Barriers to a cure for HIV: New ways to target and eradicate HIV-1 reservoirs

The Lancet

Volumn 381, Issue 9883, 2013, Pages 2109-2117

  Katlama, Christine ^a   Deeks, Steven G ^b   Autran, Brigitte ^a   Martinez Picado, Javier ^c   Van Lunzen, Jan ^d   Rouzioux, Christine ^e   Miller, Michael ^f   Vella, Stefano ^g   Schmitz, Joern E ^h   Ahlers, Jeffrey ^j   Richman, Douglas D ⁱ   Sekaly, Rafick P ^j  

^a SORBONNE UNIVERSITÉ   (France)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^d UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^e UNIVERSITÉ PARIS DESCARTES   (France)

^f MERCK RESEARCH LABORATORIES   (United States)

^g Superior Health Institute   (Italy)

^h HARVARD MEDICAL SCHOOL   (United States)

ⁱ UNIVERSITY OF CALIFORNIA   (United States)

^j Vaccine and Gene Therapy Institute of Florida   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ACLARUBICIN; ALPHA2B INTERFERON; ANTIVIRUS AGENT; APHIDICOLIN; BELINOSTAT; BRYOSTATIN 1; CHATEOCIN; COMPLEMENTARY RNA; CYTARABINE; DACTINOMYCIN; DISULFIRAM; GIVINOSTAT; HUMAN IMMUNODEFICIENCY VIRUS VACCINE; INTERLEUKIN 15; INTERLEUKIN 7; JQ 1; MARAVIROC; N (1 BENZYL 4 PIPERIDINYL) 2 (HEXAHYDRO 4 METHYL 1H 1,4 DIAZEPIN 1 YL) 6,7 DIMETHOXY 4 QUINAZOLINAMINE; NUTLIN 3; PANOBINOSTAT; PROSTRATIN; RALTEGRAVIR; RIBOZYME; ROMIDEPSIN; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; VIRUS DNA; VIRUS RNA; VORINOSTAT; ZINC FINGER NUCLEASE;

ANTIVIRAL ACTIVITY; AUTOTRANSPLANTATION; CD4+ T LYMPHOCYTE; DISEASE ERADICATION; DRUG EFFICACY; GENE THERAPY; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; INFECTION CONTROL; NONHUMAN; PRIORITY JOURNAL; REVIEW; RIBOZYME THERAPY; STEM CELL TRANSPLANTATION; VIRUS CELL INTERACTION; VIRUS LATENCY; VIRUS REACTIVATION; VIRUS REPLICATION;

EID: 84878981012     PISSN: 01406736     EISSN: 1474547X     Source Type: Journal    
DOI: 10.1016/S0140-6736(13)60104-X     Document Type: Review

References (113)

