HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells

1. Palella FJ Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. The New England journal of medicine. 1998;338(13):853–60. 9516219

2. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. The New England journal of medicine. 1997;337(11):734–9. 9287228

3. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. The New England journal of medicine. 1997;337(11):725–33. 9287227

4. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 1997;387(6629):188–91. 9144290

5. Davey RT Jr., Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(26):15109–14. 10611346

6. Blankson JN, Persaud D, Siliciano RF. The challenge of viral reservoirs in HIV-1 infection. Annual review of medicine. 2002;53:557–93. 11818490

7. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(24):13193–7. 9371822

8. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295–300. 9360927

9. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997;278(5341):1291–5. 9360926

10. Folks T, Powell DM, Lightfoote MM, Benn S, Martin MA, Fauci AS. Induction of HTLV-III/LAV from a nonvirus-producing T-cell line: implications for latency. Science. 1986;231(4738):600–2. 3003906

11. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997;387(6629):183–8. 9144289

12. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nature medicine. 2009;15(8):893–900. doi: 10.1038/nm.1972 19543283

13. Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature medicine. 2003;9(6):727–8. 12754504

14. Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. The Journal of experimental medicine. 1998;188(1):83–91. 9653086

15. Brooks DG, Zack JA. Effect of latent human immunodeficiency virus infection on cell surface phenotype. Journal of virology. 2002;76(4):1673–81. 11799162

16. Han Y, Wind-Rotolo M, Yang HC, Siliciano JD, Siliciano RF. Experimental approaches to the study of HIV-1 latency. Nature reviews Microbiology. 2007;5(2):95–106. 17224919

17. Hakre S, Chavez L, Shirakawa K, Verdin E. HIV latency: experimental systems and molecular models. FEMS microbiology reviews. 2012;36(3):706–16. doi: 10.1111/j.1574-6976.2012.00335.x 22372374

18. Calvanese V, Chavez L, Laurent T, Ding S, Verdin E. Dual-color HIV reporters trace a population of latently infected cells and enable their purification. Virology. 2013;446(1–2):283–92. doi: 10.1016/j.virol.2013.08.015 24074596

19. Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. The EMBO journal. 1990;9(5):1551–60. 2184033

20. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990;61(2):213–22. 2331748

21. Spina CA, Guatelli JC, Richman DD. Establishment of a stable, inducible form of human immunodeficiency virus type 1 DNA in quiescent CD4 lymphocytes in vitro. Journal of virology. 1995;69(5):2977–88. 7707524

22. Zhou Y, Zhang H, Siliciano JD, Siliciano RF. Kinetics of human immunodeficiency virus type 1 decay following entry into resting CD4+ T cells. Journal of virology. 2005;79(4):2199–210. 15681422

23. Pan X, Baldauf HM, Keppler OT, Fackler OT. Restrictions to HIV-1 replication in resting CD4+ T lymphocytes. Cell research. 2013;23(7):876–85. doi: 10.1038/cr.2013.74 23732522

24. Bukrinsky MI, Stanwick TL, Dempsey MP, Stevenson M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science. 1991;254(5030):423–7. 1925601

25. Pierson TC, Zhou Y, Kieffer TL, Ruff CT, Buck C, Siliciano RF. Molecular characterization of preintegration latency in human immunodeficiency virus type 1 infection. Journal of virology. 2002;76(17):8518–31. 12163571

26. Zack JA, Haislip AM, Krogstad P, Chen IS. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life cycle. Journal of virology. 1992;66(3):1717–25. 1371173

27. Korin YD, Zack JA. Progression to the G1b phase of the cell cycle is required for completion of human immunodeficiency virus type 1 reverse transcription in T cells. Journal of virology. 1998;72(4):3161–8. 9525642

28. Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W, Burggraf M, et al. SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nature medicine. 2012;18(11):1682–7. doi: 10.1038/nm.2964 22972397

