1932

Abstract

Although antiretroviral therapy (ART) can reduce viremia to below the limit of detection and allow persons living with HIV-1 (PLWH) to lead relatively normal lives, viremia rebounds when treatment is interrupted. Rebound reflects viral persistence in a stable latent reservoir in resting CD4+ T cells. This reservoir is now recognized as the major barrier to cure and is the focus of intense international research efforts. Strategies to cure HIV-1 infection include interventions to eliminate this reservoir, to prevent viral rebound from the reservoir, or to enhance immune responses such that viral replication is effectively controlled. Here we consider recent developments in understanding the composition of the reservoir and how it can be measured in clinical studies. We also discuss exciting new insights into the in vivo dynamics of the reservoir and the reasons for its remarkable stability. Finally we discuss recent discoveries on the complex processes that govern viral rebound.

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2022-01-24
2024-06-14
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Literature Cited

  1. 1. 
    Saag MS, Gandhi RT, Hoy JF, Landovitz RJ, Thompson MA et al. 2020. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society–USA panel. JAMA 324:1651–69
    [Google Scholar]
  2. 2. 
    Davey RT Jr., Bhat N, Yoder C, Chun TW, Metcalf JA et al. 1999. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. PNAS 96:15109–14
    [Google Scholar]
  3. 3. 
    Rothenberger MK, Keele BF, Wietgrefe SW, Fletcher CV, Beilman GJ et al. 2015. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. PNAS 112:1126–34
    [Google Scholar]
  4. 4. 
    Li JZ, Etemad B, Ahmed H, Aga E, Bosch RJ et al. 2016. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AIDS 30:343–53
    [Google Scholar]
  5. 5. 
    Wen Y, Bar KJ, Li JZ. 2018. Lessons learned from HIV antiretroviral treatment interruption trials. Curr. Opin. HIV AIDS 13:416–21
    [Google Scholar]
  6. 6. 
    Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF 1995. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat. Med. 1:1284–90
    [Google Scholar]
  7. 7. 
    Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA et al. 1997. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387:183–88
    [Google Scholar]
  8. 8. 
    Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C et al. 1997. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278:1295–300
    [Google Scholar]
  9. 9. 
    Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC et al. 1997. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278:1291–95
    [Google Scholar]
  10. 10. 
    Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA et al. 1997. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. PNAS 94:13193–97
    [Google Scholar]
  11. 11. 
    Coffin JM. 1992. Genetic diversity and evolution of retroviruses. Curr. Top. Microbiol. Immunol. 176:143–64
    [Google Scholar]
  12. 12. 
    Mansky LM, Temin HM. 1995. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J. Virol. 69:5087–94
    [Google Scholar]
  13. 13. 
    Kieffer TL, Finucane MM, Nettles RE, Quinn TC, Broman KW et al. 2004. 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. 189:1452–65
    [Google Scholar]
  14. 14. 
    Bailey JR, Sedaghat AR, Kieffer T, Brennan T, Lee PK et al. 2006. 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. 80:6441–57
    [Google Scholar]
  15. 15. 
    Evering TH, Mehandru S, Racz P, Tenner-Racz K, Poles MA et al. 2012. Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection. PLOS Pathog 8:e1002506
    [Google Scholar]
  16. 16. 
    Josefsson L, von Stockenstrom S, Faria NR, Sinclair E, Bacchetti P et al. 2013. The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. PNAS 110:4987–96
    [Google Scholar]
  17. 17. 
    Kearney MF, Spindler J, Shao W, Yu S, Anderson EM et al. 2014. Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLOS Pathog 10:e1004010
    [Google Scholar]
  18. 18. 
    Kearney MF, Anderson EM, Coomer C, Smith L, Shao W et al. 2015. Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy. Retrovirology 12:93
    [Google Scholar]
  19. 19. 
    Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J et al. 2016. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530:758851–56
    [Google Scholar]
  20. 20. 
    Rosenbloom DIS, Hill AL, Laskey SB, Siliciano RF. 2016. Re-evaluating evolution in the HIV reservoir. Nature 551:7681E6–9
    [Google Scholar]
  21. 21. 
    Brodin J, Zanini F, Thebo L, Lanz C, Bratt G et al. 2016. Establishment and stability of the latent HIV-1 DNA reservoir. eLife 5:e18889
    [Google Scholar]
  22. 22. 
    Van Zyl GU, Katusiime MG, Wiegand A, McManus WR, Bale MJ et al. 2017. No evidence of HIV replication in children on antiretroviral therapy. J. Clin. Investig. 127:3827–34
    [Google Scholar]
  23. 23. 
    Lorenzi JC, Cohen YZ, Cohn LB, Kreider EF, Barton JP et al. 2016. Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. PNAS 113:E7908–16
    [Google Scholar]
  24. 24. 
    Hosmane NN, Kwon KJ, Bruner KM, Capoferri AA, Beg S et al. 2017. Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics. J. Exp. Med. 214:959–72
    [Google Scholar]
  25. 25. 
    Bui JK, Sobolewski MD, Keele BF, Spindler J, Musick A et al. 2017. Proviruses with identical sequences comprise a large fraction of the replication-competent HIV reservoir. PLOS Pathog 13:e1006283
    [Google Scholar]
  26. 26. 
    Shen L, Peterson S, Sedaghat AR, McMahon MA, Callender M et al. 2008. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat. Med. 14:762–66
    [Google Scholar]
  27. 27. 
