DOCSLIB.ORG

Nnrtis Protease Other Classes STR

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nnrtis Protease Other Classes STR Clinical and Therapeutic aspects of HIV Sabine Kinloch, MD Royal Free Hospital UCL partners University College Medical School London, UK ISHEID 2014 Conflict of interest Travel grants from Gilead and BMS European Union research grant AMFAR grant Acknowledgments The ISHEID speakers for kindly providing their slides Summary - Unable to cover all presentations - ART 2014: state of art, potency, resistance drug development pipeline - Eradication paradigm ART 2014 - Multiple compounds available-LT toxicity- adherence-aging population-comorbidities-R - Newer compounds - Robust pipeline of new drugs (all classes) - Potency and resistance revisited - Gene therapy - Eradication ART 2014 - Co-morbidities: choice of ART, CV, diabetes, bone, kidney - Long-term treatment with aim of (no) or two development of resistance, decrease of side-effects (short and long-term) - LT Adherence: new ART strategies and drugs - ART for resource-limited countries, children/adolescents - Effect of ART on the epidemic ………….and costs and ……generics ART 2014 - Multiple compounds available - Exciting pipeline - Long-term toxicity - Adherence: treatment for decades - Ageing population - Comorbidities Available Antiretrovirals 2014= 25 NRTIs NNRTIs Protease Other Classes STR Abacavir Efavirenz Inhibitors Didanosine Nevirapine Atazanavir Fusion Atripla Emtricitabine Etravirine Darunavir inhibitors Eviplera Lamivudine Rilpivirine Fos-Amprenavir • Enfuvirtide Stavudine Indinavir R5 Inhibitors Stribild Tenofovir Lopinavir • Maraviroc Zidovudine Nelfinavir Integrase Ritonavir Inhibitors Saquinavir • Raltegravir Tipranavir • Elvitegravir • Dolutegravir …a potent armamentarium PI DTG† RPV LPV/r 22 NNRTI FLAMINGO 19 2 16 4,5 - 15 21 INSTI STAR UpECHO to 90% of treatment-naive patients THRIVE SPRING can now achieve undetectable HIVCASTLE, -1 STARTMRK1 RNAACTG1 -520216 13 ATADAR8 RAL EFV ATV/r DRV/r 10 14 2NN ATV/c** Study Study 103 NVP *EFV/FTC/TDF is not licensed for use in antiretroviral naive patients Large head to head study in Europe17,18 EVG/c ** ATV/c is not yet licensed for use in HIV-infected patients in Europe Small head to head study †DTG is not licensed for use in HIV-infected patients in Europe Adapted from: 1. Lennox JL, et al. Lancet 2009;374:796−806. 2. Riddler SA, et al. N Engl J Med 2008;358:2095–106. 3. Sierra-Madero J, et al. JAIDS 2010;53:582–8. 4. Molina J-M, et al. Lancet 2008;372:646–55. 5. Molina J-M, et al. JAIDS 2010;53:323–32. 6. Ortiz R, et al. AIDS 2008;22:1389–97. 7. Mills AM, et al. AIDS 2009;23:1679─88; 8. Martínez E, et al. CROI 2013. Oral presentation 772. URL: http://www.retroconference.org/2013b/Abstracts/47369.htm. 9. Gallant JE, et al. JID 2013 [Epub ahead of print]. 10. DeJesus E, et al. Lancet 2012;379:2429–38. 11. Sax PE, et al. Lancet 2012;379:2439–48. 12. Soriano V, et al. Antivir Ther 2011;16:339–48. 13. Daar ES, et al. Ann Intern Med 2011;154:445–56. 