29. Descours B, Cribier A, Chable-Bessia C, Ayinde D, Rice G, Crow Y, et al. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells. Retrovirology. 2012;9:87. doi: 10.1186/1742-4690-9-87 23092122

30. Siliciano RF, Greene WC. HIV latency. Cold Spring Harbor perspectives in medicine. 2011;1(1):a007096. doi: 10.1101/cshperspect.a007096 22229121

31. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373(6510):123–6. 7816094

32. Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995;373(6510):117–22. 7529365

33. Lassen K, Han Y, Zhou Y, Siliciano J, Siliciano RF. The multifactorial nature of HIV-1 latency. Trends in molecular medicine. 2004;10(11):525–31. 15519278

34. Ostrowski MA, Chun TW, Justement SJ, Motola I, Spinelli MA, Adelsberger J, et al. Both memory and CD45RA+/CD62L+ naive CD4(+) T cells are infected in human immunodeficiency virus type 1-infected individuals. Journal of virology. 1999;73(8):6430–5. 10400736

35. Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus KA, Reimann KA, et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science. 1999;286(5443):1353–7. 10558989

36. Eckstein DA, Penn ML, Korin YD, Scripture-Adams DD, Zack JA, Kreisberg JF, et al. HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues. Immunity. 2001;15(4):671–82. 11672548

37. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005;434(7037):1148–52. 15793562

38. Nishimura Y, Brown CR, Mattapallil JJ, Igarashi T, Buckler-White A, Lafont BA, et al. Resting naive CD4+ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(22):8000–5. 15911767

39. Wightman F, Solomon A, Khoury G, Green JA, Gray L, Gorry PR, et al. Both CD31(+) and CD31(-) naive CD4(+) T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. The Journal of infectious diseases. 2010;202(11):1738–48. doi: 10.1086/656721 20979453

40. Kreisberg JF, Yonemoto W, Greene WC. Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation. The Journal of experimental medicine. 2006;203(4):865–70. 16606671

41. Kinter A, Moorthy A, Jackson R, Fauci AS. Productive HIV infection of resting CD4+ T cells: role of lymphoid tissue microenvironment and effect of immunomodulating agents. AIDS research and human retroviruses. 2003;19(10):847–56. 14585216

42. Cohen OJ, Kinter A, Fauci AS. Host factors in the pathogenesis of HIV disease. Immunological reviews. 1997;159:31–48. 9416501

43. Kinter A, Catanzaro A, Monaco J, Ruiz M, Justement J, Moir S, et al. CC-chemokines enhance the replication of T-tropic strains of HIV-1 in CD4(+) T cells: role of signal transduction. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(20):11880–5. 9751759

44. Tellier MC, Greco G, Klotman M, Mosoian A, Cara A, Arap W, et al. Superfibronectin, a multimeric form of fibronectin, increases HIV infection of primary CD4+ T lymphocytes. Journal of immunology. 2000;164(6):3236–45. 10706716

45. Lee B, Leslie G, Soilleux E, O'Doherty U, Baik S, Levroney E, et al. cis Expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. Journal of virology. 2001;75(24):12028–38. 11711593

46. Kinter A, Arthos J, Cicala C, Fauci AS. Chemokines, cytokines and HIV: a complex network of interactions that influence HIV pathogenesis. Immunological reviews. 2000;177:88–98. 11138789

47. Saleh S, Solomon A, Wightman F, Xhilaga M, Cameron PU, Lewin SR. 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. 17881634

48. Bonczkowski P, De Spiegelaere W, Bosque A, White CH, Van Nuffel A, Malatinkova E, et al. Replication competent virus as an important source of bias in HIV latency models utilizing single round viral constructs. Retrovirology. 2014;11:70. doi: 10.1186/s12977-014-0070-3 25142072

49. Unutmaz D, KewalRamani VN, Marmon S, Littman DR. Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. The Journal of experimental medicine. 1999;189(11):1735–46. 10359577

50. Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature. 2011;474(7353):658–61. doi: 10.1038/nature10195 21720370

51. Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Segeral E, et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. 2011;474(7353):654–7. doi: 10.1038/nature10117 21613998

52. Yang HC, Xing S, Shan L, O'Connell K, Dinoso J, Shen A, et al. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. The Journal of clinical investigation. 2009;119(11):3473–86. doi: 10.1172/JCI39199 19805909

53. Tyagi M, Pearson RJ, Karn J. Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. Journal of virology. 2010;84(13):6425–37. doi: 10.1128/JVI.01519-09 20410271

54. Dahabieh MS, Ooms M, Simon V, Sadowski I. A doubly fluorescent HIV-1 reporter shows that the majority of integrated HIV-1 is latent shortly after infection. Journal of virology. 2013;87(8):4716–27. doi: 10.1128/JVI.03478-12 23408629

55. Van Lint C, Emiliani S, Ott M, Verdin E. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. The EMBO journal. 1996;15(5):1112–20. 8605881

56. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell. 2005;122(2):169–82. 16051143

57. Weinberger LS, Dar RD, Simpson ML. Transient-mediated fate determination in a transcriptional circuit of HIV. Nature genetics. 2008;40(4):466–70. doi: 10.1038/ng.116 18344999

58. Burnett JC, Miller-Jensen K, Shah PS, Arkin AP, Schaffer DV. Control of stochastic gene expression by host factors at the HIV promoter. PLoS pathogens. 2009;5(1):e1000260. doi: 10.1371/journal.ppat.1000260 19132086

59. Singh A, Razooky B, Cox CD, Simpson ML, Weinberger LS. Transcriptional bursting from the HIV-1 promoter is a significant source of stochastic noise in HIV-1 gene expression. Biophysical journal. 2010;98(8):L32–4. doi: 10.1016/j.bpj.2010.03.001 20409455

60. Swiggard WJ, Baytop C, Yu JJ, Dai J, Li C, Schretzenmair R, et al. Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. Journal of virology. 2005;79(22):14179–88. 16254353

61. Brady T, Agosto LM, Malani N, Berry CC, O'Doherty U, Bushman F. HIV integration site distributions in resting and activated CD4+ T cells infected in culture. Aids. 2009;23(12):1461–71. doi: 10.1097/QAD.0b013e32832caf28 19550285

62. Jordan A, Bisgrove D, Verdin E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. The EMBO journal. 2003;22(8):1868–77. 12682019

63. Lewinski MK, Bisgrove D, Shinn P, Chen H, Hoffmann C, Hannenhalli S, et al. Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. Journal of virology. 2005;79(11):6610–9. 15890899

64. Ducrey-Rundquist O, Guyader M, Trono D. Modalities of interleukin-7-induced human immunodeficiency virus permissiveness in quiescent T lymphocytes. Journal of virology. 2002;76(18):9103–11. 12186894

65. Evans VA, Kumar N, Filali A, Procopio FA, Yegorov O, Goulet JP, et al. Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4+ T cells. PLoS pathogens. 2013;9(12):e1003799. doi: 10.1371/journal.ppat.1003799 24339779

66. Shen A, Baker JJ, Scott GL, Davis YP, Ho YY, Siliciano RF. Endothelial cell stimulation overcomes restriction and promotes productive and latent HIV-1 infection of resting CD4+ T cells. Journal of virology. 2013;87(17):9768–79. doi: 10.1128/JVI.01478-13 23824795

67. Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, et al. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell. 2010;143(5):789–801. doi: 10.1016/j.cell.2010.11.001 21111238

68. Liszewski MK, Yu JJ, O'Doherty U. Detecting HIV-1 integration by repetitive-sampling Alu-gag PCR. Methods. 2009;47(4):254–60. doi: 10.1016/j.ymeth.2009.01.002 19195495