    Shen L, Rabi SA, Sedaghat AR, Shan L, Lai J et al. 2011. A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci. Transl. Med. 3:91ra63
    [Google Scholar]
  28. 28. 
    Jilek BL, Zarr M, Sampah ME, Rabi SA, Bullen CK et al. 2012. A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat. Med. 18:446–51
    [Google Scholar]
  29. 29. 
    Pierson T, Hoffman TL, Blankson J, Finzi D, Chadwick K et al. 2000. Characterization of chemokine receptor utilization of viruses in the latent reservoir for human immunodeficiency virus type 1. J. Virol. 74:7824–33
    [Google Scholar]
  30. 30. 
    Shan L, Deng K, Gao H, Xing S, Capoferri AA et al. 2017. Transcriptional reprogramming during effector-to-memory transition renders CD4+ T cells permissive for latent HIV-1 infection. Immunity 47:766–75.e3
    [Google Scholar]
  31. 31. 
    Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W et al. 2012. SAMHD1 restricts HIV-1 infection in resting CD4+ T cells. Nat. Med. 18:1682–87
    [Google Scholar]
  32. 32. 
    Descours B, Cribier A, Chable-Bessia C, Ayinde D, Rice G et al. 2012. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells. Retrovirology 9:87
    [Google Scholar]
  33. 33. 
    Ruffin N, Brezar V, Ayinde D, Lefebvre C, Schulze Zur Wiesch J et al. 2015. Low SAMHD1 expression following T-cell activation and proliferation renders CD4+ T cells susceptible to HIV-1. AIDS 29:519–30
    [Google Scholar]
  34. 34. 
    Nabel G, Baltimore D. 1987. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326:711–13
    [Google Scholar]
  35. 35. 
    Bohnlein E, Lowenthal JW, Siekevitz M, Ballard DW, Franza BR, Greene WC. 1988. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell 53:827–36
    [Google Scholar]
  36. 36. 
    Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB. 1989. Tumor necrosis factor α activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-κB sites in the long terminal repeat. PNAS 86:5974–78
    [Google Scholar]
  37. 37. 
    Kao SY, Calman AF, Luciw PA, Peterlin BM. 1987. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 330:489–93
    [Google Scholar]
  38. 38. 
    Herrmann CH, Rice AP. 1995. Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. J. Virol. 69:1612–20
    [Google Scholar]
  39. 39. 
    Zhu Y, Pe'ery T, Peng J, Ramanathan Y, Marshall N et al. 1997. Transcription elongation factor P-TEFb is required for HIV-1 Tat transactivation in vitro. Genes Dev 11:2622–32
    [Google Scholar]
  40. 40. 
    Liou LY, Herrmann CH, Rice AP. 2002. Transient induction of cyclin T1 during human macrophage differentiation regulates human immunodeficiency virus type 1 Tat transactivation function. J. Virol. 76:10579–87
    [Google Scholar]
  41. 41. 
    Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA et al. 1995. Viral dynamics in human immuno-deficiency virus type 1 infection. Nature 373:117–22
    [Google Scholar]
  42. 42. 
    Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M 1995. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123–26
    [Google Scholar]
  43. 43. 
    Van Lint C, Emiliani S, Ott M, Verdin E. 1996. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J. 15:1112–20
    [Google Scholar]
  44. 44. 
    He G, Ylisastigui L, Margolis DM 2002. The regulation of HIV-1 gene expression: the emerging role of chromatin. DNA Cell Biol. 21:697–705
    [Google Scholar]
  45. 45. 
    Pearson R, Kim YK, Hokello J, Lassen K, Friedman J et al. 2008. Epigenetic silencing of human immunodeficiency virus (HIV) transcription by formation of restrictive chromatin structures at the viral long terminal repeat drives the progressive entry of HIV into latency. J. Virol. 82:12291–303
    [Google Scholar]
  46. 46. 
    Jordan A, Bisgrove D, Verdin E. 2003. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J 22:1868–77
    [Google Scholar]
  47. 47. 
    Takaki A, Wiese M, Maertens G, Depla E, Seifert U et al. 2000. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat. Med. 6:578–82
    [Google Scholar]
  48. 48. 
    Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA et al. 2003. Duration of antiviral immunity after smallpox vaccination. Nat. Med. 9:1131–37
    [Google Scholar]
  49. 49. 
    Swiggard WJ, Baytop C, Yu JJ, Dai J, Li C et al. 2005. Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. J. Virol. 79:14179–88
    [Google Scholar]
  50. 50. 
    Chavez L, Calvanese V, Verdin E 2015. HIV latency is established directly and early in both resting and activated primary CD4 T cells. PLOS Pathog 11:e1004955
    [Google Scholar]
  51. 51. 
    Saleh S, Solomon A, Wightman F, Xhilaga M, Cameron PU, Lewin SR 2007. 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 110:4161–64
    [Google Scholar]
  52. 52. 
    Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS 1998. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. PNAS 95:8869–73
    [Google Scholar]
  53. 53. 
    Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J et al. 2014. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512:74–77
    [Google Scholar]
  54. 54. 
    Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M et al. 2015. Viremic relapse after HIV-1 remission in a perinatally infected child. N. Engl. J. Med. 372:786–88
    [Google Scholar]
  55. 55. 
    Colby DJ, Trautmann L, Pinyakorn S, Leyre L, Pagliuzza A et al. 2018. Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection. Nat. Med. 24:923–26
    [Google Scholar]
  56. 56. 
