poxvirus, poxvirus variolae, Prospect Hill HIV viruses, and infections that lead to cellular disorders virus, Provirus, pseudocowpox virus, pseudorabies virus, resulting from and/or associated with viral infection Such as, psittacinepox virus, quailpox virus, rabbit fibroma virus, for example, Burkitt's lymphoma, EBV-induced malignan rabbit kidney vaculolating virus, rabbit papillomavirus, cies, T and B cell lymhoproliferative disorders and leuke rabies virus, raccoon parvovirus, raccoonpox virus, Ran mias, and other viral-induced malignancies. Other neopla ikhet virus, rat cytomegalovirus, rat parvovirus, rat virus, sias that can be treated include virus-induced tumors, Rauscher's virus, recombinant vaccinia virus, recombinant malignancies, cancers, or diseases that result in a relatively virus, reovirus, reovirus 1, reovirus 2, reovirus 3, reptilian autonomous growth of cells. Neoplastic disorders include type C virus, respiratory infection virus, respiratory syncy leukemias, lymphomas, sarcomas, carcinomas Such as a tial virus, respiratory virus, reticuloendotheliosis virus, squamous cell carcinoma, a neural cell tumor, seminomas, Rhabdovirus, Rhabdovirus carpia, Rhadinovirus, Rhinovi melanomas, germ cell tumors, undifferentiated tumors, neu rus, Rhizidiovirus, Rift Valley fever virus, Riley's virus, roblastomas (which are also considered carcinomas by rinderpest virus, RNA tumor virus, Ross River virus, Rota Some), mixed cell tumors, or other malignancies. Neoplastic virus, rougeole virus, Rous sarcoma virus, rubella virus, disorders prophylactically or therapeutically treatable with rubeola virus, Rubivirus, Russian autumn encephalitis virus, compositions of the invention include Small cell lung can SA 11 simian virus, SA2 virus, Sabia virus, Sagiyama virus, cers and other lung cancers, rhabdomyosarcomas, chorio Saimirine herpesvirus 1, salivary gland virus, Sandfly fever carcinomas, glioblastoma multiformas (brain tumors), virus group, Sandjimba virus, SARS virus, SDAV (sialo bowel and gastric carcinomas, leukemias, ovarian cancers, dacryoadenitis virus), sealpox virus, Semliki Forest Virus, prostate cancers, osteosarcomas, or cancers that have metas Seoul virus, sheeppox virus, Shope fibroma virus, Shope tasized. Diseases of the immune system that are treatable papilloma virus, simian foamy virus, simian hepatitis A include Hodgkins’ disease, the non-Hodgkin’s lymphomas virus, simian human immunodeficiency virus, simian immu including the follicular and nodular lymphomas, adult T and nodeficiency virus, simian parainfluenza virus, simian T cell B cell and NK lymphoproliferative disorders such as leu lymphotrophic virus, simian virus, simian virus 40, Sim kemias and lymphomas (benign and malignant), hairy-cell plexvirus, Sin Nombre virus, Sindbis virus, smallpox virus, leukemia, hairy leukoplakia, acute myelogenous, lympho South American hemorrhagic fever viruses, sparrowpox blastic or other leukemias, chronic myelogenous leukemia, virus, Spumavirus, Squirrel fibroma virus, Squirrel monkey and myelodysplastic syndromes. Additional diseases that retrovirus, SSV 1 virus group, STLV (simian T lymphotropic can be treated or prevented include breast cell carcinomas, virus) type I, STLV (simian T lymphotropic virus) type II, melanomas and hematologic melanomas, ovarian cancers, STLV (simian T lymphotropic virus) type III, stomatitis pancreatic cancers, liver cancers, stomach cancers, colon papulosa virus, Submaxillary virus, Suid alphaherpesvirus 1. cancers, bone cancers, squamous cell carcinomas, neurofi Suid herpesvirus 2, Suipoxvirus, Swamp fever virus, Swine bromas, testicular cell carcinomas, kidney and bladder can pox virus, Swiss mouse leukemia virus, TAC virus, Tacaribe cers, cancer and benign tumors of the nervous system, and complex virus, Tacaribe virus, Tanapox virus, Taterapox adenocarcinomas. US 2017/0027944 A9 Feb. 2, 2017

0064. An embodiment of the invention is directed to 0069. Additional anti-neoplastic activities include the methods for the treatment of a patient with a viral infection ability to regulate the cell cycle, for example, by affecting or a virus-associated neoplastic disorder comprising the time in and passage through S phase, Mphase, G phase or administration of an inducing agent and an anti-viral agent Gd phase, the ability to increase intracellular cAMP levels, according to a method of the invention. Treatable infectious the ability to inhibit or stimulate histone acetylation, the diseases include viral infections caused by, without limita ability to methylate nucleic acids, and the ability to maintain tion, a hepatitis virus, a retrovirus such as HIV or HTLV, an or increase intracellular concentrations of anti-neoplastic influenza virus, a papilloma virus, a herpes virus (HSV I, agents. The neoplastic disorder may be any disease or HSV II, EBV), a polyoma virus, paramyxovirus, or corona malady that could be characterized as a neoplasm, a tumor, virus, or a “slow viral disease' such as disease caused by a malignancy, a cancer, or a disease that results in a lentiviruses, measles virus (Subacute Sclerosing panencepha relatively autonomous growth of cells. Neoplastic disorders litis), and transmissible spongiform encephalopathies. prophylactically or therapeutically treatable via the methods 0065 Viruses may exist in infected cells as autonomous of the invention include Small cell lung cancers and other particles or be integrated, as, for example, in latent infec lung cancers, rhabdomyosarcomas, choriocarcinomas, glio tions. Latent infections may be periodic, such as HSV-I and blastoma multiformas (brain tumors), bowel and gastric II or be continuously productive of virus or virus products, carcinomas, leukemias, ovarian cancers, prostate cancers, though at fairly low levels. Infections may also be lytic, with osteosarcomas, or cancers that have metastasized. Diseases infectious particles secreted or otherwise extruded or of the immune system that are treatable carrying out the expelled (virus burst) from cells. Infections may also be of methods of the invention include Hodgkins' lymphomas and parts of a virus Such as, for example, by viral genes or by the non-Hodgkin’s lymphomas including the follicular lym defective-interfering particles that are incapable of produc phomas, nodular lymphomas, T- and NK-lymphomas, tive replication on their own, but may be capable of causing Burkitt's lymphoma, adult T-cell leukemias and lymphomas, disease. hairy-cell leukemia, acute myelogenous, lymphoblastic, or 0066 Cells that can be treated include any cell that other leukemias, chronic myelogenous leukemia, and becomes infected with a virus or a part of a virus and, myelodysplastic syndromes. Additional diseases treatable preferably, infected by integration. Such cells include cells by the compositions include virally-induced cancers of the hematopoietic system, such as lymphocytes, erythro wherein the viral agent is EBV, HPV. HIV. CMV, HTLV-1 or cytes and mylocytes, neural cells, and neural-supporting HBV, breast cell carcinomas, melanomas and hematologic cells, cells of the digestive system, cells of the epithelial melanomas, ovarian cancers, pancreatic cancers, liver can system. Cells that contain integrated viral genomes or only cers, stomach cancers, colon cancers, bone cancers, parts of viral genomes may also be effectively treated. squamous cell carcinomas, neurofibromas, testicular cell 0067. Anti-neoplastic activity includes cytotoxic (tumor carcinomas, kidney and bladder cancers, tumors of the cell death) activity, but also includes, for example, the ability nervous system, and adenocarcinomas. to induce the differentiation of transformed cells including cells that comprise neoplasm due to infection (e.g. viral C.. INDUCING AGENTS infections such as a human papilloma virus, herpes viruses including Herpes Simplex virus type I or II or Epstein-Barr 0070 Inducing agents administered according to meth virus, a hepatitis virus, a human T cell leukemia virus ods of the invention include, without limitation, short-chain (HTLV) or another retrovirus), and other malignancies. fatty acid (SCFA) derivatives, histone deacetylase (HDAC) Upon differentiation, these cells lose their aggressive nature, inhibitors, phorbol esters, and cytokines. Thus, inducing no longer metastasize, are no longer proliferating, and agents administered according to methods of the invention eventually die and/or are removed by the T cells, natural include SCFA derivatives, for example, without limitation, killer cells, and macrophages of the patient’s immune sys chemicals of the structure R-R-R or, preferably, tem R—C(O)— R. R. wherein R is CH, H, NH, OH, 0068. The process of cellular differentiation is stimulated SH, COH CONH, COOH or COSH: R is CH or a or turned on by, for example, the stimulation and/or inhibi branched or linear alkyl chain; R is CONH COSH, tion of gene specific transcription. Certain gene products are COOH, COOR COR or OR; R is CH, H, NH, OH, directly involved in cellular differentiation and can trans SH or a branched or linear alkyl chain; phenyl-Rs Re form an actively dividing cell into a cell that has lost or has R7, wherein phenyl is a six carbon benzyl ring or a hydro a decreased ability to proliferate. An associated change of genated, hydroxylated or halogenated six carbon ring; Rs is the pattern of cellular gene expression can be observed. To CH, NH, OH, or SH: R is CH, NH, OH, SH, or a control this process includes the ability to reverse a malig branched or linear alkyl chain; R, is CH, H, NH, OH, nancy. Genes whose transcriptional regulation are altered in SH, CONH, COOH, COSH, COOR COR or ORs: R, the presence of compositions described herein include the is CH, H, NH, OH, SH, or a branched or linear alkyl oncogenes myc, ras, my b, jun, fos, abl, and Src. The activi chain; and phenyl-Ro Rio wherein Ro, is CH, NH, OH, ties of these gene products, as well as the activities of other SH, or a branched or linear alkyl chain; R is CH, H, NH, oncogenes, are described in Slamon, J. D., et al. 1984 OH, SH, CONH COOH, COSH COOR, CUR, or Science 224:256-62. Another example of anti-neoplastic OR; and R is CH, H, NH, OH, SH, or a branched or activity includes the ability to regulate the life cycle of the linear alkyl chain; wherein X is 0, 1, 2 or 3. Preferably, R cell, the ability to repress angiogenesis or tissue regeneration comprises between 1 to 8 carbon atoms and more preferably through the blockade or Suppression of factor activity, 1, 2, 3 or 4 carbon atoms. Preferably, R comprises between production or release, the ability to regulate transcription or 1 to 8 carbon atoms and more preferably 1, 2, 3 or 4 carbon translation, or the ability to modulate transcription of genes atoms. Preferably, Rs comprises between 1 to 8 carbon under angiogenesis, growth factor or hormonal control. atoms and more preferably 1, 2, 3 or 4 carbon atoms. US 2017/0027944 A9 Feb. 2, 2017