1. Hocqueloux L, Prazuck T, Avettand-Fenoel V, et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 2010; 24: 1598-601.
2. Lodi S, Meyer L, Kelleher A, et al. Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Arch Intern Med 2012; 172: 1-4.
3. Goujard C, Girault I, Rouzioux C, et al. HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy. Antivir Ther 2012; 17: 1001-09.
4. Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. NEJM 2009; 360: 692-98.
5. Allers K, Hutter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 2011; 117: 2791-99.
6. Henrich TJ, Sciaranghella G, Li J, et al. Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in two HIV-positive individuals. XIX International AIDS Conference; Washington, DC, USA; 22-27 July 2012. THAA0101.
7. Chun T-W, Justement JS, Moir S, et al. Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis 2007; 195: 1762-64.
8. Ananworanich J, Schuetz A, Vandergeeten C, et al. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One 2012; 7: e33948.
9. Archin NM, Vaidya NK, Kuruc JD, et al. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci USA 2012; 109: 9523-28.
10. von Wyl V, Gianella S, Fischer M, et al. Early antiretroviral therapy during primary HIV-1 infection results in a transient reduction of the viral setpoint upon treatment interruption. PLoS One 2011; 6: e27463.
11. Hufert F, van Lunzen J, Janossy G, et al. Germinal centre CD4+ T cells are an important site of HIV replication in vivo. AIDS 1997; 11: 849-57.
12. Stellbrink H, van Lunzen J, Hufert F, et al. Asymptomatic HIV infection is characterized by rapid turnover of HIV RNA in plasma and lymph nodes but not of latently infected lymph-node CD4+ T cells. AIDS 1997; 11: 1103-10.
13. Chomont N, El-Far M, Ancuta P, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 2009; 15: 893-900.
14. Deeks SG, Autran B, Berkhout B, et al. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 2012; 12: 607-14.
15. Palmer S, Maldarelli F, Wiegand A, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci USA 2008; 105: 3879-84.
16. Chun T-W, Murray D, Justement JS, et al. Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving eff ective antiretroviral therapy. J Infect Dis 2011; 204: 135-38.
17. Sigal A, Kim JT, Balazs AB, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 2011; 477: 95-58.
18. Swiggard WJ, Baytop C, Yu JJ, et al. Human immunodefi ciency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. J Virol 2005; 79: 14179-88.
19. Cameron PU, Saleh S, Sallmann G, et al. Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton. Proc Natl Acad Sci USA 2010; 107: 16934-39.
20. Bosque A, Planelles V. Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood 2009; 113: 58-65.
21. Karn J, Stoltzfus C. Transcriptional and posttranscriptional regulation of HIV-1 gene expression. Cold Spring Harb Perspect Med 2012; 2: a006916.
22. Van Duyne R, Guendel I, Narayanan A, et al. Varying modulation of HIV-1 LTR activity by Baf complexes. J Mol Biol 2011; 411: 581-96.
23. Friedman J, Cho WK, Chu CK, et al. Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol 2011; 85: 9078-89.
24. Hakre S, Chavez L, Shirakawa K, Verdin E. HIV latency: experimental systems and molecular models. FEMS Microbiol Rev 2012; 36: 706-16.
25. Rong L, Perelson AS. Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy. PLoS Comput Biol 2009; 5: e1000533.
26. Llibre J, Buzon MJ, Massanella M, et al. Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: a randomized 48-week study. Antivir Ther 2012; 17: 355-64.
27. Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 2010; 16: 460-65.
28. Yukl SA, Shergill AK, McQuaid K, 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: 2451-60.
29. Cohen J. Tissue says blood is misleading, confusing HIV cure efforts. Science 2011; 334: 1614.
30. Cannon P, June C. Chemokine receptor 5 knockout strategies. Curr Opin HIV AIDS 2011; 6: 74-79.
31. Mussolino C, Morbitzer R, Lutge F, Dannemann N, Lahaye T, Cathomen T. A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res 2011; 39: 9283-93.
32. Schiffer JT, Aubert M, Weber ND, Mintzer E, Stone D, Jerome KR. Targeted DNA mutagenesis for the cure of chronic viral infections. J Virol 2012; 86: 8920-36.