14. van Leth F, et al. Lancet 2004;363:1253–63. 15. Molina J-M, et al. Lancet 2011;378:238–46. 16. Cohen CJ, et al. Lancet 2011;378:229–37. 17. European Medicines Agency http://www.ema.europa.eu (Accessed Apr 2013). 18. ATRIPLA SmPC Available at: http://www.ema.europa.eu Last updated 12/02/2013 (Accessed Apr 2013). 19. Raffi et al. Lancet. 2013;381:735-43. 20. Walmsley S, et al. ICAAC 2012, San Francisco, USA. Oral abstract H-556b http://www.natap.org/2012/ICAAC/ICAAC_06.htm. 21. Cohen C et al. HIV11 2012. Oral presentation O425. URL: http://natap.org/2012/interHIV/InterHIV_15.htm. 22. Feinberg J et al. ICAAC 2013. Abstract H-1464a. http://www.icaaconline.com/php/icaac2013abstracts/start.htm. Toxicities: delayed recognition Strong Delay Drug / class FDA approval Toxicity signal (years) Zidovudine1 1987 Lipoatrophy 1999 12 Stavudine 1 1994 Lipoatrophy 1999 5 Hepatitis / rash at Nevirapine 1996 2005 9 higher CD4 PIs2 1996- Heart attack 2003 7 Efavirenz3 1998 Suicidality 2013 15 Tenofovir4 2001 Kidney disease 2006 5 Tenofovir5 2001 Fracture 2013 12 Raltegravir6 2007 Myopathy 2012 5 1. Saint-Marc T et al, AIDS 1999;13:1659–1667. Cross-sectional, multicentre study. N=43. 2. Friis-Mollen N et al, N Engl J Med 2003;349:1993–2003. Prospective observational study. N=23,468. 3. Mollan et al, IDSA 2013;abstract 670. Cross-study analysis. N=5332 ARV-naive patients (4 studies). 4. Cooper RD et al, Clin Infect Dis 2010; 51:496–505. Meta-analysis of 17 trials (9 RCTs) 5. Bedimo R et al, AIDS 2012;26:825–831. Retrospective analysis. N=56,600. 6. Lee FJ et al, J Acquir Immune Defic Syndr 2013;62:525–533. Cross-sectional, 2-arm prevalence study. N=318. Efficacy: newer treatments outperform EFV Favours EFV Favours Comparator -12% +12% GS-1021 (STB vs. ATR) N=700 -1.6 3.6 8.8 Week 48: Non-inferiority shown 88% vs. 84% (Snapshot) 0.7 5.1 9.4 GS-102/103/1042 (STB vs. ATR) N=1124 Week 48 (Pooled): Statistically significant 89% vs. 84% (Snapshot) higher VL response 3 -1.1 4.1 9.2 STaR (CPA vs. ATR) N=786 Week 48: Non-inferiority shown 86% vs. 82% (Snapshot) 1.1 13.4 89% vs. 82% (Snapshot) 7.2 Week 48: Statistically significant higher VL BLVL ≤100,000 cpm response -1.9 4.2 10.3 STARTMRK4 (RAL vs. EFV) N=566 Week 48: Non-inferiority shown 86% vs. 82% (ITT, NC=F) 1.7 9.5 17.3 Week 240: Statistically significant 71% vs. 61% (ITT, NC=F) higher VL response SINGLE5 (DTG vs. ATR) N=833 2.5 7.4 12.3 Week 48: Statistically significant superior VL 88% vs. 81% (Snapshot) response ECHO/THRIVE6 (RPV vs. ATR) N=1368 -1.7 2.4 6.6 Week 48: Non-inferiority shown 83% vs. 80% (Snapshot) 1.6 6.6 11.5 90% vs. 84% (TLOVR) Week 48: Statistically significant higher VL response BLVL ≤100,000 cpm -20 -15 -10 -5 0 5 10 15 20 Differences in Percentages (95% CI) Newer ARVs have demonstrated higher rates of virologic suppression compared to EFV-based regimens in HIV-1 infected ART-naïve patients 1. Sax P, et al. Lancet 2012;379:2429–38 4. Rockstroh J, et al. IAC 2012; Washington, DC. LBPE019 2. Ward D, et al. ICAAC 2012; San Francisco, CA. Oral H-555 5. Walmsley