0071 Examples of chemical compounds of the structure acetic acid, 4-chloro-2-phenoxy 2-propionic acid, 2- or R—R. R. or R—C(O)—R. R. include acids, amines, 3-phenoxybutyric acid, phenyl acetic acid, phenylpropionic monoamides and diamides of butyric acid (HC CH2— acid, 3-phenyl butyric acid, ethyl-phenyl acetic acid, CH, COOH), butyric acid ethyl ester 4-chloro-2-phenoxy-2-propionic acid, n-dimethyl butyric (CHCH2CH2COCHCH), 4,4,4-trifluorobutyric acid acid glycine amide, o-benzoyl lactic acid, o-dimethylbutyric (CFCHCHCOOH), 2,2-diethylbutyric acid,3,3-dimethyl acid lactate, cinnamic acid, dihydrocinnamic acid butyric acid (CHO), 3.3-diethyl butyric acid, fumaric (CHCHCHCOOH), a-methyl-dihydrocinnamic acid, acid (HOOCCH=CHCOOH), fumaric acid monomethyl thiophenoxy acetic acid, and amines, amides and salts of and monoethyl ester, fumaric acid monoamide (CHON). these chemicals. fumaramide (HNCOCHCHCONH), succinic acid 0075 Inducing agents include retinoic acid, retinol, cyto (HOOCCHCHCOOH) (succinamic acid and succina sine arabinoside, phorbols such as the phorbol diester 12-0- mide), 2,3-dimethyl Succinic acid and methoxyacetic acid tetradecanoylphorbol 13-acetate (TPA), teleocidine B. (CHCHOCH). indole alkaloids, cytotoxin, plant lectins from Streptomyces, 0072 Examples of chemical compounds of the structure glucocorticoids such as estrogen and progesterone, phyto phenyl-Rs—R R, include acids, amines and amides of hemagglutinin (PHA), bryostatin, growth factors (e.g. phenoxyacetic acid (CHOCHCOOH: PDGF, VEGF, EGF, FGF, NGF, TGF, BCGF), anti-sense CHOCH2COONH), 2- and 3-thiophenoxy propionic acid nucleic acids (e.g. DNA, RNA or PNA), aptamers (nucleic (CHSCH(CH)COOH: CHSCH-CHCOOH), 2- and acid oligonucleotides with secondary or tertiary structures 3-phenoxy propionic acid (CHOCH(CH)COOH: which bind with high affinity and selectivity to a target CHOCH2CHCOOH), 2- and 3-phenyl propionic acid molecule), erythropoietin (EPO), the interleukins (IL-1, (CH-CH(CH)COOH, CHCH-CHCOOH), 4-chloro IL-2, IL-3, etc.). cAMP and cAMP analogs such as dibutyrl phenoxy-2-propionic acid (ClCOCH2CH2COH), methoxy cAMP, activin, inhibin, steel factor, interferon, the bone acetic acid (HCOCHCO2H), and 2-thiophenoxy acetic morphogenic proteins (BMBs), hydroxyurea and dimethyl acid (CHSCHCOOH). sulfoxide (DMSO). Other inducing agents include interfer 0073. Examples of chemical compounds of the structure ons (e.g. Cl-, 3-, y-interferon), cytokines such as tumor phenyl-Ro Ro include acids, amines and amides of cin necrosis factor (TNF), cell receptors, and growth factor namic acid (CH-CH=CHCOOH), hydrocinnamic acid, antagonists, which may be purified or recombinantly pro dihydro cinnamic acid (CHCH-CHCOOH), a-methyl duced. hydrocinnamic acid or dihydrocinnamic acid, 2,3-dimethyl 0076 Inducing agents administered according to the hydrocinnamic or dihydrocinnamic acid, phenyl acetate methods of the invention include histone deacetylase ethyl ester (CHCHCCH)CHCOCHCH), 2-phenoxy (HDAC) inhibitors (including those of the hydroxamic acid propionic acid (CHOCH2COH), phenoxy acetic acid class and the benzamide class), DNA methyltransferase (CH-CH(OCHs)COH), and 3-phenyl butyric acid inhibitors, and proteasome inhibitors. HDAC inhibitors, a (CH3CH(CH)CHCOOH). Additional chemical com class of compounds that interfere with the function of pounds which may or may not be included in the above histone deacetylase, include, without limitation, short-chain classification scheme include monobutyrin, tributyrin (CH fatty acids (butyrate, phenylbutyrate, valproate, AN-9, etc., (OCOCHCHCH)CH(OCOCHCHCH)CH, as described above), hydroxamic acids (for example m-car (OCOCHCHCH), ethyl-phenyl acetic acid boxycinnamic acid, bishydroxamic acid, Suberic bishy (CHCHCH-CHCOOH), indol-3-propionic acid, indol droxamic acid, Trichostatin A (7-4-(dimethylamino)phe 3-butyric acid, 1- and 2-methyl cyclopropane carboxylic nyl-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide), acid (CHO and CHO), mercaptoacetic acid SAHA(suberoylanilide hydroxamic acid)/Vorinostat, oxam (CHAOS), N-acetylglycine (CHON), squaric acid flatin, ABHA, SB-55629, pyroxamide, propenamides, aroyl (CHO), 4-trifluorobutanol (CH4OF), chloropropionic pyrrolyl hydroxamides, Belinostat/PXD101, Papobinostat, acid (ClCH-CHCO2H), 3-trimethyl silyl-1-proposulfonic LAQ824 (((E)-N-hydroxy-3-4-2-hydroxyethyl-2-(1H acid sodium (CHOSS), 2-oxopantansane (CHO), indol-3-yl)ethylaminomethylphenylprop-2-enamide), isobutyl hydroxylamine HCl (CHOCl), 2-methyl LBH589, TSA), Pivanex, spiruchostatins, cyclic tetrapep butanoic acid (CHO), o-benzoyl lactate, n-dimethylbu tides (for example, trapoxin A (cyclo(S)-phenylalanyl-(S)- tyric acid glycine amide, o-dimethylbutyric acid lactate, and phenylalanyl-(R)-pipecolinyl-(2S,9S)-2-amino-8-oxo-9,10 diethylbutyric acid. epoxydecanoyl).), trapoxin B (cyclo(S)-phenylalanyl 0.074 Inducing agents useful in pharmaceutical compo phenylalanyl-(R)-prolyl-2-amino-8-oxo-9,10 sitions for the treatment of virus-associated disorders epoxydecanoyl)), HC-toxin, chlamydocin, diheteropeptin, include, without limitation, propionic acid, butyric acid, WF-3161, Cyl-1, Cyl-2, azumamide A), cyclic peptides (for Succinic acid, fumaric acid monoethyl ester, trifluorobutanol example, FK-228, FR901228), depsipeptides (for example, (CH4OF), chloropropionic acid (ClCH-CHCOOH), iso romidepsin, FK228 (E)-(1S,4S,10S.21R)-7(Z)-ethyl propionic acid, 2-oxypentasane (CHCH2CHC(O)COOH), ideno-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,2023-tet 2.2- or 3.3-dimethyl butyric acid (CHO), 2.2- or 3.3- raazabicyclo8,7,6-tricos-16-ene-3,6,9.22-pentanone), diethyl butyric acid (CHO), butyric acid ethyl ester, FK228 analogs and derivatives, largazole, largazole analogs 2-methylbutanoic acid (CHO), fumaric acid (CHO) and derivatives), peptide antibiotics (apicidin), benzamides and amides and salts thereof. Other examples include (MS275 (3-pyridinylmethyl-4-(2-aminophenyl)amino methoxyacetic acid (HC(O)CHCOOH), methoxy propi carbonylphenylmethylcarbamate, N-(2-Aminophenyl)-4- onic acid, N-acetylglycine (HCC(O)NCHCOOH), mer N-(pyridine-3ylmethoxycarbonyl)aminomethylbenz captoacetic acid (HSCHCOOH), 1- or 2-methyl cyclopro amide), CI994 (4-(Acetylamino)-N-(2-aminophenyl) pane carboxylic acid (CHO), squaric acid (CHO), 2- or benzamide), MGCD0103), electrophilic ketones (TPX, 3-phenoxy propionic acid, methoxybutyric acid, phenoxy AOR, Depudecin), aliphatic acid compounds (for example, US 2017/0027944 A9 Feb. 2, 2017 butyrate, phenylbutyrate, valproic acid), FR901375, nicoti 0080 Chemical compounds are preferably optically pure namide, NAD derivatives, Sirtinol, splitomycin, dihydro with a specific conformation (plus {+} or minus {-}). coumarin, naphthopyranone, 2-hydroxynaphthaldehydes, absolute configuration (R or S), or relative configuration (D PCYC-0402, PCYC-0403, PCI-24781 (3-(dimethylamin or L). Particular salts such as Sodium, potassium, magne omethyl)-N-2-4-(hydroxycarbamoyl)phenoxyethyl)-1- sium, calcium, choline, amino acid, ammonium or lithium, benzofuran-2-carboxamide), depudecin, tubacin, organosul or combinations of salts may also be preferred, however, fur compounds, and dimethyl sulfoxide (DMSO). Other certain salts may be more advantageous than others. For compounds wheh may also be administered as inducing example, chemical compounds that require high doses may agents, which include CHAPs, Scriptaid, Tubacin, introduce too much of a single salt to the patient. Sodium is JNJ16241199, A-161906, 6-(3-Chlorophenylureido)caproic generally an undesirable salt, because at high doses, sodium hydroxamic acid, SB939, ITF2357 ({6-(diethylamino) can increase fluid retention resulting in tissue destruction. In methyl-2-naphthylmethyl 4-(hydroxyamino)carbonyl Such instances, lower doses or combinations of different or phenylcarbamate), 4SC-201, AR-42, OPB-801, RG2833, alternative salts can be used. For example, compounds of the CUDC-101, JNJ-26481585 (C21H26N6O2), MK0683 (sub invention may be substituted with one or more halogens eroylanilide hydroxamic acid), M344 (4-(Diethylamino)-N- such as chlorine (Cl), fluorine (F), iodine (I), bromine (Br) 7-(hydroxyamino)-7-oxoheptylbenzamide), BML-201 (N- or combinations of these halogens. As known to those of (2-aminophenyl)-N'-phenyl-octanediamide), Droxinostat, ordinary skill in the art, halogenation can increase the and pivaloyloxymethylbutyrate. polarity, hydrophilicity, or lipophilicity of a chemical com 0077 Useful amines and amides include isobutylhydrox pound, which can be a desirable feature, for example, to ylamine: HCl(CHOCl), fumaric acid monoamide transform a chemical compound into a composition that is (CHON), fumaramide (HNCOCHCHCONH), succina more easily tolerated by the patient or more readily absorbed mide and isobutyramide (CHON). Salts can be sodium, by the epithelial lining of the gastrointestinal tract. Such potassium, calcium, ammonium, lithium or choline Such as compositions could be orally administered to patients. Sodium 3-trimethyl silyl-1-proposulfonic acid I0081. Therapeutically effective chemical compounds (CHOSiS:Na). Reagents which may be electrostatically may be created by modifying any of the above chemical or covalently bonded with the inducing agent include amino compounds so that after introduction into the patient, these acids such as arginine (arginine butyrate), glycine, alanine, compounds metabolize into active forms, such as the forms