    Korin YD, Brooks DG, Brown S, Korotzer A, Zack JA 2002. Effects of prostratin on T-cell activation and human immunodeficiency virus latency. J. Virol. 76:8118–23
    [Google Scholar]
  57. 57. 
    Scripture-Adams DD, Brooks DG, Korin YD, Zack JA. 2002. Interleukin-7 induces expression of latent human immunodeficiency virus type 1 with minimal effects on T-cell phenotype. J. Virol. 76:13077–82
    [Google Scholar]
  58. 58. 
    Brooks DG, Hamer DH, Arlen PA, Gao L, Bristol G et al. 2003. Molecular characterization, reactivation, and depletion of latent HIV. Immunity 19:413–23
    [Google Scholar]
  59. 59. 
    Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. 2004. Coaxing HIV-1 from resting CD4 T cells: Histone deacetylase inhibition allows latent viral expression. AIDS 18:1101–8
    [Google Scholar]
  60. 60. 
    Williams SA, Chen LF, Kwon H, Fenard D, Bisgrove D et al. 2004. Prostratin antagonizes HIV latency by activating NF-κB. J. Biol. Chem. 279:42008–17
    [Google Scholar]
  61. 61. 
    Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD et al. 2012. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487:482–85
    [Google Scholar]
  62. 62. 
    Borducchi EN, Cabral C, Stephenson KE, Liu J, Abbink P et al. 2016. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature 540:284–87
    [Google Scholar]
  63. 63. 
    Borducchi EN, Liu J, Nkolola JP, Cadena AM, Yu WH et al. 2018. Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature 563:360–64
    [Google Scholar]
  64. 64. 
    Nixon CC, Mavigner M, Sampey GC, Brooks AD, Spagnuolo RA et al. 2020. Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo. Nature 578:160–65
    [Google Scholar]
  65. 65. 
    Spivak AM, Planelles V. 2016. HIV-1 eradication: early trials (and tribulations). Trends Mol. Med. 22:10–27
    [Google Scholar]
  66. 66. 
    Folks T, Powell DM, Lightfoote MM, Benn S, Martin MA, Fauci AS 1986. Induction of HTLV-III/LAV from a nonvirus-producing T-cell line: implications for latency. Science 231:600–2
    [Google Scholar]
  67. 67. 
    Sahu GK, Lee K, Ji J, Braciale V, Baron S, Cloyd MW 2006. A novel in vitro system to generate and study latently HIV-infected long-lived normal CD4+ T-lymphocytes. Virology 355:127–37
    [Google Scholar]
  68. 68. 
    Yang HC, Xing S, Shan L, O'Connell K, Dinoso J et al. 2009. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J. Clin. Investig. 119:3473–86
    [Google Scholar]
  69. 69. 
    Tyagi M, Pearson RJ, Karn J. 2010. Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J. Virol. 84:6425–37
    [Google Scholar]
  70. 70. 
    Mbonye U, Karn J. 2017. The molecular basis for human immunodeficiency virus latency. Annu. Rev. Virol. 4:261–85
    [Google Scholar]
  71. 71. 
    Dutilleul A, Rodari A, Van Lint C. 2020. Depicting HIV-1 transcriptional mechanisms: a summary of what we know. Viruses 12:1385
    [Google Scholar]
  72. 72. 
    Crooks AM, Bateson R, Cope AB, Dahl NP, Griggs MK et al. 2015. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J. Infect. Dis. 212:1361–65
    [Google Scholar]
  73. 73. 
    Laird GM, Rosenbloom DI, Lai J, Siliciano RF, Siliciano JD 2016. Measuring the frequency of latent HIV-1 in resting CD4+ T cells using a limiting dilution coculture assay. Methods Mol. Biol. 1354:239–53
    [Google Scholar]
  74. 74. 
    Hermankova M, Siliciano JD, Zhou Y, Monie D, Chadwick K et al. 2003. Analysis of human immuno-deficiency virus type 1 gene expression in latently infected resting CD4+ T lymphocytes in vivo. J. Virol. 77:7383–92
    [Google Scholar]
  75. 75. 
    Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. 2014. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat. Med. 20:425–29
    [Google Scholar]
  76. 76. 
    Laird GM, Bullen CK, Rosenbloom DI, Martin AR, Hill AL et al. 2015. Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J. Clin. Investig. 125:1901–12
    [Google Scholar]
  77. 77. 
    Prins JM, Jurriaans S, van Praag RM, Blaak H, van Rij R et al. 1999. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 13:2405–10
    [Google Scholar]
  78. 78. 
    Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB et al. 2013. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155:540–51
    [Google Scholar]
  79. 79. 
    Musick A, Spindler J, Boritz E, Perez L, Crespo-Velez D et al. 2019. HIV infected T cells can proliferate in vivo without inducing expression of the integrated provirus. Front. Microbiol. 10:2204
    [Google Scholar]
  80. 80. 
    Kwon KJ, Timmons AE, Sengupta S, Simonetti FR, Zhang H et al. 2020. Different human resting memory CD4+ T cell subsets show similar low inducibility of latent HIV-1 proviruses. Sci. Transl. Med. 12:eaax6795
    [Google Scholar]
  81. 81. 
    Honeycutt JB, Wahl A, Baker C, Spagnuolo RA, Foster J et al. 2016. Macrophages sustain HIV replication in vivo independently of T cells. J. Clin. Investig. 126:1353–66
    [Google Scholar]
  82. 82. 