S, et al. ICAAC 2012; San Francisco, CA. Oral H-556b 3. Cohen C, et al. HIV-11 2012; Glasgow. O425; Data on File 6. Cohen C, et al. JAIDS 2012;60:33-42 ACTG 5257 - atazanavir, raltegravir and darunavir virologically equivalent in naive patients but significant differences for tolerability Phase III DTG trials in treatment-naïve ADULT subjects with HIV Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre study of: SINGLE1 N=833 • DTG (50 mg QD) with ABC/3TC FDC plus EFV/TDF/FTC FDC placebo • EFV/TDF/FTC FDC (QD) plus DTG and ABC/3TC FDC placebo Phase IIIb non-inferiority, randomised, active-controlled, multicentre, FLAMINGO2 N=484 open-label study of: • DTG (50 mg QD) + 2 NRTIs • DRV/r (800 mg*/100 mg QD) + 2 NRTIs Phase III non-inferiority, randomised, double-blind, SPRING-23,4 N=822 double-dummy, multicentre study of: • DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs • RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs *Given as 2 x 400 mg tablets NRTI, nucleoside reverse transcriptase inhibitor 1. Walmsley S et al. N Engl J Med 2013;369:1807-1818 2. Clotet B, et al. Lancet 2014 March 31 [Epub ahead of print] DRV/r, darunavir/ritonavir; QD, once daily; BID, twice daily; 3. Raffi F et al. Lancet 2013;381:735–43 FDC, fixed-dose combination 4. Raffi F et al. Lancet 2013. doi.org/10.1016/S1473-3099(13)70257-3 SINGLE: Week 96 virologic suppression (<50 copies/mL snapshot) At Week 96: DTG + ABC/3TC was superior to EFV/FTC/TDF. Statistically higher response driven by withdrawals for AEs: 3% (DTG arm) vs. 11% (EFV arm) Protocol-defined VFs (confirmed ≥ 50 copies/mL at or after W24) were identical in both arms at Weeks 48 (4%) and 96 (6%) DTG + ABC/3TC QD EFV/TDF/FTC QD 100 DTG: 80% 80 EFV: 72% 60 Week 96 adjusted difference in response (95% CI): 40 +8.0% (+2.3% to +13.8%); P=0.006 20 Proportion of % patients, 0 0 4 8 12 16 24 32 40 48 60 72 84 96 Week Adjusted mean CD4 changes from baseline: 325 cells/mm3 (DTG arm) and 281 cells/mm3 (EFV arm) 3TC, lamivudine; ABC, abacavir; CI, confidence interval; DTG. Dolutegravir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disporoxil fumarate; VF, virologic failure Walmsley S, et al. CROI 2014; Boston, MA. Abs. 14543. Dolutegravir vs efavirenz • At W96, DTG + ABC/3TC was superior to EFV/FTC/TDF [statistically higher responses; 8% (+2.3%, 13.8%)] which was driven by withdrawals due to AEs in the EFV/FTC/TDF arm (3% vs. 11%) DTG: Treatment-emergent resistance through 48 weeks DTG has demonstrated a favourable resistance profile in several studies to date SINGLE study (48 weeks), n1 DTG + ABC/3TC OD (N=414) EFV/TDF/FTC OD (N=419) INI resistant mutations 0 0 NRTI resistant mutations 0 1 (K65K/R) NNRTI resistant mutations 0 4 (K101E, K103N, G190G/A)* SPRING-2 study (48 weeks), n2 DTG OD (N=411) RAL BD (N=411) INI resistant mutations 0 1† NRTI resistant mutations 0 4†‡ FLAMINGO study (48 weeks), n3 DTG OD (N=242) DRV/r OD (N=245) Treatment-emergent primary mutations (INI, NRTI, PI) 0 0 *K101E (n=1); K103N (n=1); G190G/A (n=1); K103N + G190G/A (n=1).