asparagine, glutamine, histidine or lysine, nucleic acids above, which have the desired effect on the patient. Com including nucleosides or nucleotides, or substituents such as pounds may also be created that are metabolized in a carbohydrates, Saccharides, lipids, fatty acids, proteins or timed-release fashion allowing for a minimal number of protein fragments. Combinations of these salts with the introductions that are efficacious for longer periods of time. inducing agent can also produce useful new compounds Combinations of chemical compounds can also produce from the interaction of the combination. useful new compounds from the interaction of the combi 0078. In one embodiment of a method according to the nation. Such compounds may also produce a synergistic invention, the inducing agent is butyric acid in the form of effect when used in combination with other known or other arginine butyrate, and the antiviral agent is a nucleoside compounds. analog. Butyric acid is one of many naturally-occurring short-chain fatty acids that are generated in the Small and D. ANTIVIRAL AGENTS large bowel by metabolism of carbohydrates. Butyrate is a I0082 Anti-viral agents that can be used in the composi four-carbon fatty acid with weakly acidic properties and is tions and methods of the provided invention can include, for rapidly absorbed and metabolized. Butyrates have shown example, Substrates and Substrate analogs, inhibitors and significant anti-tumor effects. Sodium butyrate (NAB) has other agents that severely impair, debilitate or otherwise been used clinically in patients with acute myelogenous destroy virus-infected cells. Substrate analogs include amino leukemias and there has now been extensive experience with acid and nucleoside analogs. Substrates can be conjugated arginine butyrate, a salt of butyrate, in clinical studies for the with toxins or other viricidal substances. Inhibitors include treatment of J3-hemoglobinopathies, and more recently with integrase inhibitors, protease inhibitors, polymerase inhibi refractory solid neoplasms (Foss, F. M., et al. 1994 Proc. tors and transcriptase inhibitors such as reverse transcriptase ASCO 13:162; Sanders, D. A., et al. 1995 Proc. ASCO). inhibitors. 0079 Butyrate and derivatives ofbutyrate including argi I0083 Antiviral agents that can be used in the composi nine butyrate have demonstrated several effects upon trans tions and methods of the provided invention can include, for formed cell lines in vitro that include decreased DNA example, ganciclovir, Valganciclovir, oseltamivir (Tamiflu). replication leading to arrest of cell division in the G phase, Zanamivir (Relenza), abacavir, aciclovir, acyclovir, adefovir, modification of cellular morphology, and alteration of gene amantadine, amprenavir, ampligen, arbidol, atazanavir, atri expression consistent with differentiation of a given cell type pla, boceprevir, cidofovir, combivir, darunavir, delavirdine, examined (Klehr, D., et al. 1992 Biochemistry 31:3222-29). didanosine, docosanol, edoxudine, efavirenz, emitricitabine, For example, human tumor cell lines as diverse as colon, enfuVirtide, entecavir, famciclovir, fomivirsen, fosamprena breast, melanoma, hepatoma, squamous cell carcinoma of Vir, foscarnet, fosfonet, fusion inhibitors (e.g., enfuvirtide), the cervix, endometrial, adenocarcinoma, teratocarcinoma ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, cell lines, leukemic cells (HL-60), and normal human kera inosine, integrase inhibitor, interferon type III, interferon tinocytes can all be induced to differentiate in the presence type II, interferon type I, interferon, lamivudine, lopinavir, of butyrate concentrations ranging from 2-5 mM (Perrin, S. loviride, maraviroc, moroxydine, nelfinavir, nevirapine, P. et al. 1987 Biochem. Biophys. Res. Commun. 148:694 nexavir, nucleoside analogues, peginterferon alfa-2a, penci 700). The mechanism(s) of action proposed for these effects clovir, peramivir, pleconaril, podophyllotoxin, protease upon differentiation are varied and are not fully understood. inhibitor, raltegravir, reverse transcriptase inhibitor, ribavi US 2017/0027944 A9 Feb. 2, 2017 rin, rimantadine, ritonavir, pyrimidine antiviral, saquinavir, induction of lytic replication and TK expression. TK expres stavudine, Synergistic enhancer (antiretroviral), tenofovir, sion can be used as a point for attack by anti-viral agents, tenofovir disoproxil, tipranavir, trifluridine, trizivir, troman allowing for treatment of latent infections. tadine, truvada, Valaciclovir (Valtrex), Vicriviroc, vidara I0088 Preliminary in vitro studies according to the inven bine, Viramidine, Zalcitabine, and Zidovudine. tion demonstrate that induction of EBV-TK activity in 0084 Examples of nucleoside analogs include acyclovir EBV-immortalized B-cells and patient-derived tumor cells (ACV), ganciclovir (GCV), famciclovir, foscarnet, ribavirin, using these drugs is possible, and that these previously Zalcitabine (ddC), zidovudine (AZT), stavudine (D4T), lar resistant cells are rendered Susceptible to ganciclovir nivudine (3TC), didanosine (ddl), cytarabine, dideoxyade therapy. Treatment of patients with viral-associated tumors nosine, edoxudine, floXuridine, idoZuridine, inosine pra Such as EBV with inducing agents such as arginine butyrate, nobex, 2'-deoxy-5-(methylamino)uridine, trifluridine and to induce the expression of EBV-TK, and GCV, to eliminate Vidarabine. Examples of a few protease inhibitors that show EBV-TK expressing tumor cells, is an effective, non-toxic particular promise in human therapy include Saquinivir, therapy. This therapeutic regimen does not depend on the ritonavir and indinavir. Other anti-viral agents include inter associated viral genome being the cause of the tumor. ferons (e.g. Cl-, 3-, y-interferon), cytokines such as tumor Without wishing to be bound by theory, it is believed that necrosis factor (TNF), cell receptors and growth factor just the presence of the EBV genome in latent form would antagonists, which can be purified or recombinantly pro make the tumor Susceptible to this combination protocol. duced. I0089. Butyrate-associated induction of genes has been characterized for various cell types, and the genes are E INDUCED GENES INCLUDING consistently in the class of differentiation markers of a cell. VIRAL-ASSOCIATED GENES For example, in colon cancer cell lines, morphologic 0085 Inducing agents (agents that induce expression) changes observed in the presence of butyrate correlate with may act directly on the viral genome or indirectly through a increased expression of alkaline phosphatase, plasminogen cellular factor required for viral expression. For example, activator, and CEA, all markers of differentiation. Hepatoma viral gene expression can be regulated through the regula cell lines increase expression of alpha fetoprotein. Breast tion of the expression of viral transcription factors such as cancer cell lines express milk-related glycoproteins, epithe ZTA, RTA, tat, and tax, cellular transcription factors such as lial membrane antigens, and increased lipid deposition. AP-1, AP-2, Sp1, NF-kB, and other transcriptional activa Sodium butyrate can also induce expression of cellular tors and/or repressors (factors), co-activators and co-repres proteins associated with converting basal keratinacytes into sors, histone acetylators and deacetylators, DNA methylases committed epithelial cells. and demethylases, oncogenes or proto-oncogenes, or protein 0090 Alteration of expression of certain transcription kinase C. These proteins act to regulate and thereby control factors may affect regulation of gene expression and regu expression of specific viral and/or other cellular genetic lation of the cell cycle. In the breast cancer cell line MCF-7, elements. According to the methods of the invention, control butyrate induces a block in cellular proliferation that is over their expression can lead to control over the infection. associated with decreased expression of estrogen and pro Other gene products, both viral and cellular in origin, whose lactin hormone receptor mRNA expression, thus blocking expression can be regulated with inducing agents include the potential growth stimulation by estrogen and prolactin. proteases, polymerases, reverse transcriptases, cell-surface These effects are associated with increased expression of the receptors, major histocompatibility antigens, growth fac EGF receptor. Butyrate also has been shown to induce tors, and combination of these products. down-regulation of c-myc and p53 mRNA and to up I0086. Additional genes whose expression or transcrip regulate expression of the c-fos transcription factor. In tional regulation are altered in the presence of butyric acid mouse fibroblasts, butyrate will block the cell cycle in the G include the oncogenes myc, ras, my b, abl and Src. The phase. When these cells are stimulated to proliferate with activities of these gene products, as well as the activities of serum, TPA, or insulin, the immediate-early response tran other oncogenes, are described in Slamon, J. D., et al. 1984 Scription factors c-myc and c-jun are unregulated. However, Science 224:256-62. Anti-proliferative activity also includes the late G1 phase downstream gene marker cdc-2 mRNA is the ability to repress tumor angiogenesis through the block not expressed, and cells are prevented from entering S ade of angiogenesis factor activity, production or release, phase. transcriptional regulation, or the ability to modulate tran 0091. The particular combination of inducing agent with Scription of genes under angiogenesis or growth factor or anti-viral agent that is most effective against a specific holinonal control. Either would be an effective therapy, disorder can be determined by one of ordinary skill in the art particularly against both prostatic neoplasia and breast car from empirical testing and, preferably, from a knowledge of cinomas. Further activities that effect transcription and/or each agent's mechanism of action. Three such examples are cellular differentiation include increased intracellular cAMP as follows. First, many of the RNA viruses such as HIV and levels, inhibition of histone acetylation, and inhibition of other retroviruses require a reverse transcriptase to tran genomic methylation. Each of these activities is directly scribe their genome into DNA. A few of the agents that related to gene expression, and increased expression can induce expression or activity of retroviruses and their sensitize infected cells to a specific anti-viral agent. encoded genes, such as, for example, reverse transcriptase, 0087. In some embodiments, inducing agents include are known to those of ordinary skill in the art. Anti-viral arginine butyrate and/or other histone deacetylase inhibitors. agents such as nucleoside analogs can be administered to the Arginine butyrate induces EBV-TK activity in EBV patient. Those Substrate analogs will be specifically recog immortalized B-cells and patient-derived tumor cells. As nized by the reverse transcriptase that, when incorporated latently-infected B-cells do not express TK, exposure of into the infected-cell genome, prevent viral replication and these cells to agents like arginine butyrate results in a modest may also result in cell death. Second, many viruses require US 2017/0027944 A9 Feb. 2, 2017

