HIV-1 Eradication: Early Trials (and Tribulations)

Trends in Molecular Medicine

Volumn 22, Issue 1, 2016, Pages 10-27

  Spivak, Adam M ^a   Planelles, Vicente ^a  

^a UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; DIDANOSINE; DISULFIRAM; ENFUVIRTIDE; GAMMA INTERFERON; HISTONE DEACETYLASE INHIBITOR; HYDROXYUREA; INTERLEUKIN 2; OKT 3; PANOBINOSTAT; RECOMBINANT INTERLEUKIN 15; RECOMBINANT INTERLEUKIN 2; RECOMBINANT INTERLEUKIN 7; ROMIDEPSIN; VALPROIC ACID; VORINOSTAT; ZIDOVUDINE;

ANTIVIRAL THERAPY; CD4+ T LYMPHOCYTE; CLINICAL TRIAL (TOPIC); HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; LATENT VIRUS INFECTION; LYMPHOCYTOPENIA; NONHUMAN; OUTCOME ASSESSMENT; PERSISTENT VIRUS INFECTION; POLYMERASE CHAIN REACTION; REVIEW; T LYMPHOCYTE ACTIVATION; VIRAL CLEARANCE; VIREMIA; VIRUS LATENCY; VIRUS LOAD; VIRUS MUTATION; VIRUS REPLICATION; ANIMAL; DISEASE ERADICATION; DRUG EFFECTS; HIV INFECTIONS; VIROLOGY;

ANIMALS; CD4-POSITIVE T-LYMPHOCYTES; DISEASE ERADICATION; HIV INFECTIONS; HIV-1; HUMANS; VIRUS LATENCY;

EID: 84952864287     PISSN: 14714914     EISSN: 1471499X     Source Type: Journal    
DOI: 10.1016/j.molmed.2015.11.004     Document Type: Review

References (106)

