Current HIV/AIDS Reports

, Volume 9, Issue 1, pp 5–15

HIV Reservoirs and Strategies for Eradication

  • Miranda Z. Smith
  • Fiona Wightman
  • Sharon R. Lewin
The Science of HIV (AL Landay, Section Editor)

Abstract

Combination antiretroviral therapy (cART) has led to a reduction in morbidity and mortality in HIV-infected patients but therapy is lifelong and there is no cure for HIV. The major barriers to cure include HIV latency, which has been identified in different T-cell subsets, as well as persistence of HIV in anatomical reservoirs. We review recent developments in our understanding of the major reservoirs of HIV in patients on cART as well as how latency is established and maintained in T cells. Finally, we review the scientific rationale of and clinical experience with pharmacotherapeutic strategies aimed at eliminating latently infected cells.

Keywords

Latency Reservoirs Viremia Eradication CD4+ T cells Tissue Gastrointestinal tract Activation Antiretroviral treatment 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Δ32/Δ32 stem-cell transplantation. N Engl J Med. 2009;360:692–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Allers K, Hütter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2011;117:2791–9.PubMedCrossRefGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997;387(6629):183–8.PubMedCrossRefGoogle Scholar
  5. 5.
    • Wightman F, Solomon A, Khoury G, et al. Both CD31(+) and CD31(-) naive CD4(+) T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. J Infect Dis. 2010;202:1738–48. This study demonstrated the significant contribution of naïve CD4+ T cells to HIV persistence on cART and showed that the absolute number of infected naïve CD4+ T cells may increase following cART.PubMedCrossRefGoogle Scholar
  6. 6.
    Fabre-Mersseman V, Dutrieux J, Louise A, et al. CD4 recent thymic emigrants are infected by HIV in vivo, implication for pathogenesis. AIDS. 2011;25(9):1153–62.PubMedCrossRefGoogle Scholar
  7. 7.
    •• Carter CC, Onafuwa-Nuga A, McNamara LA, et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010;16:446–51. The first demonstration of latently infected hematopoietic progenitor cells in patients on stable cART.PubMedCrossRefGoogle Scholar
  8. 8.
    Carter CC, McNamara LA, Onafuwa-Nuga A, et al. HIV-1 utilizes the CXCR4 chemokine receptor to infect multipotent hematopoietic stem and progenitor cells. Cell Host Microbe. 2011;9(3):223–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Gorry PR, Howard JL, Churchill MJ, et al. Diminished production of human immunodeficiency virus type 1 in astrocytes results from inefficient translation of gag, env, and nef mRNAs despite efficient expression of Tat and Rev. J Virol. 1999;73:352–61.PubMedGoogle Scholar
  10. 10.
    Churchill MJ, Gorry PR, Cowley D, et al. Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J Neurovirol. 2006;12:146–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Churchill MJ, Wesselingh SL, Cowley D, et al. Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol. 2009;66:253–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Chun T-W, Nickle DC, Justement JS, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197:714–20.PubMedCrossRefGoogle Scholar
  13. 13.
    • Yukl SA, Gianella S, Sinclair E, et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis. 2010;202:1553–61. This study highlighted the importance of the GI tract as a major reservoir for virus in patients on cART. Importantly, this study suggested that different processes may drive viral persistence in different anatomical regions of the GI tract and the periphery.PubMedCrossRefGoogle Scholar
  14. 14.
    • 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(16):2451–60. This was a small observational study of raltegravir intensification in patients on cART with intense sampling of the GI tract. The study suggested that ongoing replication may occur in the GI tract, specifically the ileum, in some patients on cART.PubMedCrossRefGoogle Scholar
  15. 15.
    Lerner P, Guadalupe M, Donovan R, et al. Gut mucosal viral reservoir in HIV infected patients is not the major source of rebound plasma viremia following HAART interruption. J Virol. 2011;85:4772–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Fischer-Smith T, Croul S, Sverstiuk AE, et al. CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection. J Neurovirol. 2001;7:528–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Edén A, Fuchs D, Hagberg L, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis. 2010;202:1819–25.PubMedCrossRefGoogle Scholar
  18. 18.