Load more

Recommended publications
  • Mechanisms of HIV Persistence in HIV Reservoirs
    Mechanisms of HIV persistence in HIV reservoirs 1. Mayibongwe Louis Mzingwane* Department of Medical Virology, Faculty of Health Sciences, University of Pretoria, P. Bag X323, ARCADIA 0007, Pretoria, South Africa Department of Pathology, Faculty of Medicine, National University of Science and Technology, P. O Box AC 939, Ascot, Bulawayo, Zimbabwe Email: [email protected] 2. Caroline T. Tiemessen Centre for HIV and Sexually Transmitted Infections, National Institute of communicable Diseases, Private Bag X4, Sandringham, 2131, Johannesburg, South Africa Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Email: [email protected] *Corresponding author Keywords: HIV reservoirs, persistent viremia Running head: HIV compartments and persistence 1 Summary The establishment and maintenance of HIV reservoirs which lead to persistent viremia in patients on antiretroviral (ARV) drugs remains the greatest challenge of the highly active antiretroviral therapy (HAART) era. Cellular reservoirs include resting memory CD4+ T lymphocytes, these implicated as the major HIV reservoir, having a half-life of approximately 44 months while this is less than 6 hours for HIV in plasma. In some individuals persistent viremia consists of invariant HIV clones not detected in circulating resting CD4+ T lymphocytes suggesting other possible sources of residual viremia. Some anatomical reservoirs that may harbour such cells include the brain and the central nervous system (CNS), the gastrointestinal tract (GIT) and the gut-associated lymphoid tissue (GALT) and other lymphoid organs and the genital tract. The presence of immune cells and other HIV susceptible cells, occurring in differing compositions in anatomical reservoirs, coupled with variable and poor drug penetration which results in suboptimal drug concentrations in some sites, are all likely factors that fuel the continued low level replication and persistent viremia during treatment.
    [Show full text]
  • Directed Evolution of an HIV-1 LTR Specific Recombinase for Anti-Retroviral Therapy- a Proof of Concept Study
    Directed evolution of an HIV-1 LTR specific recombinase for anti-retroviral therapy- a proof of concept study. DISSERTATION zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) vorgelegt der Fakultät Mathematik und Naturwissenschaften der Technischen Universität Dresden von INDRANI SARKAR geboren am 03.12.1974, Kolkata, INDIA. Gutachter: Dr. Frank Buchholz Prof. Dr. Francis Stewart Prof. Dr. Joachim Hauber Eingereicht am 14.06.2006 Tag der Verteidigung: i Acknowledgements First and foremost I would like to thank my supervisor, Frank Buchholz for giving me the opportunity to work in his group and for motivating and supporting me through all these years. I am extremely grateful to him for having unlimited patience especially during the long evolution phase of this project and for always giving me helpful advice. He has been very supportive and reassuring in every situation. I am also thankful to him for the great lab retreats he organized. I would like to thank my TAC committee member Francis Stewart for his helpful suggestions. I am grateful to Joachim Hauber and Ilona Hauber (Heinrich-Pette Institute, Hamburg) who collaborated with me on this project and helped me to develop this project and provided me with the HIV-1 LTR based vectors and cell lines. I would like to thank Bianca Habermann for modeling of mutations and also Mayte Pissabarro with whom I had first looked into the recombinase mutations. A special thanks to all my lab members who made the lab a nice place to work in and also MPI-CBG for the friendly and cooperative atmosphere.
    [Show full text]
  • HIV Cure Research: Advances and Prospects
    HIV cure research: advances and prospects. Caroline P Passaes, Asier Sáez-Cirión To cite this version: Caroline P Passaes, Asier Sáez-Cirión. HIV cure research: advances and prospects.. Virology, Elsevier, 2014, 454-455, pp.340-52. 10.1016/j.virol.2014.02.021. pasteur-01420527 HAL Id: pasteur-01420527 https://hal-pasteur.archives-ouvertes.fr/pasteur-01420527 Submitted on 24 Apr 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial - ShareAlike| 4.0 International License HIV cure research: advances and prospects Caroline P. Passaesa,b, Asier Saez-Ciriona a Unité de Régulation des Infections Rétrovirales, Institut Pasteur, 25–28 rue du Dr Roux, 75724 Paris Cedex 15, France. b CEA, Division of Immuno-Virology, iMETI/DSV, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France. Email addresses: [email protected]/[email protected] [email protected] Corresponding author: Asier Saez-Cirion Unité de Régulation des Infections Rétrovirales - Institut Pasteur 25–28 rue du Dr Roux, 75724 Paris Cedex 15, France Tel: +33 145688944; Fax: +33 145688957 E-mail: [email protected] 1 Abstract Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved.