33. Tebas P. Disruption of CCR5 in zinc finger nuclease-treated CD4 T cells: phase I trials. 18th conference on retroviruses and opportunistic infections; Boston, MA, USA; Feb 27-March 2, 2011. 165.
34. Mitsuyasu RT, Merigan TC, Carr A, et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med 2009; 15: 285-92.
35. Wheeler LA, Trifonova R, Vrbanac V, et al. Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras. J Clin Invest 2011; 121: 2401-12.
36. van Lunzen J, Glaunsinger T, Stahmer I, et al. Transfer of autologous gene-modified T Cells in HIV-infected patients with advanced immunodeficiency and drug-resistant virus. Mol Ther 2007; 15: 1024-33.
37. von Laer D, Baum C, Schambach A, et al. Gene therapeutic approaches for immune modulation in AIDS. Anti Inflam Anti Allergy Agents Med Chem 2007; 6: 121-40.
38. Chan JK, Greene WC. Dynamic roles for NF-κB in HTLV-I and HIV-1 retroviral pathogenesis. Immunol Rev 2012; 246: 286-310.
39. Wolschendorf F, Bosque A, Shishido T, et al. Kinase control prevents HIV-1 reactivation in spite of high levels of induced NF-kB activity. J Virol 2012; 86: 4548-58.
40. Mitsuyasu R, Gelman R, Cherng D, et al. The virologic, immunologic, and clinical effects of interleukin 2 with potent antiretroviral therapy in patients with moderately advanced human immunodeficiency virus infection: a randomized controlled clinical trial-AIDS Clinical Trials Group 328. Arch Intern Med 2007; 167: 597-605.
41. Stellbrink H, Hufert F, Tenner-Racz K, et al. Kinetics of productive and latent HIV infection in lymphatic tissue and peripheral blood during triple-drug combination therapy with or without additional interleukin-2. Antivir Ther 1998; 3: 209-14.
42. Kulkosky J, Nunnari G, Otero M, 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: 1403-11.
43. Wolschendorf F, Duverger A, Jones J, et al. Hit-and-run stimulation: a novel concept to reactivate latent HIV-1 infection without cytokine gene induction. J Virol 2010; 84: 8712-20.
44. Perez M, de Vinuesa AG, Sanchez-Duff hues G, et al. Bryostatin-1 synergizes with histone deacetylase inhibitors to reactivate HIV-1 from latency. Curr HIV Res 2010; 8: 418-29.
45. DeChristopher BA, Loy BA, Marsden MD, Schrier AJ, Zack JA, Wender PA. Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro. Nat Chem 2012; 4: 705-10.
46. Van Lint C, Emiliani S, Ott M, Verdin E. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J 1996; 15: 1112-20.
47. Siliciano JD, Lai J, Callender M, et al. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J Infect Dis 2007; 195: 833-36.
48. Archin NM, Cheema M, Parker D, et al. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One 2010; 5: e9390.
49. Routy JP, Tremblay CL, Angel JB, 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: 291-96.
50. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 2012; 487: 482-85.
51. Geleziunas R, Stephan G, Wei G, et al. Search for small molecule activators of latent HIV. International symposium on HIV and emerging infectious diseases; Marseille; May 25, 2012.
52. Kim YK, Mbonye U, Hokello J, Karn J. T-cell receptor signaling enhances transcriptional elongation from latent HIV proviruses by activating P-TEFb through an ERK-dependent pathway. J Mol Biol 2011; 410: 896-916.
53. Gallastegui E, Marshall B, Vidal D, et al. Combination of biological screening in a cellular model of viral latency and virtual screening identifi es novel compounds that reactivate HIV-1. J Virol 2012; 86: 3795-808.
54. Kovochich M, Marsden MD, Zack JA. Activation of latent HIV using drug-loaded nanoparticles. PLoS One 2011; 6: e18270.
55. Wightman F, Ellenberg P, Churchill M, Lewin SR. HDAC inhibitors in HIV. Immunol Cell Biol 2012; 90: 47-54.
56. Rasmussen T, Sogaard O, Melchjorsen J, et al. The histone deacetylase inhibitor (HDACi) panobinostat (LBH589) stimulates HIV-1 expression more potently than other HDACi in clinical use and disrupts HIV latency at clinically achievable concentrations. 19th conference on retrovirus ando Infections; Seattle; March 5-8, 2012, 370.
57. Imai K, Togami H, Okamoto T. Involvement of histone H3 lysine 9 (H3K9) methyltransferase G9a in the maintenance of HIV-1 latency and its reactivation by BIX01294. J Biol Chem 2010; 285: 16538-45.