    Avalos CR, Abreu CM, Queen SE, Li M, Price S et al. 2017. Brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir. mBio 8:e01186-17
    [Google Scholar]
  83. 83. 
    Andrade VM, Mavian C, Babic D, Cordeiro T, Sharkey M et al. 2020. A minor population of macrophage-tropic HIV-1 variants is identified in recrudescing viremia following analytic treatment interruption. PNAS 117:9981–90
    [Google Scholar]
  84. 84. 
    Stevenson M. 2017. HIV persistence in macrophages. Nat. Med. 23:538–39
    [Google Scholar]
  85. 85. 
    Veenhuis RT, Abreu CM, Shirk EN, Gama L, Clements JE. 2021. HIV replication and latency in monocytes and macrophages. Semin. Immunol. 51:101472
    [Google Scholar]
  86. 86. 
    Bruner KM, Hosmane NN, Siliciano RF. 2015. Towards an HIV-1 cure: measuring the latent reservoir. Trends Microbiol. 23:192–203
    [Google Scholar]
  87. 87. 
    Massanella M, Yek C, Lada SM, Nakazawa M, Shefa N et al. 2018. Improved assays to measure and characterize the inducible HIV reservoir. EBioMedicine 36:113–21
    [Google Scholar]
  88. 88. 
    Abdel-Mohsen M, Richman D, Siliciano RF, Nussenzweig MC, Howell BJ et al. 2020. Recommendations for measuring HIV reservoir size in cure-directed clinical trials. Nat. Med. 26:1339–50
    [Google Scholar]
  89. 89. 
    Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. 1990. HIV-1 entry into quiescent primary lymphocytes: Molecular analysis reveals a labile, latent viral structure. Cell 61:213–22
    [Google Scholar]
  90. 90. 
    Bukrinsky MI, Stanwick TL, Dempsey MP, Stevenson M. 1991. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 254:423–27
    [Google Scholar]
  91. 91. 
    Pierson TC, Kieffer TL, Ruff CT, Buck C, Gange SJ, Siliciano RF. 2002. Intrinsic stability of episomal circles formed during human immunodeficiency virus type 1 replication. J. Virol. 76:4138–44
    [Google Scholar]
  92. 92. 
    Pierson TC, Zhou Y, Kieffer TL, Ruff CT, Buck C, Siliciano RF 2002. Molecular characterization of preintegration latency in human immunodeficiency virus type 1 infection. J. Virol. 76:8518–31
    [Google Scholar]
  93. 93. 
    Zhou Y, Zhang H, Siliciano JD, Siliciano RF. 2005. Kinetics of human immunodeficiency virus type 1 decay following entry into resting CD4+ T cells. J. Virol. 79:2199–210
    [Google Scholar]
  94. 94. 
    Blankson JN, Finzi D, Pierson TC, Sabundayo BP, Chadwick K et al. 2000. Biphasic decay of latently infected CD4+ T cells in acute human immunodeficiency virus type 1 infection. J. Infect. Dis. 182:1636–42
    [Google Scholar]
  95. 95. 
    Sanchez G, Xu X, Chermann JC, Hirsch I. 1997. Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J. Virol. 71:2233–40
    [Google Scholar]
  96. 96. 
    Sheehy AM, Gaddis NC, Choi JD, Malim MH. 2002. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418:646–50
    [Google Scholar]
  97. 97. 
    Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA et al. 2013. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLOS Pathog. 9:e1003174
    [Google Scholar]
  98. 98. 
    Siliciano JD, Siliciano RF. 2005. Enhanced culture assay for detection and quantitation of latently infected, resting CD4+ T-cells carrying replication-competent virus in HIV-1-infected individuals. Methods Mol. Biol. 304:3–15
    [Google Scholar]
  99. 99. 
    Laird GM, Eisele EE, Rabi SA, Lai J, Chioma S et al. 2013. Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLOS Pathog. 9:e1003398
    [Google Scholar]
  100. 100. 
    Rosenbloom DI, Elliott O, Hill AL, Henrich TJ, Siliciano JM, Siliciano RF. 2015. Designing and interpreting limiting dilution assays: general principles and applications to the latent reservoir for human immunodeficiency virus-1. Open Forum. . Infect. Dis. 2:ofv123
    [Google Scholar]
  101. 101. 
    Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K et al. 1999. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat. Med. 5:512–17
    [Google Scholar]
  102. 102. 
    Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K et al. 2003. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat. Med. 9:727–28
    [Google Scholar]
  103. 103. 
    Imamichi H, Dewar RL, Adelsberger JW, Rehm CA, O'Doherty U et al. 2016. Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy. PNAS 113:8783–88
    [Google Scholar]
  104. 104. 
    Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB et al. 2016. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat. Med. 22:1043–49
    [Google Scholar]
  105. 105. 
    Delviks-Frankenberry K, Galli A, Nikolaitchik O, Mens H, Pathak VK, Hu WS. 2011. Mechanisms and factors that influence high frequency retroviral recombination. Viruses 3:1650–80
    [Google Scholar]
  106. 106. 
    Bruner KM, Wang Z, Simonetti FR, Bender AM, Kwon KJ et al. 2019. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature 566:120–25
    [Google Scholar]
  107. 107. 