an active protease to assemble virus capsids to be packaged arteries of the nasal area provide a rapid and efficient access with viral genome. Protease inhibitors or proteases that alter to the upper areas of the head. Sprays also provide imme cleavage patterns so that packaging cannot occur can be diate access to the pulmonary system and are the preferable specifically targeted with an anti-viral agent that comprises methods for administering compositions to these areas. an amino acid analog or toxic conjugate. Third, arginine Access to the gastrointestinal tract is gained using oral, butyrate and isobutyramide enhance expression of viral enema, or injectable forms of administration. For example, thymidine kinase and other viral protein kinases in EBV administration of the anti-viral agent to the subject after the infected lymphocytes. Ganciclovir or famcyclovir, in the first period of a cycle of therapy (i.e., during the remainder presence of the viral thymidine kinase or other viral kinases, of the cycle, during which only anti-viral agent without destroys the infected cell. Treatment of infected cells with inducing agent is administered) is preferably oral. As a both agents, according to the invention, will selectively result, the Subject can go through the reminder of the cycle destroy EBV virus-infected cells. In another aspect, of of therapy at home. However, the patient may go through up infected cells with both agents, according to the invention, to about ten, preferably less than or equal to six, cycles of will selectively disable or disrupt the viral activity within the therapy. cells in vivo. 0096. Administration of the anti-viral agent (amount and frequency) is well-known to or can be readily determined by F. FORMULATIONS, ROUTES OF the person of ordinary skill in the art. ADMINISTRATION, AND EFFECTIVE DOSES 0097. As indicated above, orally active compositions are 0092 Administration of the compositions described preferred for at least a portion of the cycle of therapy, as oral herein may be by oral, parenteral, Sublingual, rectal, or administration is usually the safest, most convenient, and enteral administration, or pulmonary absorption or topical economical mode of drug delivery. Oral administration can, application. Compositions can be directly or indirectly however, be disadvantageous, because compositions are administered to the patient. Indirect administration is per poorly absorbed through the gastrointestinal lining. Com formed, for example, by administering the composition to pounds that are poorly absorbed tend to be highly polar. cells ex vivo and Subsequently introducing the treated cells Consequently, compounds that are effective, as described to the patient. The cells may be obtained from the patient to herein, may be made orally bioavailable by reducing or be treated or from a genetically related or unrelated patient. eliminating their polarity. This can often be accomplished by Related patients offer Some advantage by lowering the formulating a composition with a complimentary reagent immunogenic response to the cells to be introduced. For that neutralizes its polarity, or by modifying the compound example, using techniques of antigen matching, immuno with a neutralizing chemical group. Oral bioavailability is logically compatible donors can be identified and utilized. also a problem, because drugs are exposed to the extremes 0093. Both inducing and anti-viral agents can be pur of gastric pH and gastric enzymes. These problems can be chased commercially and prepared as a mixed composition overcome in a similar manner by modifying the molecular using techniques well-known to those of ordinary skill in the structure to be able to withstand very low pH conditions and art. resist the enzymes of the gastric mucosa Such as by neu 0094) Direct administration of a composition may be by tralizing an ionic group, by covalently bonding an ionic oral, parenteral, Sublingual, rectal Such as Suppository or interaction, or by Stabilizing or removing a disulfide bond or enteral administration, or by pulmonary absorption or topi other relatively labile bond. cal application. Parenteral administration may be by intra 0.098 Compounds may also be used in combination with venous injection, Subcutaneous injection, intramuscular other agents to maximize the effect of the compositions injection, intra-arterial injection, intrathecal injection, intra administered in an additive or synergistic manner. Compo peritoneal injection, or direct injection or other administra sitions may also comprise proteinaceous agents such as tion to the site of the neoplasm. An infusion pump (to infuse, growth factors and/or cytokines, which are viral inducers. for example, the inducing agent into the Subject's circulatory Such proteinaceous agents may also be aminated, glycosy system during the first period of a cycle of therapy) is lated, acylated, neutralized, phosphorylated, or otherwise generally used intravenously, although Subcutaneous, arte derivatized to form compositions that are more suitable for rial, and epidural infusions are occasionally used. Injectable the method of administration to the patient or for increased forms of administration are sometimes preferred for maxi stability during shipping or storage. Cytokines that may be mal effect. When long-term administration by injection is effective in combination with the compositions described necessary, medi-ports, in-dwelling catheters, or automatic herein include growth factors such as B cell growth factor pumping mechanisms are also preferred, wherein direct and (BCGF), fibroblast-derived growth factor (FDGF), granulo immediate access is provided to the arteries in and around cyte/macrophage colony Stimulating factor (GM-CSF), the heart and other major organs and organ systems. The granulocyte colony stimulating factor (G-CSF), macrophage inducing agent and anti-viral agent may, in an embodiment colony stimulating factor (M-CSF), epidermal growth factor of the invention, be administered through the same intrave (EGF), vascular endothelial growth factor (VEGF), platelet nous line. derived growth factor (PDGF) nerve growth factor (NGF), 0095. An effective method of administration to a specific stem cell factor (SCF), and transforming growth factor site may be by transdermal transfusion, such as with a (TGF). These growth factors plus a composition may further transdermal patch, by direct contact to the cells or tissue, if stimulate cellular differentiation and/or the expression of accessible, such as a skin tumor, or by administration to an certain MHC antigens or tumor antigens. For example, internal site through an incision or some other artificial BCGF plus a composition may be effective in treating opening into the body. Compositions may also be adminis certain B cell leukemias. NGF plus a composition may be tered to the nasal passages as a spray. Diseases localized to useful in treating certain neuroblastomas and or nerve cell the head and brain area are treatable in this fashion, as tumors. In a similar fashion, other agents such as differen US 2017/0027944 A9 Feb. 2, 2017 tiating agents may be useful in combination with a compo ological stability can also be measured by observing the sition of the invention to prevent or treat a neoplastic duration of biological effects on the patient. Clinical Symp disorder. Other differentiating agents include B cell differ toms that are important from the patient's perspective entiating factor (BCDF), erythropoietin (EPO), steel factor, include a reduced frequency or duration, or elimination of activin, inhibin, the bone morphogenic proteins (BMPs), the need for transfusions or chelation therapy. Preferably, a retinoic acid or retinoic acid derivatives such as retinol, the stable compound has an in vivo half-life of greater than prostaglandins, and TPA. about 15 minutes, a serum half-life of greater than about 15 0099. Alternatively, other cytokines and related antigens minutes, or a biological effect which continues for greater in combination with a composition may also be useful to than 15 minutes after treatment has been terminated or the treat or prevent certain virus-associated cellular disorders, serum level of the compound has decreased by more than virus infections, and other viral disorders. Potentially useful half. cytokines include tumor necrosis factor (TNF), the interleu 0103 Preferably, compositions are also not significantly kins IL-1, IL-2, 11-3, IL-4, IL-5, IL-6, etc., recombinant IL biotransformed, degraded, or excreted by catabolic pro receptors, growth factors, colony Stimulating factors, eryth cesses associated with metabolism. Although there may be ropoietin (EPO), the interferon (IFN) proteins IFN-C, IFN Some biotransformation, degradation, or excretion, these B, and IFN-y; cyclic AMP including dibutyryl cyclic AMP. functions are not significant, if the composition is able to hemin, DMSO, hydroxyurea, hypoxanthine, glucocorticoid exert its desired effect. hormones, and cytosine arabinoside. Therapies using com 0104 Compositions are also preferably safe at effective binations of these agents would be safe and effective thera dosages. Safe compositions are compositions that are not pies against malignancies and other forms of cancer. Com Substantially toxic (e.g. cytotoxic or myelotoxic), or muta binations of therapies may also be effective in inducing genic at required dosages, do not cause adverse reactions or regression or elimination of a tumor or some other form of side effects, and are well-tolerated. Although side effects cellular disorder resulting from and/or associated with viral may occur, compositions are substantially safe if the benefits infection Such as compositions of the invention plus radia achieved from their use outweigh disadvantages that may be tion therapy, toxin or drug-conjugated antibody therapy attributable to side effects. Unwanted side effects include using monoclonal or polyclonal antibodies directed against nausea, vomiting, hepatic or renal damage or failure, hyper the transformed cells, or specific anti-sense therapy. Effects sensitivity, allergic reactions, cardiovascular problems, gas may be additive, logarithmic, or synergistic, and methods trointestinal disturbances, seizures, and other central ner involving combinations of therapies may be simultaneous vous system difficulties, fever, bleeding or hemorrhaging, protocols, intermittent protocols or protocols that are empiri serum abnormalities, and respiratory difficulties. cally determined. 