    Thacker TC, Zhou X, Estes JD, et al. Follicular dendritic cells and human immunodeficiency virus type 1 transcription in CD4+ T cells. J Virol. 2009;83:150–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Evans V, Saleh S, Haddad E et al. Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4+ T-cells [abstract TUPE0026]. Poster presented at the XVIII International AIDS Conference. Vienna, Austria; 18–23 July, 2010.Google Scholar
  20. 20.
    Lambert-Niclot S, Peytavin G, Duvivier C, et al. Low frequency of intermittent HIV-1 semen excretion in patients treated with darunavir-ritonavir at 600/100 milligrams twice a day plus two nucleoside reverse transcriptase inhibitors or monotherapy. Antimicrob Agents Chemother. 2010;54(11):4910–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Cu-Uvin S, DeLong AK, Venkatesh KK, et al. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS. 2010;24(16):2489–97.PubMedCrossRefGoogle Scholar
  22. 22.
    van Leeuwen E, Ter Heine R, van der Veen F, et al. Penetration of atazanavir in seminal plasma of men infected with human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2007;51:335–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Le Tortorec A, Le Grand R, Denis H, et al. Infection of semen-producing organs by SIV during the acute and chronic stages of the disease. PLoS One. 2008;3:e1792.PubMedCrossRefGoogle Scholar
  24. 24.
    Roulet V, Satie A-P, Ruffault A, et al. Susceptibility of human testis to human immunodeficiency virus-1 infection in situ and in vitro. Am J Pathol. 2006;169:2094–103.PubMedCrossRefGoogle Scholar
  25. 25.
    • North TW, Higgins J, Deere JD, et al. Viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for AIDS. J Virol. 2010;84:2913–22. A comprehensive assessment of anatomical viral reservoirs in SHIV-infected macaques following cART, showing that lymphoid tissue and the GI tract were significant tissue reservoirs, while detection of HIV DNA in the CNS or genital tract was rare.PubMedCrossRefGoogle Scholar
  26. 26.
    Queen SE, Mears BM, Kelly KM, et al. Replication-Competent Simian Immunodeficiency Virus (SIV) Gag escape mutations archived in latent reservoirs during antiretroviral treatment of SIV-infected macaques. J Virol. 2011;85:9167–75.PubMedCrossRefGoogle Scholar
  27. 27.
    Dinoso JB, Rabi SA, Blankson JN, et al. A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J Virol. 2009;83:9247–57.PubMedCrossRefGoogle Scholar
  28. 28.
    Clements JE, Gama L, Graham DR, et al. A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system. Curr Opin HIV AIDS. 2011;6:37–42.PubMedCrossRefGoogle Scholar
  29. 29.
    Palmer S, Wiegand AP, Maldarelli F, 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;41:4531–6.PubMedCrossRefGoogle Scholar
  30. 30.
    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 U S A. 2008;105:3879–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS. 2011;25(7):885–97.PubMedCrossRefGoogle Scholar
  32. 32.
    Bailey JR, Sedaghat AR, Kieffer T, et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol. 2006;80:6441–57.PubMedCrossRefGoogle Scholar
  33. 33.
    Anderson JA, Archin NM, Ince W, et al. Clonal sequences recovered from plasma from patients with residual HIV-1 viremia and on intensified antiretroviral therapy are identical to replicating Viral RNAs recovered from circulating resting CD4+ T cells. J Virol. 2011;85:5220–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Sedaghat AR, Siliciano JD, Brennan TP, et al. Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART. PLoS Pathog. 2007;3:e122.PubMedCrossRefGoogle Scholar
  35. 35.
    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 effective antiretroviral therapy. J Infect Dis. 2011;204:135–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Contreras-Galindo R, Kaplan MH, Leissner P, et al. Human endogenous retrovirus K (HML-2) elements in the plasma of people with lymphoma and breast cancer. J Virol. 2008;82:9329–36.PubMedCrossRefGoogle Scholar
  37. 37.
    Contreras-Galindo R, Kaplan MH, Markovitz DM, et al. Detection of HERV-K(HML-2) viral RNA in plasma of HIV type 1-infected individuals. AIDS Res Hum Retroviruses. 2006;22:979–84.PubMedCrossRefGoogle Scholar
  38. 38.