    Bender AM, Simonetti FR, Kumar MR, Fray EJ, Bruner KM et al. 2019. The landscape of persistent viral genomes in ART-treated SIV, SHIV, and HIV-2 infections. Cell Host Microbe 26:73–85.e4
    [Google Scholar]
  108. 108. 
    Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK et al. 2003. DNA deamination mediates innate immunity to retroviral infection. Cell 113:803–9
    [Google Scholar]
  109. 109. 
    Wiegand HL, Doehle BP, Bogerd HP, Cullen BR. 2004. A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins. EMBO J 23:2451–58
    [Google Scholar]
  110. 110. 
    Hiener B, Horsburgh BA, Eden JS, Barton K, Schlub TE et al. 2017. Identification of genetically intact HIV-1 proviruses in specific CD4+ T cells from effectively treated participants. Cell Rep 21:813–22
    [Google Scholar]
  111. 111. 
    Sharaf R, Lee GQ, Sun X, Etemad B, Aboukhater LM et al. 2018. HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers. J. Clin. Investig. 128:4074–85
    [Google Scholar]
  112. 112. 
    Cohn LB, Silva IT, Oliveira TY, Rosales RA, Parrish EH et al. 2015. HIV-1 integration landscape during latent and active infection. Cell 160:420–32
    [Google Scholar]
  113. 113. 
    Simonetti FR, White JA, Tumiotto C, Ritter KD, Cai M et al. 2020. Intact proviral DNA assay analysis of large cohorts of people with HIV provides a benchmark for the frequency and composition of persistent proviral DNA. PNAS 117:18692–700
    [Google Scholar]
  114. 114. 
    Peluso MJ, Bacchetti P, Ritter KD, Beg S, Lai J et al. 2020. Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy. JCI Insight. 5:e132997
    [Google Scholar]
  115. 115. 
    Kinloch NN, Ren Y, Conce Alberto WD, Dong W, Khadka P et al. 2021. HIV-1 diversity considerations in the application of the intact proviral DNA assay (IPDA). Nat. Commun. 12:165
    [Google Scholar]
  116. 116. 
    Gaebler C, Falcinelli SD, Stoffel E, Read J, Murtagh R et al. 2021. Sequence evaluation and comparative analysis of novel assays for intact proviral HIV-1 DNA. J. Virol. 95:e01986-20
    [Google Scholar]
  117. 117. 
    Gandhi RT, Cyktor JC, Bosch RJ, Mar H, Laird GM et al. 2020. Selective decay of intact HIV-1 proviral DNA on antiretroviral therapy. J. Infect. Dis. 223:225–33
    [Google Scholar]
  118. 118. 
    Gandhi R, Cyktor JC, Bosch R, Mar H, Laird G et al. 2020. Intact proviral DNA levels decline in people with HIV on antiretroviral therapy. Paper presented at Conference on Retroviruses and Opportunistic Infections Boston, MA: March 8–11. https://www.natap.org/2020/CROI/croi_236.htm
    [Google Scholar]
  119. 119. 
    Einkauf KB, Lee GQ, Gao C, Sharaf R, Sun X et al. 2019. Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy. J. Clin. Investig. 129:988–98
    [Google Scholar]
  120. 120. 
    Antar AA, Jenike KM, Jang S, Rigau DN, Reeves DB et al. 2020. Longitudinal study reveals HIV-1-infected CD4+ T cell dynamics during long-term antiretroviral therapy. J. Clin. Investig. 130:3543–59
    [Google Scholar]
  121. 121. 
    Jiang C, Lian X, Gao C, Sun X, Einkauf KB et al. 2020. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature 585:261–67
    [Google Scholar]
  122. 122. 
    Fromentin R, Chomont N. 2021. HIV persistence in subsets of CD4+ T cells: 50 shades of reservoirs. Semin. Immunol. 51:101438
    [Google Scholar]
  123. 123. 
    Descours B, Petitjean G, Lopez-Zaragoza JL, Bruel T, Raffel R et al. 2017. CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. Nature 543:564–67
    [Google Scholar]
  124. 124. 
    Bertagnolli LN, White JA, Simonetti FR, Beg SA, Lai J et al. 2018. The role of CD32 during HIV-1 infection. Nature 561:E17–19
    [Google Scholar]
  125. 125. 
    Perez L, Anderson J, Chipman J, Thorkelson A, Chun TW et al. 2018. Conflicting evidence for HIV enrichment in CD32+ CD4 T cells. Nature 561:E9–16
    [Google Scholar]
  126. 126. 
    Osuna CE, Lim SY, Kublin JL, Apps R, Chen E et al. 2018. Evidence that CD32a does not mark the HIV-1 latent reservoir. Nature 561:E20–28
    [Google Scholar]
  127. 127. 
    Cohn LB, da Silva IT, Valieris R, Huang AS, Lorenzi JCC et al. 2018. Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation. Nat. Med. 24:604–9
    [Google Scholar]
  128. 128. 
    Pardons M, Baxter AE, Massanella M, Pagliuzza A, Fromentin R et al. 2019. Single-cell characterization and quantification of translation-competent viral reservoirs in treated and untreated HIV infection. PLOS Pathog. 15:e1007619
    [Google Scholar]
  129. 129. 
    Liu R, Yeh YJ, Varabyou A, Collora JA, Sherrill-Mix S et al. 2020. Single-cell transcriptional landscapes reveal HIV-1-driven aberrant host gene transcription as a potential therapeutic target. Sci. Transl. Med. 12:eaaz0802
    [Google Scholar]
  130. 130. 