    [Show full text]
  • CONFERENCE CAROUSEL Editor’S Letter
    MARCH-APRIL 2012 IAVIReportThe Publication on AIDS Vaccine Research WWW.IAVIREPORT.ORG | VOLUME 16, NUMBER 2 CROI AND KEYSTONE: CONFERENCE CAROUSEL EDITor’s lETTER When managing editor Kristen Jill Kresge informed her staff that she was leaving the editing of IAVI Report in my hands while she went off to have a baby, I imagine their response was, well, polite. Or maybe not: Kristen is, as subscribers to this magazine doubtless know, a tough act to follow, even temporarily. Fortunately for me, she had the grace—and good sense—to plan out the issue before she went on leave. Aware that major HIV conferences were looming, Kristen dispatched her reporters to cover them. You will notice that they did so with gusto. Our sweeping report from the 19th Conference on Retrovi- ruses and Opportunistic Infections (CROI) may not qualify as light summer reading, but it does have a little something for everybody (see page 4). It recounts how researchers are harnessing new technolo- gies to solve the structure of the recalcitrant HIV spike, and shares insights gleaned from the continu- ing analysis of samples collected during the RV144 trial, which demonstrated for the first time that a wvaccine can prevent HIV transmission. Another segment delves into similar analyses of trials evaluat- ing antiretroviral treatment as a mode of prevention. For those with an appetite for basic biology, the article includes absorbing descriptions of HIV’s interaction with an elusive subclass of T helper cells, and research parsing the evolution of HIV’s intracellular defenses. Our articles on the Keystone Symposia this season are much more focused.
    [Show full text]
  • Highlights from the 2014 International Symposium on HIV
    Lafeuillade et al. AIDS Research and Therapy 2014, 11:28 http://www.aidsrestherapy.com/content/11/1/28 RESEARCH Open Access Highlights from the 2014 International Symposium on HIV & Emerging Infectious Diseases (ISHEID): from cART management to the end of the HIV pandemic Alain Lafeuillade1*, Mark Wainberg2, Marie-Lise Gougeon3, Sabine Kinloch-de Loes4, Philippe Halfon5 and Hervé Tissot-Dupont6 Abstract The 2014 International Symposium on HIV and Emerging Infectious Diseases (ISHEID) provided a forum for investigators to hear the latest research developments in the clinical management of HIV and HCV infections as well as HIV cure research. Combined anti-retroviral therapy (c-ART) has had a profound impact on the disease prognosis and transformed this infection into a chronic disease. However, HIV is able to persist within the infected host and the pandemic is still growing. The main 2014 ISHEID theme was, hence “Together for a world without HIV and AIDS”. In this report we not only give details on this main topic but also summarize what has been discussed in the areas of HCV coinfection and present a short summary on currently emerging viral diseases. Keywords: HIV, HCV, Hepatitis E, Antiretroviral drugs, HIV vaccine, HIV cure, HIV reservoirs Introduction The conference started by “The Thirty Years of Dis- The 2014 International Symposium on HIV and Emerging coveries of HIV” and “The Ten Big Mistakes We Did”. Infectious Diseases (ISHEID) was held in Marseille, Stefano Vella reminded us of the hopes in the early days France, on May 21-23. This meeting attracted more than of the epidemic of a prophylactic vaccine within the next 900 delegates from all over the world (75% outside France) 3 years.