58. Contreras X, Mzoughi O, Gaston F, Peterlin BM, Bahraoui E. Protein kinase C-delta regulates HIV-1 replication at an early post-entry step in macrophages. Retrovirology 2012; 9: 37.
59. Bouchat S, Gatot J-S, Kabeya K, et al. Histone methyltransferase inhibitors induce HIV-1 recovery in resting CD4+ T cells from HIV-1-infected HAART-treated patients. AIDS 2012; 26: 1473-82.
60. Banerjee C, Archin N, Michaels D, et al. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol 2012; 92: 1147-54.
61. Ye F, Lattif AA, Xie J, Weinberg A, Gao S. Nutlin-3 induces apoptosis, disrupts viral latency and inhibits expression of angiopoietin-2 in Kaposi sarcoma tumor cells. Cell Cycle 2012; 11: 1393-99.
62. Xing S, Bullen CK, Shroff NS, et al. Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation. J Virol 2011; 85: 6060-64.
63. Shishido T, Wolschendorf F, Duverger A, et al. Selected drugs with reported secondary cell-diff erentiating capacity prime latent HIV-1 infection for reactivation. J Virol 2012; 86: 9055-69.
64. Lichterfeld M, Gandhi R, Simmons R, et al. Induction of strong HIV-1-specifi c CD4+ T-cell responses using an HIV-1 gp120/NefTat vaccine adjuvanted with AS02A in antiretroviral-treated HIV-1- infected individuals. J Acquir Immune Defic Syndr 2012; 59: 1-9.
65. Lisziewicz J, Bakare N, Calarota S, et al. Single DermaVir immunization: dose-dependent expansion of precursor/memory T cells against all HIV antigens in HIV-1 infected individuals. PLoS One 2012; 7: e35416.
66. Reuse S, Calao M, Kabeya K, et al. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One 2009; 4: e6093.
67. Desimmie BA, Humbert M, Lescrinier E, et al. Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication. Mol Ther 2012; 20: 2064-75.
68. Sahu G, Cloyd M. Latent HIV in primary T lymphocytes is unresponsive to histone deacetylase inhibitors. Virol J 2011; 8: 1-6.
69. Sakane N, Kwon HS, Pagans S, et al. Activation of HIV Transcription by the Viral Tat Protein Requires a Demethylation Step Mediated by Lysine-specific Demethylase 1 (LSD1/KDM1). PLoS Pathog 2011; 7: e1002184.
70. Spivak A, Andrade A, Hoh R, et al. Safety and feasibility of using disulfiram to enhance HIV transcription among long-term ARV-treated adults: preliminary results from a pilot study. 19th conference on retroviruses and opportunistic infections; Seattle; March 5-8. 48.
71. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 2012; 5: ra46.
72. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2012; 209: 1201-17.
73. Che K, Shankar E, Muthu S, et al. P38MAPK/STAT3 pathway signaling regulates expression of inhibitory molecules in T-cells activated by HIV-1 exposed dendritic cells. Mol Med 2012; 18: 1169-82.
74. Said EA, Dupuy FP, Trautmann L, et al. Programmed death-1- induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 2010; 16: 452-59.
75. Hatano H, Jain V, Hunt PW, et al. Cell-based Measures of Viral Persistence Are Associated with Immune Activation and PD-1 Expressing CD4+ T cells. J Infect Dis (in press).
76. Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 2006; 12: 1198-202.
77. Peretz Y, He Z, Shi Y, et al. CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction. PLoS Pathogns 2012; 8: e1002840.
78. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011; 11: 330-42.
79. Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 2009; 119: 997-1007.
80. Sereti I, Dunham RM, Spritzler J, et al. IL-7 administration drives T cell cycle entry and expansion in HIV-1 infection. Blood 2009; 113: 6304-14.
81. Levy Y, Sereti I, Tambussi G, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis 2012; 55: 291-300.
82. Wang F-X, Xu Y, Sullivan J, et al. IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J Clin Invest 2005; 115: 128-37.
83. Vandergeeten C, DaFonseca S, Fromentin R, Sekaly R, Chomont N. Differential impact of IL-7 and IL-15 on HIV reservoir persistence. 5th International workshop on HIV pesistence during therapy; St Maarten, Dec 6-9, 2011, 29.
84. Sandler NG, Wand H, Roque A, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 2011; 203: 780-90.
85. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12: 1365-71.
86. Marchetti G, Cozzi-Lepri A, Merlini E, et al. Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count. AIDS 2011; 25: 1385-94.