    Neidleman J, Luo X, Frouard J, Xie G, Hsiao F et al. 2020. Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir. eLife 9:e60933
    [Google Scholar]
  131. 131. 
    Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA et al. 2009. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med. 15:893–900
    [Google Scholar]
  132. 132. 
    Perreau M, Savoye AL, De Crignis E, Corpataux JM, Cubas R et al. 2013. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J. Exp. Med. 210:143–56
    [Google Scholar]
  133. 133. 
    Buzon MJ, Martin-Gayo E, Pereyra F, Ouyang Z, Sun H et al. 2014. Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells. J. Virol. 88:10056–65
    [Google Scholar]
  134. 134. 
    Buzon MJ, Sun H, Li C, Shaw A, Seiss K et al. 2014. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat. Med. 20:139–42
    [Google Scholar]
  135. 135. 
    Soriano-Sarabia N, Bateson RE, Dahl NP, Crooks AM, Kuruc JD et al. 2014. Quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells. J. Virol. 88:14070–77
    [Google Scholar]
  136. 136. 
    Sun H, Kim D, Li X, Kiselinova M, Ouyang Z et al. 2015. Th1/17 polarization of CD4 T cells supports HIV-1 persistence during antiretroviral therapy. J. Virol. 89:11284–93
    [Google Scholar]
  137. 137. 
    Banga R, Procopio FA, Noto A, Pollakis G, Cavassini M et al. 2016. PD-1 and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat. Med. 22:754–61
    [Google Scholar]
  138. 138. 
    Baxter AE, Niessl J, Fromentin R, Richard J, Porichis F et al. 2016. Single-cell characterization of viral translation-competent reservoirs in HIV-infected individuals. Cell Host Microbe 20:368–80
    [Google Scholar]
  139. 139. 
    Lee GQ, Orlova-Fink N, Einkauf K, Chowdhury FZ, Sun X et al. 2017. Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells. J. Clin. Investig. 127:2689–96
    [Google Scholar]
  140. 140. 
    Kulpa DA, Talla A, Brehm JH, Ribeiro SP, Yuan S et al. 2019. Differentiation into an effector memory phenotype potentiates HIV-1 latency reversal in CD4+ T cells. J. Virol. 93:e00969-19
    [Google Scholar]
  141. 141. 
    Ruterbusch M, Pruner KB, Shehata L, Pepper M. 2020. In vivo CD4+ T cell differentiation and function: revisiting the Th1/Th2 paradigm. Annu. Rev. Immunol. 38:705–25
    [Google Scholar]
  142. 142. 
    Vibholm LK, Lorenzi JCC, Pai JA, Cohen YZ, Oliveira TY et al. 2019. Characterization of intact proviruses in blood and lymph node from HIV-infected individuals undergoing analytical treatment interruption. J. Virol. 93:e01920-18
    [Google Scholar]
  143. 143. 
    Martin AR, Bender AM, Hackman J, Kwon KJ, Lynch BA et al. 2020. Similar frequency and inducibility of intact HIV-1 proviruses in blood and lymph nodes. J. Infect. Dis. 224:258–68
    [Google Scholar]
  144. 144. 
    Bozzi G, Simonetti FR, Watters SA, Anderson EM, Gouzoulis M et al. 2019. No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: implications for HIV eradication. Sci. Adv. 5:eaav2045
    [Google Scholar]
  145. 145. 
    Lee M, Mandl JN, Germain RN, Yates AJ 2012. The race for the prize: T-cell trafficking strategies for optimal surveillance. Blood 120:1432–38
    [Google Scholar]
  146. 146. 
    Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G et al. 2008. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J. Infect. Dis. 197:714–20
    [Google Scholar]
  147. 147. 
    Estes JD, Kityo C, Ssali F, Swainson L, Makamdop KN et al. 2017. Defining total-body AIDS-virus burden with implications for curative strategies. Nat. Med. 23:1271–76
    [Google Scholar]
  148. 148. 
    Cadena AM, Ventura JD, Abbink P, Borducchi EN, Tuyishime H et al. 2021. Persistence of viral RNA in lymph nodes in ART-suppressed SIV/SHIV-infected rhesus macaques. Nat. Commun. 12:1474
    [Google Scholar]
  149. 149. 
    De Scheerder MA, Vrancken B, Dellicour S, Schlub T, Lee E et al. 2019. HIV rebound is predominantly fueled by genetically identical viral expansions from diverse reservoirs. Cell Host Microbe 26:347–58.e7
    [Google Scholar]
  150. 150. 
    Shankarappa R, Margolick JB, Gange SJ, Rodrigo AG, Upchurch D et al. 1999. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J. Virol. 73:10489–502
    [Google Scholar]
  151. 151. 
    Dornadula G, Zhang H, VanUitert B, Stern J, Livornese L Jr. et al. 1999. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA 282:1627–32
    [Google Scholar]
  152. 152. 
    Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM et al. 2003. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J. Clin. Microbiol. 41:4531–36
    [Google Scholar]
  153. 153. 
    Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA et al. 2007. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLOS Pathog 3:e46
    [Google Scholar]
  154. 154. 
    Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ et al. 2009. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. PNAS 106:9403–8
    [Google Scholar]
  155. 155. 
    Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM et al. 2010. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLOS Med 7:e1000321
    [Google Scholar]
  156. 156. 