1. Hammer S.M., et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N. Engl. J. Med. 1997, 337:725-733.
2. Gulick R.M., et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N. Engl. J. Med. 1997, 337:734-739.
3. Egger M., et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002, 360:119-129.
4. Mellors J.W., et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann. Intern. Med. 1995, 122:573-579.
5. Mellors J.W., et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996, 272:1167-1170.
6. Mocroft A., et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998, 352:1725-1730.
7. Palella F.J., et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N. Engl. J. Med. 1998, 338:853-860.
8. Chun T.W., et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. U.S.A. 1997, 94:13193-13197.
9. Finzi D., et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997, 278:1295-1300.
10. Wong J.K., et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997, 278:1291-1295.
11. Crooks A.M., et al. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J. Infect. Dis. 2015, 212:1361-1365.
12. + T cells. Nat. Med. 2003, 9:727-728.
13. Ruelas D.S., Greene W.C. An integrated overview of HIV-1 latency. Cell 2013, 155:519-529.
14. Davey R.T., et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natl. Acad. Sci. U.S.A. 1999, 96:15109-15114.
15. Josefsson L., et al. The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:E4987-E4996.
16. Dinoso J.B., et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:9403-9408.
17. Gandhi R.T., et al. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J. Acquir. Immune Defic. Syndr. 2012, 59:229-235.
18. McMahon D., et al. Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin. Infect. Dis. 2010, 50:912-919.
19. Yukl S.A., et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 2010, 24:2451-2460.
20. + T cells. J. Infect. Dis. 2015, 212:1345-1347.
21. Hutter G., et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N. Engl. J. Med. 2009, 360:692-698.
22. Durand C.M., et al. Developing strategies for HIV-1 eradication. Trends Immunol. 2012, 33:554-562.
23. Rasmussen T.A., et al. Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum. Vaccines Immunotherapeutics 2013, 9:993-1001.
24. Van Lint C., et al. HIV-1 transcription and latency: an update. Retrovirology 2013, 10:67.
25. Cannon P., June C. Chemokine receptor 5 knockout strategies. Curr. Opin. HIV AIDS 2011, 6:74-79.
26. Tebas P., et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 2014, 370:901-910.
27. Deeks S.G. HIV: shock and kill. Nature 2012, 487:439-440.
28. Choudhary S.K., Margolis D.M. Curing HIV: pharmacologic approaches to target HIV-1 latency. Annu. Rev. Pharmacol. Toxicol. 2011, 51:397-418.
29. Xing S., Siliciano R.F. Targeting HIV latency: pharmacologic strategies toward eradication. Drug Discov. Today 2013, 18:541-551.
30. Towards an HIV cure: a global scientific strategy. Nat. Rev. Immunol. 2012, 12:607-614. International AIDS Society Scientific Working Group on HIV Cure.
31. Richman D.D., et al. The challenge of finding a cure for HIV infection. Science 2009, 323:1304-1307.
32. Bruner K.M., et al. Towards an HIV-1 cure: measuring the latent reservoir. Trends Microbiol. 2015, 23:192-203.
33. Eisele E., Siliciano R.F. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 2012, 37:377-388.
34. Eriksson S., et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 2013, 9:e1003174.
35. Bullen C.K., et al. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat. Med. 2014, 20:425-429.
36. + T lymphocytes in vivo. J. Virol. 2003, 77:7383-7392.
37. Laird G.M., et al. Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS Pathog. 2013, 9:e1003398.
38. Nettles R.E., et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA 2005, 293:817-829.
39. Palmer S., et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J. Clin. Microbiol. 2003, 41:4531-4536.
40. Rasmussen T.A., et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV 2014, 1:e13-e21.
41. Ho Y.C., et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 2013, 155:540-551.
42. Sanchez G., et al. Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J. Virol. 1997, 71:2233-2240.
43. Hill A.L., et al. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. Proc. Natl. Acad. Sci. U.S.A. 2014, 111:13475-13480.
44. Singh A., Weinberger L.S. Stochastic gene expression as a molecular switch for viral latency. Curr. Opin. Microbiol. 2009, 12:460-466.
45. Chun T.W., et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS 2010, 24:2803-2808.
46. Kaufmann D.E., et al. Limited durability of viral control following treated acute HIV infection. PLoS Med. 2004, 1:e36.
47. Lafeuillade A., et al. Predictors of plasma human immunodeficiency virus type 1 RNA control after discontinuation of highly active antiretroviral therapy initiated at acute infection combined with structured treatment interruptions and immune-based therapies. J. Infect. Dis. 2003, 188:1426-1432.
48. Saez-Cirion A., et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013, 9:e1003211.
49. Steingrover R., et al. HIV-1 viral rebound dynamics after a single treatment interruption depends on time of initiation of highly active antiretroviral therapy. AIDS 2008, 22:1583-1588.
50. Yerly S., et al. Proviral HIV-DNA predicts viral rebound and viral setpoint after structured treatment interruptions. AIDS 2004, 18:1951-1953.
51. Ciuffi A., et al. Bioinformatics and HIV latency. Curr. HIV/AIDS Rep. 2015, 12:97-106.
52. Henrich T.J., et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J. Infect. Dis. 2013, 207:1694-1702.
53. Persaud D., et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N. Engl. J. Med. 2013, 369:1828-1835.
54. Henrich T.J., et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann. Intern. Med. 2014, 161:319-327.
55. Luzuriaga K., et al. Viremic relapse after HIV-1 remission in a perinatally infected child. N. Engl. J. Med. 2015, 372:786-788.