    Bieda K, Hoffmann A, Boller K. Phenotypic heterogeneity of human endogenous retrovirus particles produced by teratocarcinoma cell lines. J Gen Virol. 2001;82:591–6.PubMedGoogle Scholar
  39. 39.
    Sharkey ME, Teo I, Greenough T, et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nat Med. 2000;6:76–81.PubMedCrossRefGoogle Scholar
  40. 40.
    •• Buzón 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;16:460–5. This randomized study of raltegravir intensification demonstrated a clear increase in 2-LTR circles in a subset of patients and provided evidence that residual replication on cART likely occurs, at least in some patients.PubMedCrossRefGoogle Scholar
  41. 41.
    • Sigal A, Kim JT, Balazs AB et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 2011. This study demonstrated in vitro that the efficiency of viral inhibition by ARV was significantly lower in models of cell-cell transfer of virus compared to cell free infection.Google Scholar
  42. 42.
    Zack JA, Arrigo SJ, Weitsman SR, et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990;61:213–22.PubMedCrossRefGoogle Scholar
  43. 43.
    Doitsh G, Cavrois M, Lassen KG, et al. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell. 2010;143:789–801.PubMedCrossRefGoogle Scholar
  44. 44.
    Pace MJ, Agosto L, O’Doherty U. R5 HIV env and vesicular stomatitis virus G protein cooperate to mediate fusion to naive CD4+ T Cells. J Virol. 2011;85:644–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang Z, Schuler T, Zupancic M, et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science. 1999;286:1353–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Eckstein DA, Penn ML, Korin YD, et al. HIV-1 actively replicates in naive CD4+ T cells residing within human lymphoid tissues. Immunity. 2001;15:671–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Bosque A, Planelles V. Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood. 2009;113:58–65.PubMedCrossRefGoogle Scholar
  48. 48.
    Marini A, Harper JM, Romerio F. Reactivation of HIV-1 latency. J Immunol. 2011;181:7713–20.Google Scholar
  49. 49.
    •• 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 U S A. 2010;107:16934–9. This study described a novel mechanism of how latency is established by direct infection of resting CD4+ T cells following incubation with chemokines that bind to chemokine receptors highly expressed on the surface of resting cells.PubMedCrossRefGoogle Scholar
  50. 50.
    Saleh S, Solomon A, Wightman F, et al. CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency. Blood. 2007;110(13):4161–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Brady T, Agosto LM, Malani N, et al. HIV integration site distributions in resting and activated CD4+ T cells infected in culture. AIDS. 2009;23:1461–71.PubMedCrossRefGoogle Scholar
  52. 52.
    Vatakis DN, Kim S, Kim N, et al. Human immunodeficiency virus integration efficiency and site selection in quiescent CD4+ T cells. J Virol. 2009;83:6222–33.PubMedCrossRefGoogle Scholar
  53. 53.
    Shan L, Yang H-C, Rabi SA et al. Influence of host gene transcription level and orientation on HIV-1 latency in a primary cell model. J Virol 2011.Google Scholar
  54. 54.
    Archin NM, Espeseth A, Parker D, et al. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses. 2009;25(2):207–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Matalon S, Palmer BE, Nold MF, et al. The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression on CD4(+) T-cells and monocytes and is superior to valproic acid for latent HIV-1 expression in vitro. J Acquir Immune Defic Syndr. 2010;54:1–9.PubMedGoogle Scholar
  56. 56.
    Contreras X, Schweneker M, Chen C-S, et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem. 2009;284:6782–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Kim HG, Kim K-C, Roh T-Y, et al. Gene silencing in HIV-1 latency by polycomb repressive group. Virology J. 2011;8:179.CrossRefGoogle Scholar
  58. 58.
    Imai K, Togami H, Okamoto T. Involvement of histone H3 Lysine 9 (H3K9) methyl transferase G9a in the maintenance of HIV-1 latency and its reactivation by BIX01294. J Biol Chem. 2010;285:16538–45.PubMedCrossRefGoogle Scholar
  59. 59.
    Friedman J, Cho W-K, Chu CK, et al. Epigenetic silencing of HIV-1 by the histone H3 lysine 27 Methyltransferase enhancer of Zeste 2 (EZH2). J Virol. 2011;85(17):9078–89.PubMedCrossRefGoogle Scholar
  60. 60.
    Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5:512–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Da Fonseca S, El Far M, Boulassel R et al. A role for negative regulators of T cell activation in the establishment and maintenance of the HIV reservoir [abstract MOPE082]. Poster presented at the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome, Italy; 17–20 July, 2011.Google Scholar
  62. 62.
    Vandergeeten C, Da Fonseca S, Sereti I et al. Differential impact of IL-7 and IL-15 on HIV reservoir persistence [abstract MOAA0101]. Paper presented at the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome, Italy; 17–20 July, 2011.Google Scholar
  63. 63.
    Sheth PM, Chege D, Shin LYY, et al. Immune reconstitution in the sigmoid colon after long-term HIV therapy. Mucosal Immunol. 2008;1:382–8.PubMedCrossRefGoogle Scholar
  64. 64.
    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 [abstract WELBA01]. Paper presented at the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome, Italy; 17–20 July, 2011.Google Scholar
  65. 65.
    Hatano H, Hayes TL, Dahl V, et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. 2011;203:960–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Mavigner M, Delobel P, Cazabat M, et al. HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy. PLoS One. 2009;4:e7658.PubMedCrossRefGoogle Scholar
  67. 67.
    Cohen J. The emerging race to cure HIV infections. Science. 2011;332:784–5. 7–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Wightman F, Ramanayake S, Saleh S et al. Potency and toxicity of HDACi and other immune activators in inducing HIV production using a primary resting T-cell model of HIV latency [abstract 198]. Poster presented at the 18th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 27–March 2, 2011.Google Scholar
  69. 69.
    Choi B-S, Lee HS, Oh Y-T, et al. Novel histone deacetylase inhibitors CG05 and CG06 effectively reactivate latently infected HIV-1. AIDS. 2010;24:609–11.PubMedCrossRefGoogle Scholar
  70. 70.
    Shehu-Xhilaga M, Rhodes D, Wightman F, et al. The novel histone deacetylase inhibitors metacept-1 and metacept-3 potently increase HIV-1 transcription in latently infected cells. AIDS. 2009;23(15):2047–50.PubMedCrossRefGoogle Scholar
  71. 71.
    Archin NM, Keedy KS, Espeseth A et al. Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. AIDS 2009;1799–806.Google Scholar
  72. 72.
    Victoriano AFB, Imai K, Togami H, et al. Novel histone deacetylase inhibitor NCH-51 activates latent HIV-1 gene expression. FEBS Lett. 2011;585:1103–11.PubMedCrossRefGoogle Scholar
  73. 73.
    Blazkova J, Trejbalova K, Halfon P et al. CpG methylation controls reactivation of HIV from latency. PLoS Pathog 2009;5.Google Scholar
  74. 74.
    Fernandez G, Zeichner SL. Cell line-dependent variability in HIV activation employing DNMT inhibitors. Virology J. 2010;7:266.CrossRefGoogle Scholar
  75. 75.
    Bouchat S, Gatot J-S, Kabeya K et al. Reactivation of HIV-1 gene expression by histone methyltransferase inhibitors or DNA methylation inhibitors [abstract MOPE086]. Poster presented at the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Rome, Italy; 17–20 July, 2011.Google Scholar
  76. 76.
    Kulkosky J. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood. 2001;98:3006–15.PubMedCrossRefGoogle Scholar
  77. 77.
    Burnett JC, Lim K-I, Calafi A, et al. Combinatorial latency reactivation for HIV-1 subtypes and variants. J Virol. 2010;84:5958–74.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    Mehla R, Bivalkar-Mehla S, Zhang R, et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One. 2010;5:e11160.PubMedCrossRefGoogle Scholar
  80. 80.
    • Kovochich M, Marsden MD, Zack JA. Activation of latent HIV using drug-loaded nanoparticles. PLoS One. 2011;6:e18270. This study described the development of nanoparticles to deliver the PKC activator bryostatin to activate latent HIV, a novel technology for latency reactivation that could potentially be cell specific.PubMedCrossRefGoogle Scholar
  81. 81.