    Tobin NH, Learn GH, Holte SE, Wang Y, Melvin AJ et al. 2005. Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus. J. Virol. 79:9625–34
    [Google Scholar]
  157. 157. 
    Wang Z, Gurule EE, Brennan TP, Gerold JM, Kwon KJ et al. 2018. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. PNAS 115:E2575–84
    [Google Scholar]
  158. 158. 
    Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. 2002. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110:521–29
    [Google Scholar]
  159. 159. 
    Han Y, Lassen K, Monie D, Sedaghat AR, Shimoji S et al. 2004. Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J. Virol. 78:6122–33
    [Google Scholar]
  160. 160. 
    Maldarelli F, Wu X, Su L, Simonetti FR, Shao W et al. 2014. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345:179–83
    [Google Scholar]
  161. 161. 
    Wagner TA, McLaughlin S, Garg K, Cheung CY, Larsen BB et al. 2014. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345:570–73
    [Google Scholar]
  162. 162. 
    Cesana D, Santoni de Sio FR, Rudilosso L, Gallina P, Calabria A et al. 2017. HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells. Nat. Commun. 8:498
    [Google Scholar]
  163. 163. 
    Bushman FD. 2020. Retroviral insertional mutagenesis in humans: evidence for four genetic mechanisms promoting expansion of cell clones. Mol. Ther. 28:352–56
    [Google Scholar]
  164. 164. 
    Simonetti FR, Sobolewski MD, Fyne E, Shao W, Spindler J et al. 2016. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. PNAS 113:1883–88
    [Google Scholar]
  165. 165. 
    Reeves DB, Duke ER, Wagner TA, Palmer SE, Spivak AM, Schiffer JT. 2018. A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation. Nat. Commun. 9:4811–15
    [Google Scholar]
  166. 166. 
    Coffin JM, Wells DW, Zerbato JM, Kuruc JD, Guo S et al. 2019. Clones of infected cells arise early in HIV-infected individuals. JCI Insight 4:e128432
    [Google Scholar]
  167. 167. 
    Simonetti FR, Zhang H, Soroosh GP, Duan J, Rhodehouse K et al. 2021. Antigen-driven clonal selection shapes the persistence of HIV-1-infected CD4+ T cells in vivo. J. Clin. Investig. 131:e145254
    [Google Scholar]
  168. 168. 
    Boyman O, Krieg C, Homann D, Sprent J 2012. Homeostatic maintenance of T cells and natural killer cells. Cell. Mol. Life Sci. 69:1597–608
    [Google Scholar]
  169. 169. 
    Henrich TJ, Hobbs KS, Hanhauser E, Scully E, Hogan LE et al. 2017. Human immunodeficiency virus type 1 persistence following systemic chemotherapy for malignancy. J. Infect. Dis. 216:254–62
    [Google Scholar]
  170. 170. 
    Mendoza P, Jackson JR, Oliveira TY, Gaebler C, Ramos V et al. 2020. Antigen-responsive CD4+ T cell clones contribute to the HIV-1 latent reservoir. J. Exp. Med. 217:e20200051
    [Google Scholar]
  171. 171. 
    Gantner P, Pagliuzza A, Pardons M, Ramgopal M, Routy JP et al. 2020. Single-cell TCR sequencing reveals phenotypically diverse clonally expanded cells harboring inducible HIV proviruses during ART. Nat. Commun. 11:4089–88
    [Google Scholar]
  172. 172. 
    Reeves DB, Duke ER, Hughes SM, Prlic M, Hladik F, Schiffer JT. 2017. Anti-proliferative therapy for HIV cure: a compound interest approach. Sci. Rep. 7:4011
    [Google Scholar]
  173. 173. 
    Hataye JM, Casazza JP, Best K, Liang CJ, Immonen TT et al. 2019. Principles governing establishment versus collapse of HIV-1 cellular spread. Cell Host Microbe 26:748–63.e20
    [Google Scholar]
  174. 174. 
    Kulpa DA, Talla A, Brehm JH, Ribeiro SP, Yuan S et al. 2019. Differentiation into an effector memory phenotype potentiates HIV-1 latency reversal in CD4+ T cells. J. Virol. 93:e00969-19
    [Google Scholar]
  175. 175. 
    Bosque A, Famiglietti M, Weyrich AS, Goulston C, Planelles V. 2011. Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells. PLOS Pathog 7:e1002288
    [Google Scholar]
  176. 176. 
    Halvas EK, Joseph KW, Brandt LD, Guo S, Sobolewski MD et al. 2020. HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus. J. Clin. Investig. 130:5847–57
    [Google Scholar]
  177. 177. 
    Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV. 2005. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell 122:169–82
    [Google Scholar]
  178. 178. 
    Lenasi T, Contreras X, Peterlin BM. 2008. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe 4:123–33
    [Google Scholar]
  179. 179. 
    Shan L, Yang HC, Rabi SA, Bravo HC, Shroff NS et al. 2011. Influence of host gene transcription level and orientation on HIV-1 latency in a primary-cell model. J. Virol. 85:5384–93
    [Google Scholar]
  180. 180. 
    Hill AL, Rosenbloom DI, Fu F, Nowak MA, Siliciano RF. 2014. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. PNAS 111:13475–80
    [Google Scholar]
  181. 181. 