    [Show full text]
  • Abstracts from the International Symposium HIV & Emerging Infectious Diseases 2014 Marseille, France
    BMC Infectious Diseases 2014, Volume 14 Suppl 2 http://www.biomedcentral.com/bmcinfectdis/supplements/14/S2/ MEETING ABSTRACTS Open Access Abstracts from the International Symposium HIV & Emerging Infectious Diseases 2014 Marseille, France. 21-23 May 2014 Published: 23 May 2014 These abstracts are available online at http://www.biomedcentral.com/bmcinfectdis/supplements/14/S2/ Conclusion: UDS was more sensitive than the standard Sanger ORAL PRESENTATIONS sequencing. A combination of UDS and DeepChek® software for the interpretation of DR results saved a considerable amount of time and would help clinicians provide suitable treatments. A cut-off of 1% allowed MANAGING ANTIRETROVIRAL THERAPY, a better characterization of the viral population by identifying additional PART 1 resistance mutations and improving the DR interpretation. O1 Clinical impact of ultra deep versus Sanger sequencing detection of O2 minority mutations on HIV-1 drug resistance genotype interpretation First-line therapy with LPV/r vs NVP and 2 NRTIs in a developing after virological failure country: W144 of a randomized trial Sofiane Mohamed1,4*, Guillaume Penaranda1, Dimitri Gonzalez2, Claire Camus1, Nathan Clumeck*, Claude Mwamba, Kabamba Kabeya, Vincent Calvez, Hacène Khiri1, Ronan Boulmé2, Chalom Sayada2, Patrick Philibert3, Serge Matanda, Dolorès Vaira, Gilles Peytavin, Coca Necsoi, Marc Delforge, Daniel Olive4, Philippe Halfon1 David Kadiebwe, Chantal Milolo, Joe Ilunga, Liévin Kapend 1Alphabio Laboratory, Marseille, France; 2Advanced Biological Laboratories Saint Pierre University Hospital, Brussels, Belgium (ABL), Luxembourg, Luxembourg; 3European Hospital, Marseille, France; BMC Infectious Diseases 2014, 14(Suppl 2):O2 4Paoli Calmettes Institute, Tumor Immunology Laboratory and INSERM Center of Cancer Research, Marseille, France Aim: In resource-limited countries, NNRTI-based regimen may result in BMC Infectious Diseases 2014, 14(Suppl 2):O1 emergence of more HIV drug resistance because of a low genetic barrier.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,871,516 B2 Hauber Et Al
    USOO887.1516 B2 (12) United States Patent (10) Patent No.: US 8,871,516 B2 Hauber et al. (45) Date of Patent: Oct. 28, 2014 (54) USE OF TAILORED RECOMBINASES FOR (56) References Cited THE TREATMENT OF RETROVRAL INFECTIONS U.S. PATENT DOCUMENTS 6,262,341 B1 7/2001 Baszczynski et al. (75) Inventors: Joachim Hauber, Hamburg (DE); 6,890,726 B1 5/2005 Sauer et al. Frank Buchholz, Dresden (DE); Ilona 7,112,715 B2 9, 2006 Chambon et al. Hauber, Hamburg (DE); Francis A 2006, OO14264 A1 1/2006 Sauer et al. Stewart, Dresden (DE); Indrani 2009/0217400 A1* 8/2009 Carmi et al. .................... 800, 14 Sarkar, Kolkata (IN) FOREIGN PATENT DOCUMENTS (73) Assignees: Technische Universität Dresden, WO O2/44409 A2 6, 2002 Dresden (DE); WO 2005/081632 A2 * 9, 2005 Max-Planck-Gesellschaft Zur WO 2008/083931 A1 T 2008 Forderung der Wissenschaften E.V. OTHER PUBLICATIONS München (DE); Heinrich-Pette-Institut fir Experimentelle Virologie und Abremski et al., “Studies on the Properties of P1 Site-Specific Immunologie an der Universität Recombination: Evidence for Topologically Unlinked Products fol Hamburg, Hamburg (DE) lowing Recombination.” Cell 32: 1301-1311, Apr. 1983. Abremski et al., “Bacteriophage P1 Site-specific Recombination— (*) Notice: Subject to any disclaimer, the term of this Purification and Properties of the Cre Recombinase Protein.” J. Biol. patent is extended or adjusted under 35 Chem. 259(3): 1509-1514, Feb. 10, 1984. U.S.C. 154(b) by 651 days. Adachi et al., “Production of Acquired Immunodeficiency Syn drome-Associated Retrovirus in Human and Nonhuman Cells (21) Appl.