0105 Compositions useful for treating viral disorders 0100 Compositions are preferably physiologically stable preferably do not substantially affect the viability of a cell at therapeutically effective concentrations. Physiological Such as a normal mammalian cell. Normal cell viability, the stable compounds are compounds that do not break down or viability of an untransformed or uninfected cell, can be otherwise become ineffective upon introduction to a patient determined from analyzing the effects of the composition on prior to having a desired effect. Compounds are structurally one or more biological processes of the cell. resistant to catabolism, and, thus, physiologically stable, or 0106 Useful combination therapies will be understood coupled by electrostatic or covalent bonds to specific and appreciated by those of skill in the art. Potential advan reagents to increase physiological stability. Such reagents tages of such combination therapies include the ability to use include amino acids Such as arginine, glycine, alanine, less of each of the individual active ingredients to minimize asparagine, glutamine, histidine, or lysine, nucleic acids toxic side effects, synergistic improvements in efficacy, including nucleosides or nucleotides, or Substituents such as improved ease of administration or use, and/or reduced carbohydrates, saccharides and polysaccharides, lipids, fatty overall expense of compound preparation or formulation. acids, proteins, or protein fragments. Useful coupling part For example, the inducing agent and anti-viral agent may be ners include, for example, glycol, such as polyethylene administered to the subject in combination with one or more glycol, glucose, glycerol, glycerin, and other related Sub cytokines selected from the group consisting, for example, Stances. of IL-3, GM-CSF, stern cell factor (SCF), and IL-6. 0101. A combination therapy can include administering 0107 Administration of the inducing agent and the anti an agent that reduces side effects of treatments, for example, viral agent to a subject according to a method of the anti-cancer treatments. A combinational therapy can also invention may be for prophylaxis or therapeutic treatment of include administering an agent that reduces the frequency of a confirmed or Suspected viral disorder. administration of other therapies. The agent can be an agent 0108) Administration may be to an adult, an adolescent, that decreases growth of tumor after the anti-cancer effects a child, a neonate, an infant or in utero. of other therapies have decreased. The additional agent or 0109 Administration of the inducing agent and the anti therapy can also be another anti-viral or anti-cancer agent or viral agent during the first period of a cycle of therapy therapy. according to a method of the invention may be in a single or 0102 Physiological stability can be measured from a in separate composition(s). Administration of either agent number of parameters such as the half-life of the compound may be continuous or sporadic, as necessary. For example, or the half-life of active metabolic products derived from the the inducing agent may be administered to the Subject via a compound. Certain compounds of the invention have in vivo continuous infusion throughout the first period of the cycle half-lives of greater than about fifteen minutes, greater than of therapy. Alternatively, the inducing agent may be admin about one hour, greater than about two hours, and greater istered to the Subject per infusion over a single span of a few than about four hours, eight hours, twelve hours, or longer. to several hours per day every day throughout the first period Although a compound is stable using this criteria, physi of the cycle of therapy. Alternatively, the inducing agent may US 2017/0027944 A9 Feb. 2, 2017 be administered in a single parenteral bolus, or orally, daily mined by those of ordinary skill in the art using, for for several days throughout the first part of the cycle, or example, DNA fragmentation analysis. A decreased amount weekly. Anti-viral agents are administered to the Subject per of fragmentation indicates that cellular viability is boosted. known or readily determined regimens (for example, one to Determinations of increased or decreased viability can also two intravenous administrations per day throughout the first be concluded from an analysis of the results of multiple period of the cycle of therapy, followed by one to two oral different assays. Where multiple tests provide conflicting administrations per day throughout the remainder of the results, accurate conclusions can still be drawn by those of cycle of therapy). Patients with a suspected or diagnosed ordinary skill based upon the cell type, the correctness or viral-associated disorder may only require one or a few correlation of the tests with actual conditions, and the type cycles of therapy until the disorder has been effectively of composition. OWCO. 0113 Compositions can be prepared in solution as a 0110 Methods for the treatment of viral disorders may dispersion, mixture, liquid, spray, capsule, or as a dry solid include augmenting the treatment methods of the invention Such as a powder or pill, as appropriate or desired. Solid with conventional chemotherapy, radiation therapy, anti forms may be processed into tablets or capsules or mixed or body therapy, and/or other forms of therapy. Some conven dissolved with a liquid Such as water, alcohol, Saline or other tional chemotherapeutic agents that would be useful in salt solutions, glycerol, Saccharides or polysaccharide, oil, or combination therapy with methods and compositions of the a relatively inert Solid or liquid. Liquids, pills, capsules or invention include the cyclophosphamides such as alkylating tablets administered orally may also include flavoring agents agents, the purine and pyrimidine analogs such as mercap to increase palatability. Additionally, all compositions may topurine, the vinca and vinca-like alkaloids, the etoposides further comprise agents to increase shelf-life, such as pre or etoposide-like drugs, the antibiotics such as deoxyrubocin servatives, anti-oxidants, and other components necessary and bleomycin, the corticosteroids, the mutagens such as the and suitable for manufacture and distribution of the com nitrosoureas, antimetabolites including methotrexate, the position. Compositions further comprise a pharmaceutically platinum based cytotoxic drugs, the hormonal antagonists acceptable carrier or excipient. Carriers are chemical or Such as anti-insulin and anti-androgen, the anti-estrogens multi-chemical compounds that do not significantly alter or Such as tamoxifen, and other agents such as doxorubicin, affect the active ingredients of the compositions. Examples L-asparaginase, DTIC, maMSA, procarbazine, hexameth include water, alcohols such as glycerol and polyethylene ylmelamine, and mitoxantrone. These agents could be given glycol, glycerin, oils, salts such as Sodium, potassium, simultaneously or alternately as defined by a protocol magnesium, and ammonium, fatty acids, Saccharides, or designed to maximize effectiveness, but minimize toxicity to polysaccharides. Carriers may be single Substances or the patient’s body. chemical or physical combinations of these substances. 