87. van Grevenynghe J, Halwani R, Chomont N, et al. Lymph node architecture collapse and consequent modulation of FOXO3a pathway on memory T- and B-cells during HIV infection. Semin Immunol 2008; 20: 196-203.
88. Zeng M, Southern PJ, Reilly CS, et al. Lymphoid tissue damage in HIV-1 infection depletes naive T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog 2012; 8: e1002437.
89. Tenner-Racz K, Stellbrink H, van Lunzen J, et al. The unenlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 T cell counts are sites for virus replication and CD4 T cell proliferation. The impact of highly active antiretroviral therapy. J Exp Med 1998; 187: 949-59.
90. Stellbrink H, van Lunzen J. Lymph nodes during antiretroviral therapy. Curr Opin Infect Dis 2001; 14: 17-22.
91. Popovic M, Tenner-Racz K, Pelser C, et al. Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy. Proc Natl Acad Sci USA 2005; 102: 14807-12.
92. Catalfamo M, Wilhelm C, Tcheung L, et al. CD4 and CD8 T cell immune activation during chronic HIV infection: roles of homeostasis, HIV, type I IFN, and IL-7. J Immunol 2011; 186: 2106-16.
93. Chen H, Li C, Huang J, et al. CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21. J Clin Invest 2011; 121: 1549-60.
94. Kvale D, Ormaasen V, Kran A, et al. Immune modulatory eff ects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment. AIDS 2006; 20: 813-20.
95. Pettersen FO, Torheim EA, Dahm AE, et al. An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J Virol 2011; 85: 6557-66.
96. Peters JM, Shah YM, Gonzalez FJ. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer 2012; 12: 181-95.
97. Mencarelli A, Francisci D, Renga B, et al. Ritonavir-induced lipoatrophy and dyslipidaemia is reversed by the anti-infl ammatory drug lefl unomide in a PPAR-γ-dependent manner. Antivir Ther 2012; 17: 669-78.
98. Murray SM, Down CM, Boulware DR, et al. Reduction of immune activation with chloroquine therapy during chronic HIV infection. J Virol 2010; 84: 12082-86.
99. Piconi S, Parisotto S, Rizzardini G, et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood 2011; 118: 3263-72.
100. Paton N, Goodall R, Dunn D, et al. Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial. JAMA 2012; 308: 353-61.
101. Shan L, Deng K, Shroff N, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 2012; 36: 491-501.
102. Descours B, Avettand-Fenoel V, Blanc C, et al. Immune responses driven by protective human leukocyte antigen alleles from long-term nonprogressors are associated with low HIV reservoir in central memory CD4 T cells. Clin Infect Dis 2012; 54: 1495-503.
103. Almeida J, Price D, Papagno L, et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med 2007; 204: 2473-85.
104. Berger CT, Frahm N, Price DA, et al. High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted Gag-derived epitopes associated with relative HIV control. J Virol 2011; 85: 9334-45.
105. Autran B, Carcelain G, Combadiere B, Debre P. Therapeutic vaccines for chronic infections. Science 2004; 305: 205-08.
106. Vanham G, Van Gulck E. Can immunotherapy be useful as a "functional cure" for infection with Human Immunodefi ciency Virus-1? Retrovirology 2012; 9: 72.
107. Garcia F, Climent N, Assoumou L, et al. A therapeutic dendritic cell-based vaccine for HIV-1 infection. J Infect Dis 2011; 203: 473-78.
108. Li JZ, Brumme CJ, Lederman MM, et al. Characteristics and outcomes of initial virologic suppressors during analytic treatment interruption in a therapeutic HIV-1 gag vaccine trial. PLoS One 2012; 7: e34134.
109. Azzoni L, Foulkes AS, Papasavvas E, et al. Pegylated Interferon-alpha-2A mono-therapy results in suppression of HIV-1 replication and decreased cell-associated HIV DNA integration. J Infect Dis 2013; 207: 213-22.
110. Ahlers JD, Belyakov IM. Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS. Trends Immunol 2010; 31: 120-30.
111. Vezys V, Penaloza-MacMaster P, Barber DL, et al. 4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection. J Immunol 2011; 187: 1634-42.
112. Aubert RD, Kamphorst AO, Sarkar S, et al. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. Proc Natl Acad Sci USA 2011; 108: 21182-87.
113. Sneller MC, Kopp WC, Engelke KJ, et al. IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of CD8+ T effector memory population in peripheral blood. Blood 2011; 118: 6845-48.