    Lopez-Huertas MR, Mateos E, Diaz-Gil G, et al. Protein kinase C (PKC) theta (θ) is a specific target for the inhibition of the human immunodeficiency virus type 1 (HIV-1) replication in CD4+ T lymphocytes. J Biol Chem. 2011;1:1–25.Google Scholar
  82. 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.PubMedGoogle Scholar
  83. 83.
    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.PubMedCrossRefGoogle Scholar
  84. 84.
    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.PubMedGoogle Scholar
  85. 85.
    Lin S, Zhang Y, Ying H, Zhu H. HIV-1 Reactivation induced by apicidin involves histone modification in latently infected cells. Curr HIV Res 2011.Google Scholar
  86. 86.
    • 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;85:6060–4. Using a novel in vitro model of HIV latency and high-throughput screening of a drug library, this study identified that the anti-alcohol drug disulfiram can reactivate latent HIV in vitro.PubMedCrossRefGoogle Scholar
  87. 87.
    Micheva-Viteva S, Kobayashi Y, Edelstein LC, et al. High-throughput screening uncovers a compound that activates latent HIV-1 and acts cooperatively with a HDAC inhibitor. J Biol Chem. 2011;286(24):21083–91.PubMedCrossRefGoogle Scholar
  88. 88.
    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.PubMedCrossRefGoogle Scholar
  89. 89.
    Rosenblatt J, Glotzbecker B, Mills H, et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother. 2011;34:409–18.PubMedCrossRefGoogle Scholar
  90. 90.
    Szeto GL, Brice AK, Yang H-C, et al. Minocycline attenuates HIV infection and reactivation by suppressing cellular activation in human CD4+ T cells. J Infect Dis. 2010;201:1132–40.PubMedCrossRefGoogle Scholar
  91. 91.
    Sharkey M, Babic DZ, Greenough T, et al. Episomal viral cDNAs identify a reservoir that fuels viral rebound after treatment interruption and that contributes to treatment failure. PLoS Pathog. 2011;7:e1001303.PubMedCrossRefGoogle Scholar
  92. 92.
    Kieffer TL, Finucane MM, Nettles RE, et al. Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without evolution in treated adults with undetectable HIV loads. J Infect Dis. 2004;189:1452–65.PubMedCrossRefGoogle Scholar
  93. 93.
    Mens H, Pedersen AG, Jørgensen LB, et al. Investigating signs of recent evolution in the pool of proviral HIV type 1 DNA during years of successful HAART. AIDS Res Hum Retroviruses. 2007;23:107–15.PubMedCrossRefGoogle Scholar
  94. 94.
    Dinoso JB, Kim SY, Wiegand AM, 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;106:9403–8.PubMedCrossRefGoogle Scholar
  95. 95.
    McMahon D, Jones J, Wiegand A, 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(6):912–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Gandhi RT, Bosch RJ, Aga E, et al. No evidence for decay of the latent reservoir in HIV-1-infected patients receiving intensive enfuvirtide-containing antiretroviral therapy. J Infect Dis. 2010;201:293–6.PubMedCrossRefGoogle Scholar
  97. 97.
    Hermankova M, Ray SC, Ruff C, et al. HIV-1 drug resistance profiles in children and adults with viral load of <50 copies/ml receiving combination therapy. JAMA. 2001;286(2):196–207.PubMedCrossRefGoogle Scholar
  98. 98.
    Kearney M, Spindler J, Shao W, et al. Genetic diversity of simian immunodeficiency virus encoding HIV-1 reverse transcriptase persists in macaques despite antiretroviral therapy. J Virol. 2011;85(2):1067–76.PubMedCrossRefGoogle Scholar
  99. 99.
    Matalon S, Rasmussen TA, Dinarello CA. HDAC inhibitors for purging HIV-1 from the latent reservoir. Mol Med 2011.Google Scholar
  100. 100.
    Lewis MG, Dafonseca S, Chomont N et al. Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS 2011;1–10.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Miranda Z. Smith
    • 1
    • 2
  • Fiona Wightman
    • 1
    • 2
  • Sharon R. Lewin
    • 1
    • 2
    • 3
  1. 1.Department of Medicine, Central Clinical SchoolMonash UniversityMelbourneAustralia
  2. 2.Centre for VirologyBurnet InstituteMelbourneAustralia
  3. 3.Infectious Diseases UnitAlfred HospitalMelbourneAustralia

Personalised recommendations