    Cockerham LR, Hatano H, Deeks SG. 2016. Post-treatment controllers: role in HIV “cure” research. Curr. HIV/AIDS Rep. 13:1–9
    [Google Scholar]
  182. 182. 
    Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S et al. 2014. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann. Intern. Med. 161:319–27
    [Google Scholar]
  183. 183. 
    Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A et al. 2009. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N. Engl. J. Med. 360:692–98
    [Google Scholar]
  184. 184. 
    Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Peppa D et al. 2019. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 568:244–48
    [Google Scholar]
  185. 185. 
    Henrich TJ, Hatano H, Bacon O, Hogan LE, Rutishauser R et al. 2017. HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: an observational study. PLOS Med. 14:e1002417
    [Google Scholar]
  186. 186. 
    Bar KJ, Sneller MC, Harrison LJ, Justement JS, Overton ET et al. 2016. Effect of HIV antibody VRC01 on viral rebound after treatment interruption. N. Engl. J. Med. 375:2037–50
    [Google Scholar]
  187. 187. 
    Mendoza P, Gruell H, Nogueira L, Pai JA, Butler AL et al. 2018. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561:479–84
    [Google Scholar]
  188. 188. 
    Giron LB, Papasavvas E, Azzoni L, Yin X, Anzurez A et al. 2020. Plasma and antibody glycomic biomarkers of time to HIV rebound and viral setpoint. AIDS 34:681–86
    [Google Scholar]
  189. 189. 
    Offersen R, Yu WH, Scully EP, Julg B, Euler Z et al. 2020. HIV antibody Fc N-linked glycosylation is associated with viral rebound. Cell Rep. 33:108502
    [Google Scholar]
  190. 190. 
    Pasternak AO, Grijsen ML, Wit FW, Bakker M, Jurriaans S et al. 2020. Cell-associated HIV-1 RNA predicts viral rebound and disease progression after discontinuation of temporary early ART. JCI Insight. 5:e134196
    [Google Scholar]
  191. 191. 
    De Scheerder MA, Van Hecke C, Zetterberg H, Fuchs D, De Langhe N et al. 2020. Evaluating predictive markers for viral rebound and safety assessment in blood and lumbar fluid during HIV-1 treatment interruption. J. Antimicrob. Chemother. 75:1311–20
    [Google Scholar]
  192. 192. 
    Prator CA, Thanh C, Kumar S, Pan T, Peluso MJ et al. 2020. Circulating CD30+CD4+ T cells increase before human immunodeficiency virus rebound after analytical antiretroviral treatment interruption. J. Infect. Dis. 221:1146–55
    [Google Scholar]
  193. 193. 
    Salantes DB, Zheng Y, Mampe F, Srivastava T, Beg S et al. 2018. HIV-1 latent reservoir size and diversity are stable following brief treatment interruption. J. Clin. Investig. 128:3102–15
    [Google Scholar]
  194. 194. 
    Lu CL, Pai JA, Nogueira L, Mendoza P, Gruell H et al. 2018. Relationship between intact HIV-1 proviruses in circulating CD4+ T cells and rebound viruses emerging during treatment interruption. PNAS 115:E11341–48
    [Google Scholar]
  195. 195. 
    Cohen YZ, Lorenzi JCC, Krassnig L, Barton JP, Burke L et al. 2018. Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117. J. Exp. Med. 215:2311–24
    [Google Scholar]
  196. 196. 
    Onafuwa-Nuga A, Telesnitsky A. 2009. The remarkable frequency of human immunodeficiency virus type 1 genetic recombination. Microbiol. Mol. Biol. Rev. 73:451–80
    [Google Scholar]
  197. 197. 
    Liu PT, Keele BF, Abbink P, Mercado NB, Liu J et al. 2020. Origin of rebound virus in chronically SIV-infected rhesus monkeys following treatment discontinuation. Nat. Commun. 11:5412
    [Google Scholar]
  198. 198. 
    Bertagnolli LN, Varriale J, Sweet S, Brockhurst J, Simonetti FR et al. 2020. Autologous IgG antibodies block outgrowth of a substantial but variable fraction of viruses in the latent reservoir for HIV-1. PNAS 117:32066–77
    [Google Scholar]
  199. 199. 
    Gondim MVP, Sherrill-Mix S, Bibollet-Ruche F, Russell RM, Trimboli S et al. 2021. Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption. Sci. Transl. Med. 13:eabd8179
    [Google Scholar]
  200. 200. 
    Wei X, Decker JM, Wang S, Hui H, Kappes JC et al. 2003. Antibody neutralization and escape by HIV-1. Nature 422:307–12
    [Google Scholar]
  201. 201. 
    Richman DD, Wrin T, Little SJ, Petropoulos CJ. 2003. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. PNAS 100:4144–49
    [Google Scholar]
  202. 202. 
    Abrahams MR, Joseph SB, Garrett N, Tyers L, Moeser M et al. 2019. The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation. Sci. Transl. Med. 11:eaaw5589
    [Google Scholar]
  203. 203. 
    Veenhuis RT, Kwaa AK, Garliss CC, Latanich R, Salgado M et al. 2018. Long-term remission despite clonal expansion of replication-competent HIV-1 isolates. JCI Insight 3:e122795
    [Google Scholar]
  204. 204. 
    Iyer SS, Bibollet-Ruche F, Sherrill-Mix S, Learn GH, Plenderleith L et al. 2017. Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness. PNAS 114:E590–99
    [Google Scholar]
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