    [Show full text]
  • New Treatments and Targets
    NEW TREATMENTS AND TARGETS P174 Universal Tre (uTre) recombinase specifically targets the majority of HIV-1 isolates Karpinski, J*; Chemnitz, J; Hauber, I; Abi-Ghanem, J; Paszkowski-Rogacz, M; Surendranath, V; Chakrabort, D; Hackmann, K; Schröck, E; Pisabarro, M; Hauber, J; Buchholz, F (Dresden, Germany) P175 Targeted destruction of HIV positive cells Sharma, J*; Dodgen, C; Skepu, A; Meyer, M (Cape Town, South Africa) *Indicates presenting author. Universal Tre (uTre) recombinase specifically targets the majority of HIV-1 isolates Janet Karpinski1, Jan Chemnitz2, Ilona Hauber2, Helga Hofmann-Sieber2, Carola Schäfer2, Niklas Beschorner2, Josephine Abi-Ghanem3, Maciej Paszkowski- Rogacz1, Vineeth Surendranath4, Debojyoti Chakraborty1, Karl Hackmann5, Evelin Schröck5, María Teresa Pisabarro3, Joachim Hauber2, Frank Buchholz1,4 1Department of Medical Systems Biology, Medical Faculty Carl Gustav Carus, TU Dresden, Germany, 2Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Hamburg, Germany, 3Department of Structural Bioinformatics, TU Dresden, Germany, 4Max-Planck-Institute for Molecular Cell Biology and Genetics, Dresden, Germany, 5Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, TU Dresden, Germany ABSTRACT Background: Current drugs against HIV can suppress the progression to AIDS but Methods: We employed the search tool SeLOX [3] in Results: Highly specific enzymatic activity on loxLTRu is demonstrated for cannot clear the patient from the virus. Because of potential side effects of these drugs order to find a well-conserved HIV-1 proviral sequence uTre in both Escherichia coli and human cells. Naturally occurring viral variants and the possible development of drug resistance, finding a cure for HIV infection that could serve as target site for a universal Tre from with single mutations within the loxLTRu sequence are also shown to be remains a high priority of HIV/AIDS research.
    [Show full text]
  • NIH Public Access Author Manuscript Clin Pharmacol Ther
    NIH Public Access Author Manuscript Clin Pharmacol Ther. Author manuscript; available in PMC 2014 March 05. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Clin Pharmacol Ther. 2013 January ; 93(1): 46–56. doi:10.1038/clpt.2012.202. Prospects for Treatment of Latent HIV KM Barton1, BD Burch2, N Soriano-Sarabia2, and DM Margolis1,2,3 1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 2Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Abstract Recent advances in antiretroviral therapy (ART) have drastically improved the quality of life for people with HIV infection. However, owing to the persistence of latent HIV in the presence of therapy, patients must remain on therapy indefinitely. Currently, the solution to the HIV pandemic rests on the prevention of new infections and many decades of ART for the steadily expanding number of people infected worldwide. ART is costly, requires ongoing medical care, and can have side effects, thereby preventing its universal availability. Therefore, to escape the ironic burdens of therapy, efforts have begun to develop treatments for latent HIV infection. Current approaches propose either complete eradication of infection or induction of a state of stringent control over viral replication without ART. This review will discuss these strategies in detail and their potential for clinical development. More than 30 million people are currently infected with HIV, and more than two million became newly infected in 2010.1 Significant progress has been made in the treatment of HIV infection, and current therapies allow infected individuals to attain near-normal life spans.