0111 Virus-infected cells may also be treated in vivo by 0114 Compositions administered as part of the methods administering the inducing agent and the anti-viral agent of the invention comprise an inducing agent to induce directly to the patient. For example, patients exposed to expression of a gene product in a virus-infected cell and an mutagens, carcinogens, radiation, or other cancer-producing anti-viral agent whose anti-viral activity relates to or is agents may be continuously treated with compositions to directed to the expressed product. The gene product inhibit the expected development of a neoplastic condition. expressed may be a viral enzyme or a cellular enzyme or Patients who have been genetically screened and determined activity that is largely expressed in virus-infected cells. to be at high risk for the future development of a neoplasia Expression products that can be targeted include enzymes may also be administered compositions, possibly beginning involved with DNA replication, which may be either for at birth and possibly for life. Both prophylactic and thera repair or replication of the genome, assembly of complete peutic uses are readily acceptable, because these compounds virus particles, generation of viral membrane or walls, RNA are generally safe and non-toxic at effective dosages. transcription or protein translation, or combinations of these 0112 Detrimental interference with one or more of these activities. Interference with these processes can be per cellular processes becomes significant when the process formed by inducing and then acting on an enzyme and, becomes abnormal. Examples of quantitatable and qualifi preferably, a critical enzyme in the process. able biological processes include the processes of cell divi sion, protein synthesis, nucleic acid (DNA or RNA) synthe 0115 Administration Therapy sis, nucleic acid (principally DNA) fragmentation, and 0116 Preferably, compositions administered contain apoptosis. Other processes include specific enzyme activi chemicals that are substantially non-toxic. Substantially ties, the activities of the cellular transportation systems such non-toxic means that the composition, although possibly as the transportation of amino acids by System A (neutral), possessing some degree of toxicity, is not harmful to the system B (acidic) or system C (basic), and the expression of long-term health of the patient. Although the active compo a cell Surface protein. Each of these parameters is easily nent of the composition may not be toxic at the required determined as significantly detrimental, for example, in levels, there may also be problems associated with admin tissue culture experiments, in animal experiments, or in istering the necessary Volume or amount of the final form of clinical studies using techniques known to those of ordinary the composition to the patient. For example, if the compo skill in the art. Abnormal cell division, for example, can be sition contains a salt, although the active ingredient may be mitosis which occurs too rapidly, as in a malignancy, or at a concentration that is safe and effective, there can be a unstably, resulting in programmed cell death or apoptosis, harmful build-up of sodium, potassium, or another ion. With detected by increased DNA degradation. The determination a reduced requirement for the composition or at least the of abnormal cell viability can be made on comparison with active component of that composition, the likelihood of Such untreated control cells. Compositions preferably increase problems can be reduced or even eliminated. Consequently, normal cell viability. Increased cell viability can be deter although patients may suffer minor or short term detrimental US 2017/0027944 A9 Feb. 2, 2017

side-effects, the advantages of taking the composition out and expense and a lower effective dose can lessen the weigh the negative consequences. number and severity of complications that can be experi 0117 Treatment of a patient may be therapeutic and/or enced by a Subject. As such, pulsing can be more effective prophylactic. Therapeutic treatment involves administration than continuous administration of the same composition. of an inducing agent and an anti-viral agent according to a 0.125 Individual pulses can be delivered to a subject method of the invention to a patient suffering from one or continuously over a period of several hours, such as about 2, more symptoms of or having been diagnosed as being 4, 6, 8, 10, 12, 14 or 16 hours, or several days, such as 2, 3, afflicted with a viral disorder. Relief and even partial relief 4, 5, 6, or 7 days, or from about 1 hour to about 24 hours or from one or more of the symptoms may correspond to an from about 3 hours to about 9 hours. Alternatively, periodic increased life span or, simply, an increased quality of life. doses can be administered in a single bolus or a small Further, treatments that alleviate a pathological symptom number of injections of the composition over a short period can allow for other treatments to be administered. of time, for example, less than 1 or 2 hours. For example, 0118 Prophylactic treatments involve administration of arginine butyrate can be administered over a period of 4 days an inducing agent and an anti Viral agent according to a with infusions for about 8 hours per day or overnight, method of the invention to a patient having a confirmed or followed by a period of 7 days of no treatment. Suspected viral disorder without having any overt Symp 0.126 The interval between pulses or the interval of no toms. Administration can begin at birth and continue, if delivery can be greater than 24 hours or can be greater than necessary, for life. Both prophylactic and therapeutic uses 48 hours, and can be for even longer Such as for 3, 4, 5, 6, are readily acceptable, because these compounds are gen 7, 8, 9 or 10 days, two, three or four weeks or even longer. erally safe and non-toxic. The interval between pulses can be determined by one of 0119 Treatments Aids ordinary skill in the art. The interval between pulses can be 0120 Aids for the treatment of human viral disorders and calculated by administering another dose of the composition virus-associated cellular and neoplastic disorders contain when the composition or the active component of the compositions described herein in predetermined amounts, composition is no longer detectable in the patient prior to which can be individualized in concentration or dose for a delivery of the next pulse. Intervals can also be calculated particular patient. Compositions, which may be liquids or from the in vivo half-life of the composition. Intervals can Solids, are placed into reservoirs or temporary storage areas be calculated as greater than the in vivo half-life, or 2, 3, 4, within the aid. At predetermined intervals, a set amount of 5 and even 10 times greater than the composition half-life. one or more compositions is administered to the patient. Intervals can be 25, 50, 100, 150, 200, 250300 and even 500 Compositions to be injected may be administered through, times the half life of the chemical composition. for example, infusion pumps, mediports, or in-dwelling I0127. The number of pulses in a single therapeutic regi catheters. Aids may further comprise mechanical controls or men can be as little as two, but can be from about 5 to 10, electrical controls devices, such as a programmable com 10 to 20, 15 to 30 or more. Subjects (e.g., patients) can puter or computer chip, to regulate the quantity or frequency receive one or more agents (e.g., drugs) for life according to of administration to patients. Examples include both single the methods of this invention. Compositions can be admin and dual rate infusers and programmable infusers. Delivery istered by most any means, and can be delivered to the of the composition may also be continuous for a set period patient as an injection (e.g. intravenous, Subcutaneous, of time. Aids may be fixed or portable, allowing the patient intraarterial), infusion or instillation, and more preferably by as much freedom as possible. The use of a portable aid oral ingestion. Various methods and apparatus for pulsing allows the patient to receive at least a portion of the compositions by infusion or other forms of delivery to the treatment regimen outside of the hospital. patient are disclosed in U.S. Pat. Nos. 4,747,825; 4,723,958; 0121 Administration Schedule 4,948,592: 4,965,251 and 5,403,590. 0122 Administration of one or more agents (e.g., a viral I0128. In one embodiment, the inducing agent and the inducing agent and/or an antiviral) can be intermittent; for anti-viral agent are administered for about five days, and the example, administration can be once every two days, every anti-viral agent is Subsequently administered without the three days, every five days, once a week, once or twice a inducing agent for an additional period of about sixteen days month, and the like. The amount, forms, and/or amounts of for a total cycle of about 21 days. Cycles of treatment may the different forms can be varied at different times of occur in immediate Succession or with an interval of no administration. treatment between cycles. 0123 Pulsed administration of one or more pharmaceu 0129. A pharmaceutical composition comprising a viral tical compositions can be used for the treatment or preven inducing agent can be administered to a subject before a tion of a viral-induced inflammatory disease. Pulsed admin pharmaceutical composition comprising an antiviral agent is istration can be more effective than continuous treatment as administered to the Subject. A pharmaceutical composition pulsed doses can be lower than would be expected from comprising a viral inducing agent can be co-administered to continuous administration of the same composition. Each a subject with a pharmaceutical composition comprising an pulse dose can be reduced and the total amount of drug antiviral agent. A pharmaceutical composition comprising a administered over the course of treatment to the patient can viral inducing agent can be co-administered with a pharma be minimized. ceutical composition comprising an antiviral agent and a 0.124 With pulse therapy, in vivo levels of an agent can pharmaceutical composition comprising one or more addi drop below that level required for effective continuous tion agents. The pharmaceutical compositions can be pro treatment. Pulsed administration can reduce the amount of vided by pulsed administration. For example, a pharmaceu the composition administered to the patient per dose or per tical composition comprising a viral inducing agent can be total treatment regimen with an increased effectiveness. administered to a subject, followed by administration of a Pulsed administration can provide a saving in time, effort pharmaceutical composition comprising an antiviral agent to US 2017/0027944 A9 Feb. 2, 2017 17 the subject after an interval of time has passed, and this order intravenously (IV) over 1 hour twice per day, and continued of administration the same or similar time interval can be throughout the cycle. AB was continuously infused at a repeated, for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 starting dose of 500 mg/kg/day. Dose escalation was con or more times. tinued as follows until MTD was established: (0132) Level 1: 500 mg/kg/day IV for 2 days INCORPORATION BY REFERENCE I0133) Level 2: 1000 mg/kg/day IV for 2 days 0130. Each of the applications and patents cited in this I0134) Level 3: 1500 mg/kg/day IV for 2 days text, as well as each document