56. + count-guided interruption of antiretroviral treatment. N. Engl. J. Med. 2006, 355:2283-2296. Strategies for Management of Antiretroviral Therapy Study.
57. Ghosn J., Delaugerre C. Can we avoid treatment interruption studies in the search for an HIV cure?. AIDS 2015, 29:1575-1577.
58. Li J.Z., et al. The need for treatment interruption studies and biomarker identification in the search for an HIV cure. AIDS 2015, 29:1429-1432.
59. Ho D.D., et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:123-126.
60. Perelson A.S., et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997, 387:188-191.
61. Zack J.A., et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 1990, 61:213-222.
62. + T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat. Med. 1999, 5:651-655.
63. Lafeuillade A., et al. Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission. J. Acquir. Immune Defic. Syndr. 2001, 26:44-55.
64. Stellbrink H.J., et al. Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS 2002, 16:1479-1487.
65. Kulkosky J., et al. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J. Infect. Dis. 2002, 186:1403-1411.
66. Prins J.M., et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 1999, 13:2405-2410.
67. van Laar J.M., et al. Reversible neurotoxicity during interleukin-2 therapy for metastatic renal cell carcinoma. Eur. J. Cancer 1995, 31A:1895-1897.
68. Sosman J.A., et al. Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects. J. Clin. Oncol. 1993, 11:1496-1505.
69. + cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J. Virol. 2010, 84:6425-6437.
70. Mbonye U., Karn J. Transcriptional control of HIV latency: cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology 2014, 454-455:328-339.
71. Lehrman G., et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 2005, 366:549-555.
72. Routy J.P. Valproic acid: a potential role in treating latent HIV infection. Lancet 2005, 366:523-524.
73. Sagot-Lerolle N., et al. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS 2008, 22:1125-1129.
74. Siliciano J.D., et al. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J. Infect. Dis. 2007, 195:833-836.
75. + cell infection. PLoS ONE 2010, 5:e9390.
76. + T cells. AIDS 2008, 22:1131-1135.
77. Routy J.P., et al. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012, 13:291-296.
78. Schooley R.T., Mellors J.W. No cure yet for HIV-1, but therapeutic research presses on. J. Infect. Dis. 2007, 195:770-772.
79. + T cell model without inducing global T cell activation. J. Virol. 2011, 85:6060-6064.
80. Doyon G., et al. Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog. AIDS 2013, 27:F7-F11.
81. Spivak A.M., et al. A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin. Infect. Dis. 2014, 58:883-890.
82. + T cells after multiple doses of vorinostat. J. Infect. Dis. 2014, 210:728-735.
83. Archin N.M., et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 2012, 487:482-485.
84. Elliott J.H., et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014, 10:e1004473.
85. Procopio F.A., et al. A novel assay to measure the magnitude of the inducible viral reservoir in HIV-infected individuals. EBioMedicine 2015, 2:872-881.
86. Ocio E.M., et al. Evidence of long-term disease control with panobinostat maintenance in patients with relapsed multiple myeloma. Haematologica 2015, 100:e289-e291.
87. Richardson P.G., et al. Panobinostat: a novel pan-deacetylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma. Expert Rev. Anticancer Ther. 2015, 15:737-748.
88. Wei D.G., et al. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog. 2014, 10:e1004071.
89. Sogaard O.S., et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015, 11:e1005142.
90. + T cells from aviremic patients. PLoS Pathog. 2013, 9:e1003834.
91. Dinoso J.B., et al. A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J. Virol. 2009, 83:9247-9257.
92. Mavigner M., et al. Persistence of virus reservoirs in ART-treated SHIV-infected rhesus macaques after autologous hematopoietic stem cell transplant. PLoS Pathog. 2014, 10:e1004406.
93. Denton P.W., et al. Generation of HIV latency in humanized BLT mice. J. Virol. 2012, 86:630-634.
94. Honeycutt J.B., et al. HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model. Retrovirology 2013, 10:121.
95. Marsden M.D., et al. HIV latency in the humanized BLT mouse. J. Virol. 2012, 86:339-347.
96. Marsden M.D., Zack J.A. Studies of retroviral infection in humanized mice. Virology 2015, 479-480:297-309.
97. Laird G.M., et al. Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J. Clin. Invest. 2015, 125:1901-1912.
98. + T cells from aviremic patients. Antimicrob. Agents Chemother. 2015, 59:5984-5991.
99. Darcis G., et al. An in-depth comparison of latency-reversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified bryostatin-1+JQ1 and ingenol-B+JQ1 to potently reactivate viral gene expression. PLoS Pathog. 2015, 11:e1005063.
100. Jiang G., et al. Synergistic reactivation of latent HIV expression by ingenol-3-angelate, PEP005, targeted NF-kB signaling in combination with JQ1 induced p-TEFb activation. PLoS Pathog. 2015, 11:e1005066.
101. Dampier W., et al. HIV excision utilizing CRISPR/Cas9 technology: attacking the proviral quasispecies in reservoirs to achieve a cure. MOJ Immunol. 2014, 1:00022.
102. Mousseau G., et al. An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription. Cell Host Microbe 2012, 12:97-108.
103. Mousseau G., et al. The Tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from latency. mBio 2015, 6:e00465.
104. Agosto L.M., et al. Patients on HAART often have an excess of unintegrated HIV DNA: implications for monitoring reservoirs. Virology 2011, 409:46-53.
105. O'Doherty U., et al. A sensitive, quantitative assay for human immunodeficiency virus type 1 integration. J. Virol. 2002, 76:10942-10950.
106. Elliott J.H., et al. Short term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV 2015, 2:e520-e529.