    [Show full text]
  • Tat-Independent Lentivirus Genomes for Vaccination and Host/Pathogen Interaction Studies Deepanwita Bose
    Tat-independent lentivirus genomes for vaccination and host/pathogen interaction studies Deepanwita Bose To cite this version: Deepanwita Bose. Tat-independent lentivirus genomes for vaccination and host/pathogen interac- tion studies. Human health and pathology. Université Grenoble Alpes, 2017. English. NNT : 2017GREAV009. tel-01938074 HAL Id: tel-01938074 https://tel.archives-ouvertes.fr/tel-01938074 Submitted on 28 Nov 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTÉ UNIVERSITÉ GRENOBLE ALPES Spécialité : Virologie/Microbiologie/Immunologie Arrêté ministériel : 7 août 2006 Présentée par Deepanwita BOSE Thèse dirigée par Dr. Yahia Chebloune préparée au sein du Laboratoire Pathogénèse et Vaccination Lentivirales (PAVAL Lab) dans l'École Doctorale Chimie & Sciences du Vivant (ED218) Tat-independent lentivirus genomes for vaccination and host/pathogen interaction studies. Thèse soutenue publiquement le 26 Janvier 2017, devant le jury composé de : Dr. Giuseppe Bertoni Maitre de conférences, IVI, Bern, Suisse Rapporteur Pr. Francois Villinger Professeur, Director of New Iberia Research Center, USA, Rapporteur Pr. Philippe Sabatier Professeur à l’Université Grenoble Alpes, Président Dr.Yahia Chebloune Research Director, à l’Université Grenoble Alpes, Examinateur Dr.
    [Show full text]
  • A M S J HIV/AIDS: Let’S See How Far We’Ve Come
    Review Article A M S J HIV/AIDS: let’s see how far we’ve come Lauren Fowler Lauren is a third year medical student at Griffith University. She has an undergraduate degree Third Year Medicine (Undergraduate) in science from the University of Sydney, and completed immunology honours in HIV retroviral Griffith University genetics, studying microRNA changes during HIV infection. She has a passion for the intricacies BSc (Hons) of the immune system and the pursuit of a cure for HIV. Now more than ever, HIV positive people are living longer and healthier lives because of access to antiretroviral therapy. Healthcare organisations are working to ensure that HIV positive people all over the world have access to the medical care they need to stay healthy. In the last few years, research into vaccine development, genetics-based approaches and novel therapies have achieved some progress and drug therapy regimens have become more effective. Public health strategies have aimed to reduce transmission, and early access to treatment has dramatically improved quality of life. With resources and funding aimed in the right directions, it will be possible to continue making significant progress towards better prevention, improved treatment options and perhaps even a cure for HIV and the elimination of the global AIDS epidemic. This article reviews some of the successes and difficulties in the scientific, research and treatment arm of infection progression to AIDS, and divides the infection into stages combating the HIV epidemic. There is still much work to be done, reflecting the decline in immune function. [11] The stages of infection but for now, let’s see how far we’ve come.
    [Show full text]
  • Directed Evolution of a Recombinase That Excises the Provirus of Most
    ARTICLES Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity Janet Karpinski1,2,11, Ilona Hauber2,11, Jan Chemnitz2,11, Carola Schäfer2,3, Maciej Paszkowski-Rogacz1, Deboyoti Chakraborty1, Niklas Beschorner2, Helga Hofmann-Sieber2,3, Ulrike C Lange2–4, Adam Grundhoff2,3, Karl Hackmann5, Evelin Schrock5, Josephine Abi-Ghanem6, M Teresa Pisabarro6, Vineeth Surendranath7, Axel Schambach8, Christoph Lindner9, Jan van Lunzen2,3,10, Joachim Hauber2,3 & Frank Buchholz1,7 Current combination antiretroviral therapies (cART) efficiently suppress HIV-1 reproduction in humans, but the virus persists as integrated proviral reservoirs in small numbers of cells. To generate an antiviral agent capable of eradicating the provirus from infected cells, we employed 145 cycles of substrate-linked directed evolution to evolve a recombinase (Brec1) that site- specifically recognizes a 34-bp sequence present in the long terminal repeats (LTRs) of the majority of the clinically relevant HIV-1 strains and subtypes. Brec1 efficiently, precisely and safely removes the integrated provirus from infected cells and is efficacious on clinical HIV-1 isolates in vitro and in vivo, including in mice humanized with patient-derived cells. Our data suggest that Brec1 has potential for clinical application as a curative HIV-1 therapy. Although substantial advances have been made in the treatment of HIV We now report the development and application of the broad-range infection using cART, present therapies do not cure HIV-infected indi- recombinase 1 (Brec1) that is active against the majority of HIV-1 viduals1–3. A small population of latent, transcriptionally silent but still primary isolates.
    [Show full text]