or reference cited in each of I0135) Level 4: 2000 mg/kg/day IV until day 21 the applications and patents (including during the prosecu 0.136. A total of 15 patients were evaluated for anti-tumor tion of each issued patent; 'application cited documents'), response (Table 1). A complete response (CR) was defined and each of the PCT and foreign applications or patents as disappearance of detectable malignant disease on imaging corresponding to and/or claiming priority from any of these or physical examination (e.g., for skin lesions or tonsillar applications and patents, and each of the documents cited or masses). A partial response (PR) was defined as a 50% referenced in each of the application cited documents, are decrease in tumor size (the Sum of the product of the largest hereby expressly incorporated herein by reference and may perpendicular diameters) or measurable lesions chosen for be employed in the practice of the invention. More generally, analysis prior to beginning of treatment. For lesions which documents or references are cited in this text, either in a could only be measured in 1 dimension, Such as skin Reference List before the claims, or in the text itself, and, (cutaneous T cell lymphoma), a greater than 50% decrease each of these documents or references (“herein cited refer in the largest dimension qualified as a PR. For the 3 patients ences”), as well as each document or reference cited in each who died from co-morbidities, anti-tumor responses were of the herein cited references (including any manufacturers confirmed pathologically at autopsy. specifications, instructions, etc.), is hereby expressly incor 0.137 Four patients were classified as achieving CRs, porated herein by reference. including 2 with PTLD, 1 with extranodal NK/T cell lym phoma and 1 with peripheral T-cell lymphoma. Three of EXAMPLES these patients died after completing therapy as a result of co-morbid conditions and complications presumed related to Example 1 tumor regression. Autopsy examination of 2 subjects revealed apparent complete disappearance of tumor, while Phase 1 Study of AB Plus Ganciclovir in Patients the third patient demonstrated significant necrosis of with EBV Associated Lymphoid Malignancies residual lymphoma at autopsy. 0131 Fifteen patients with EBV-associated lymphoid 0.138 Six patients were classified as partial responses malignancies, who had histologically confirmed lymphoid (PRs), including 3 with PTLD, 1 with diffuse large-cell neoplasms that were EBV+, were treated with AB and GCV. B-cell lymphoma, 1 with extranodal NK/T-cell lymphoma Prior therapies (varying in different subjects) included ritux and 1 with Subcutaneous panniculitis-like T-cell lymphoma. imab, chemotherapy, chemoradiotherapy and bone marrow 0.139. The remaining 5 patients were classified as non transplant. GCV was administered at a rate of 5 mg/kg responders (NR). 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, 19 d 2OOO PR confusion; mucositis; headache; nausea/vomiting: tumor regression preceding bowel perforation* 2OOO PR confusion: nausea/vomiting; anorexia 2OOO NR confusion; restlessness; somnolence; nausea, vomiting; abdominal pain; vision change; orthostasis 1 OOO,1OOO NR 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 ysis leading to pancreatitis/hepatitis 10 1 OOO,800 NR Elevated BUN, encephalopathy 11 <1, 8 d 1SOO.1SOO PR Diarrhea: hepatomegaly 12 2OOO,2OOO NR Nausea; pneumonia; port infection US 2017/0027944 A9 Feb. 2, 2017 18

TABLE 1-continued Treatment Courses in Patients With EBV Associated Lymphoid Malignancies Treated with AB and GCV Patient HDHTD Outcome, Number No. Cycles (mg/kg/day) 1 cycle Adverse Events 13 3 938,938 PR Nausea; anorexia; weight loss; anemia; thrombocytopenia; lethargy; insomnia; hypokalemia 14 <1, 19 d 12SO.12SO NR Sinus, throat, back pain; thrombocytopenia: hypokalemia; lethargy 15 <1, 5 d 1OOO1 OOO PR Lethargy; increased dyspnea; polymicrobial pneumonia acute respiratory distress syndrome

*fatal AE; H DHTD-highest dose highest tolerated dose.

0140. In summary 10 out of 15 patients showed a degree resolved for first time in 9 weeks. Measure of the tumor of response to treatment of AB in combination with the marker serum LDH was reduced from 899 to 328 (normal). antiviral ganciclovir. Additionally, EBV, CMV, and HH6 viral load became unde tectable. These findings indicate that a shorter, more patient Example 2 accessible regimen of the virus-target therapeutic strategy is more efficacious. Phase II Trial of Low-Dose Arginine Butyrate and Ganciclovir/Valganciclovir in EBV (+) Lymphoid Malignancies TABLE 2 Quantification of tumor response evaluated by CT Scan. 0141. It has previously been found that continuous infu Tumor dimensions in cm. sion of inducing agent, for example, arginine butyrate, may not be necessary to maintain viral thymidine kinase expres Pre-Treatment Post-Treatment sion and sensitization to anti-viral agents in EBV-associated Dimension Dimension Dimension Dimension tumors, but that, in fact, cells that survived initial exposure Location 1 2 1 2 to the inducing agent plus the anti-viral agent remained R. Upper lobe 0.7 0.7 None None susceptible to further cycles of combination treatment R. Mid Lobe 1.1 1.1 None None (Ghosh, S. K., et al. 2007 Blood Cells, Molecules, and R. Lower Lobe 1.4 O.8 O.8 O.6 Diseases 38:57-65, incorporated herein in its entirety). How L. Upper Lobe O.9 O.8 None None ever, it was neither anticipated nor expected that after some L. Lower Lobe O.9 O6 O.6 O.S Lingular O.9 0.7 None None first period of treatment with inducing agent and anti-viral Hepatic Seg. 6 1.1 1.1 None None agent, one could continue the anti-viral treatment effectively Hepatic Seg. 8 1.O 0.7 None None within a cycle of therapy without continued administration L. Ant. Abd. Wall 1.1 1.9 None None of the inducing agent (continued administration including R. Ant. Abd. Wall O.9 O.S O.9 O.S continued periods of pulsing throughout). 0142. A clinical trial was instituted utilizing a 5-day infusion of arginine butyrate and 21 days of ganciclovir/ Example 3 valganciclovir for EBV+ lymphomas and Post-transplant Lymphoproliferative Disorder (PTLD). The first patient Analysis of Efficacy of the Herpes Anti-Virals enrolled in the protocol (with Rituximab-refractory PTLD following a cord stem cell transplantation for Hodgkin 0144. There are 12 mammalian HDACs, and any one of Disease) tolerated the treatment regimen well, with resolu which might be required for repression of TK gene during tion of cough within three days and a decrease in LDH latency in tumors. HDAC isozyme-specific siRNAs were levels. used to to knockdown individual HDACs in tumor lines 0143 Treatment with arginine butyrate (AB) was admin expressing latent EBV to determine which one of them istered in a hospital/inpatient basis. The subject was a 32 induces reactivation of TK from latency, rendering it Sus year old with EBV-related post-transplant lymphoma who ceptible to anti-virals. had failed multiple therapies (chemotherapy, Rituxan). The (0145 The EBV-positive B lymphoma cell line P3HR1 subject received AB 1,000 mg/kg/dose intravenously for 5 was used throughout these assays. The P3HR1 cell line was days (day 1-5). The dose was given continuously over 24 originally derived from Burkitt's lymphoma patient. EBV hours. AB was given through a long IV line or port due to maintains a latent state of replication in this cell line. Cells hypertonicity. Ganciclovir at 5 mg/kg IV over 1 hour was were maintained in RPMI 1640 with 10% fetal bovine serum given twice a day for five days (day 1-5). Valganciclovir 900 containing 100 U penicillin per ml and 100 ug streptomycin mg was given orally twice per day for 16 days (day 6-21). per ml. The HDAC inhibitors used were from five different At the end of the 21-day cycle, imaging studies were done classes: a) short chain fatty acids, b) hydroxamic acids, c) to determine response and revealed elimination of nearly all benzamides, d) cyclic tetrapeptides, and e) largaZoles. tumor masses (FIG. 1). Four of six target lesions resolved 0146 To measure the relative level of TK mRNA in completely, and two additional lesions decreased in size. various total RNA preparations, reverse transcription and (Table 2) The subjects symptoms of fever and cough quantitative PCR using real time PCR technology was used. US 2017/0027944 A9 Feb. 2, 2017

Five micrograms of total RNA was reverse-transcribed using expression at a higher level than that seen with efficient random hexamer primers and Superscript III clNA synthe concentrations of butyrate (1.0 mM) (FIG. 5B). sis kit (Invitrogen). The cDNA was diluted to a final volume 0152 LHB589-Panobinostat: The growth inhibitory of 60 ul with sterile water, 8 ul of which was then used in activity of LHB589 at a 50 nM concentration was compa each real time PCR reaction in an ABI 7500 Sequencher rable to that of NaB at 1.0 mM (FIG. 6A). When the cells using SYBR-Green technology. Primers used for the ampli were treated for 3 days or longer, LHB589 was extremely fication of TK were EBV-TK1-F: 5'-AGATGACGACGGC toxic to the cells at any concentrations 100 nM or above. CTCTACCA-3'; EBV-TK1-R: 5'-CCTCCTTCTGTGCAC Although when treated for 24 h only, cells survived well GAAGT-3'. The B-actin mRNA level in those samples were even at a concentration of 5 uM. TK expression level in determined similarly using B-actin-specific primers Actin/ presence of LHB589 was quite high compared to optimum hu-F: 5'-GCTCGTCGTCGACAACGGCTC-3'; Actin/hu-R: concentration of NaB (2.5 mM) (FIG. 6B). 5'-CAAACATGATCTGGGTCATCTTCTC-3'. The relative (O153 PXD101-Belinostat: PXD101 induced high level level of TK expression in a sample was calculated following of TK expression at the 5 uM concentration. (FIG. 7). normalization of B-actin expression level. 0154 Oxamflatin: Oxamflatin showed synergistic activ 0147 Toxicity assays with two anti-herpesvirus drugs, ity with GCV towards reducing cell growth. At a 200 nM Gancicovir (GCV) and Penciclovir (PCV), treated to P3HR1 concentration, the activity level (growth Suppression) was cells alone was conducted as a control. A total of 3x10 more than what typically seen with 1.0 mM NaB. (FIG. 8) P3HR1 cells were incubated with various concentrations of GCV or PCV and incubated for 6 days. Viable cell counts C. Cyclic Tetrapeptide were measured and toxicity was expressed as percentage of cell growth compared to untreated cells. As shown in FIGS. 0155 Apicidin: The cyclic tetrapeptide group of HDACi 2A and 2B, PCV was less toxic to the cells compared to examined was apicidin. A toxicity assay with apicidin alone GCV. The effect of 40 uM GCV and PCV in combination showed that concentrations of apicidin higher than 200 nM treatment approach with 1.0 mM Na-butyrate in P3HR1 was quite toxic to the cells. The combination treatment assay cells was compared (FIG. 2C). Inhibition of cell growth with (FIG.9) showed that at 100 nM and 200 nM concentrations, 40 uM PCV (76%) was much less than with 40 uM GCV apicidin reduced cell growth by 40-50% over cells treated (38%). This lower level of inhibition of cell growth with with apicidin alone. However, the 200 nM concentration cell PCV did not change significantly when the drug was used at growth was significantly retarded without any GCV and a higher concentrations (FIG. 2D). 500 nM concentration was very toxic to the cells. Example 4 D. Benzamide 0156 Experiments show that the benzamide class of Analysis of Efficacy of HDAC Inhibitors HDAC inhibitors were extremely potent in sensitizing P3HR1 cells to GCV-mediated effects. As shown below A. Short Chain Fatty Acids (FIG. 10A) a 500 nM concentration of MS-275 was as efficient as 1.0 mM NaB. Higher concentrations were 0148. Two SCFA HDAC inhibitors, Na-butyrate (NaB) extremely toxic to the cells. Interestingly, MS-275 also and valproic acid (VA) were tested. In a combination treat strongly induced TK expression at 500 nM and higher ment approach, NaB+GCV reduced growth of EBV-positive concentrations (FIG. 10B). TK expression was also induced P3HR1 cells significantly (up to 50% more) compared to at only 6 hr post treatment. Based on these results, an even cells treated with NaB or GCV alone (FIG. 3A). The optimal shorter exposure to MS-275 was examined to see if it would concentration of NaB for this purpose was found to be 1.0 be sufficient to sensitize P3HR1 cells to GCV-mediated mM. Responses from 1.0 mMNaB was used as a control for killing. Cells with were treated with MS-275+GCV for interpreting results in this experiment. At a higher concen shorter time periods of 24 hr or 48 hr (as opposed to 72 hr) tration NaB alone reduces cell growth to a significant and then further incubated in presence of GCV for up to 6 degree, and the synergistic effects of GCV are lost at those days, at which time the viable cell counts were enumerated. concentrations of NaB. The other HDACi used in this As shown in FIG. 10C, even at just 24 hr exposure to experiment, VA, also had very similar activity (FIG. 3B). MS-275 sensitized the cells to GCV-mediated effects as Analysis of TK mRNA level by RT and real-time PCR efficiently as a 72 hr continuous treatment. This further however showed that VA was less efficient than NaB in demonstrates that MS-275 is very effective sensitizing agent inducing TK expression (FIG. 3C). for combination treatment studies. B. Hydroxamic Acids E. Largazole 0149. A total of five different HDAC inhibitors from the 0157 Largazole is a member of macrocyclic depsipeptide hydroxamic acid group were examined as combination that was originally isolated from coral reef cyanobacteria. therapies. These inhibitors include scriptaid, SAHA, Largazole is a potent HDAC inhibitor with specificity panobinostat-LHB589, belinostat-PXD 101 and oxamflatin. towards HDAC class 1 and 2 only. Additionally, largazole 0150 Scriptaid: Scriptaid showed strong synergistic has very low IC 50 and HDAC isozyme specificity. 16 effect with GCV in reducing cell growth of P3HR1 cells, different analogs of the largazole were tested (ab6-113b. especially at 500 nM and 1 uM concentrations (FIG. 4A). ab6-113a, ab6-123a, abó-123b, ab6-164b, ab6-156b, 232a, 0151 SAHA-Vorinostat: The combination treatment 233a, 238a, 233b, 234b, 235b, 234a, 235a, 237a, 212b, experiment with SAHA showed that it was less effective in TLN1 357, TNL2 380, ART01) for synergistic cell killing reducing cell growth when combined with an antiviral agent activity in combination with GCV (FIGS. 12A, 12B, 12C, compared to butyrate (FIG. 5A) although it did induce TK 12D and 12E). 13 largazole derivatives were tested both in US 2017/0027944 A9 Feb. 2, 2017 20 combination treatment approach and also for their ability to be active, whereas 2,2-dimethylbutyrate (ST20) and 2-(cqui induce EBV TK (FIG. 12F). Several of the largazoles nazolin-4-ylamino)butanoic acid (RB3) increased viral pro showed potent cell killing activity in combination with GCV. duction at levels similar to the control of vehicle alone. DMSO was vehicle for some of the compounds tested. Example 5 0159. While preferred embodiments of the present inven tion have been shown and described herein, it will be Analysis of Efficacy of Combination Treatment obvious to those skilled in the art that such embodiments are with HIV-Infected Cells provided by way of example only. Numerous variations, changes, and Substitutions will now occur to those skilled in 0158 Virus production (p24 release) was examined in an the art without departing from the invention. It should be HIV-1-infected monocyte line. Cells were treated or not understood that various alternatives to the embodiments of treated with HDAC-inhibitors and other compounds. P24 the invention described herein may be employed in practic release expressed as optical density (“OD) (FIG. 13), and ing the invention. It is intended that the following claims then converted to pg of protein (FIG. 14). Arginine butyrate, define the scope of the invention and that methods and phorbol myristate acetate (PMA), trichostatin A (TSA), structures within the scope of these claims and their equiva LHB589, apicidin (API) and largazole (LARG) are shown to lents be covered thereby.

SEQUENCE LISTING

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caaacatgat citgggtcatc ttct c 25 US 2017/0027944 A9 Feb. 2, 2017 21

1. A method for treating neoplasma associated with 11. The method of claim 1, wherein the anti-viral agent is Epstein-Barr infection in a Subject, comprising a nucleoside analog selected from the group consisting of administering to the Subject an inducing agent to induce acyclovir (ACV), ganciclovir (GCV), Valganciclovir, fam expression of a viral gene product in a virus-infected cyclovir, penciclovir (PCV), foscarnet, ribavirin, Zalcitabine cell of the Subject and an anti-viral agent whose anti (ddC), zidovudine (AZT), stavudine (D4T), lamivudine viral activity is directed to the viral gene product (3TC), didanosine (ddl), cytarabine, dideoxyadenosine, expressed, wherein said inducing agent is a HDAC edoxudine, floXuridine, idoZuridine, inosine pranobex, inhibitor, wherein the HDAC inhibitor is a hydroxamic 2'-deoxy-5-(methylamino)uridine, trifluridine and Vidara acid derivative, and wherein said subject is not treated bine. with radiation therapy. 12. The method of claim 1, wherein said anti-viral agent 2. The method according to claim 1, wherein said neo is ganciclovir or Valganciclovir. plasia associated with Epstein-Barr virus infection is a 13. The method of claim 1, wherein the inducing agent is cancer associated with Epstein-Barr virus infection. an HDAC inhibitor having inhibitory activity at 500 nM 3. The method according to claim 1, wherein said neo plasia is selected from the group consisting of lymphoma, concentration. Hodgkin disease, Burkitts lymphoma, post-transplantation 14. The method of claim 1, wherein the inducing agent is lymphoproliferative disease, viral associated lymphoprolif an HDAC inhibitor capable of inducing TK expression at erative disease, hemophagocytic syndrome, nasopharyngeal 500 nM. carcinoma, gastric carcinoma, and breast cancer. 15. The method of claim 1, wherein the inducing agent is 4. The method according to claim 1, wherein said neo an HDAC inhibitor capable of inducing TK expression plasia is lymphoma. within 6 hours of treatment. 5. The method of claim 1, wherein the inducing agent 16. The method of claim 1, wherein said inducing agent induces expression of a viral gene product in a virus-infected is administered orally. cell of the subject, wherein the viral gene product is a viral 17. The method of claim 1, wherein said inducing agent enzyme, an oncogene or proto-oncogene, a transcription and said anti-viral agent are administered for at least one factor, a protease, a polymerase, a reverse transcriptase, a cycle of therapy, said cycle comprising: cell Surface receptor, a structural protein, a major histocom patibility antigen, a growth factor, or a combination thereof. i. administering the inducing agent and the anti-viral 6. The method of claim 4, wherein the viral gene product agent to the Subject over a first period of time; and is a viral enzyme selected from a thymidine kinase (TK) or ii. continuing the administration of the anti-viral agent to protein kinase (PK). the Subject for a second period; wherein said second 7. The method of claim 1, wherein said inducing agent is period represents the remainder of the cycle; panobinostat (LBH589). 18. The method of claim 15, wherein during the first 8. The method of claim 1 wherein said inducing agent period the anti-viral agent and inducing agent are adminis induces viral TK expression. tered in the same composition. 9. The method of claim 1, wherein said inducing agent is 19. The method of claim 15, wherein said first period of administered at a dose of about 0.1 to about 2000 mg/kg/day time is less than or equal to one-half of the length of the or about 1 to about 100 mg/m/day. cycle. 10. The method of claim 1, wherein said anti-viral agent is selected from the group consisting of an interferon, an 20. The method of claim 17, wherein said first period of amino acid analog, a nucleoside analog, an integrase inhibi time is less than or equal to about 5 days, and wherein said tor, a protease inhibitor, a polymerase inhibitor, and a cycle is less than or equal to about 21 days. transcriptase inhibitor. k k k k k