Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals

Autoři: Elizabeth R. Wonderlich aff001;  Krupa Subramanian aff001;  Bryan Cox aff002;  Ann Wiegand aff003;  Carol Lackman-Smith aff001;  Michael J. Bale aff003;  Mars Stone aff004;  Rebecca Hoh aff006;  Mary F. Kearney aff003;  Frank Maldarelli aff003;  Steven G. Deeks aff006;  Michael P. Busch aff004;  Roger G. Ptak aff001;  Deanna A. Kulpa aff002
Působiště autorů: Southern Research, Frederick, Maryland, United States of America aff001;  Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America aff002;  HIV DRP, NCI at Frederick, NIH, Frederick, Maryland, United States of America aff003;  Vitalant Research Institute, San Francisco, California, United States of America aff004;  Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, United States of America aff005;  University of California, San Francisco (UCSF), San Francisco, California, United States of America aff006
Vyšlo v časopise: Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008074
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008074


Studies have demonstrated that intensive ART alone is not capable of eradicating HIV-1, as the virus rebounds within a few weeks upon treatment interruption. Viral rebound may be induced from several cellular subsets; however, the majority of proviral DNA has been found in antigen experienced resting CD4+ T cells. To achieve a cure for HIV-1, eradication strategies depend upon both understanding mechanisms that drive HIV-1 persistence as well as sensitive assays to measure the frequency of infected cells after therapeutic interventions. Assays such as the quantitative viral outgrowth assay (QVOA) measure HIV-1 persistence during ART by ex vivo activation of resting CD4+ T cells to induce latency reversal; however, recent studies have shown that only a fraction of replication-competent viruses are inducible by primary mitogen stimulation. Previous studies have shown a correlation between the acquisition of effector memory phenotype and HIV-1 latency reversal in quiescent CD4+ T cell subsets that harbor the reservoir. Here, we apply our mechanistic understanding that differentiation into effector memory CD4+ T cells more effectively promotes HIV-1 latency reversal to significantly improve proviral measurements in the QVOA, termed differentiation QVOA (dQVOA), which reveals a significantly higher frequency of the inducible HIV-1 replication-competent reservoir in resting CD4+ T cells.

Klíčová slova:

Cell differentiation – Cytokines – HIV-1 – Memory T cells – T cells – Viral persistence and latency – Viral replication


1. Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A. 1998;95(15):8869–73. Epub 1998/07/22. doi: 10.1073/pnas.95.15.8869 9671771; PubMed Central PMCID: PMC21169.

2. Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, 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(3):e33948. Epub 2012/04/06. doi: 10.1371/journal.pone.0033948 22479485; PubMed Central PMCID: PMC3316511.

3. Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, et al. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature. 2014;512(7512):74–7. doi: 10.1038/nature13594 25042999; PubMed Central PMCID: PMC4126858.

4. Colby DJ, Trautmann L, Pinyakorn S, Leyre L, Pagliuzza A, Kroon E, et al. Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection. Nat Med. 2018;24(7):923–6. Epub 2018/06/13. doi: 10.1038/s41591-018-0026-6 29892063; PubMed Central PMCID: PMC6092240.

5. Wong JK, Hezareh M, Günthard 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. doi: 10.1126/science.278.5341.1291 9360926.

6. Kearney MF, Wiegand A, Shao W, Coffin JM, Mellors JW, Lederman M, et al. Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy. J Virol. 2016;90(3):1369–76. Epub 2015/11/20. doi: 10.1128/JVI.02139-15 26581989; PubMed Central PMCID: PMC4719635.

7. Joos B, Fischer M, Kuster H, Pillai SK, Wong JK, Boni J, et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc Natl Acad Sci U S A. 2008;105(43):16725–30. Epub 2008/10/22. doi: 10.1073/pnas.0804192105 18936487; PubMed Central PMCID: PMC2575487.

8. Rothenberger MK, Keele BF, Wietgrefe SW, Fletcher CV, Beilman GJ, Chipman JG, et al. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc Natl Acad Sci U S A. 2015;112(10):E1126–34. Epub 2015/02/26. doi: 10.1073/pnas.1414926112 25713386; PubMed Central PMCID: PMC4364237.

9. Kearney MF, Spindler J, Shao W, Yu S, Anderson EM, O'Shea A, et al. Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLoS Pathog. 2014;10(3):e1004010. Epub 2014/03/22. doi: 10.1371/journal.ppat.1004010 24651464; PubMed Central PMCID: PMC3961343.

10. Imamichi H, Crandall KA, Natarajan V, Jiang MK, Dewar RL, Berg S, et al. Human immunodeficiency virus type 1 quasi species that rebound after discontinuation of highly active antiretroviral therapy are similar to the viral quasi species present before initiation of therapy. J Infect Dis. 2001;183(1):36–50. Epub 2000/12/07. doi: 10.1086/317641 11106537.

11. Chun TW, Davey RT Jr., Ostrowski M, Shawn Justement J, Engel D, Mullins JI, et al. Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nat Med. 2000;6(7):757–61. Epub 2000/07/11. doi: 10.1038/77481 10888923.

12. Lerner P, Guadalupe M, Donovan R, Hung J, Flamm J, Prindiville T, et al. The gut mucosal viral reservoir in HIV-infected patients is not the major source of rebound plasma viremia following interruption of highly active antiretroviral therapy. J Virol. 2011;85(10):4772–82. Epub 2011/02/25. doi: 10.1128/JVI.02409-10 21345945; PubMed Central PMCID: PMC3126205.

13. 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. Nat Med. 2009;15(8):893–900. doi: 10.1038/nm.1972 19543283; PubMed Central PMCID: PMC2859814.

14. Bacchus C, Cheret A, Avettand-Fenoel V, Nembot G, Melard A, Blanc C, et al. A single HIV-1 cluster and a skewed immune homeostasis drive the early spread of HIV among resting CD4+ cell subsets within one month post-infection. PLoS One. 2013;8(5):e64219. doi: 10.1371/journal.pone.0064219 23691172; PubMed Central PMCID: PMC3653877.

15. Chomont N, DaFonseca S, Vandergeeten C, Ancuta P, Sekaly RP. Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr Opin HIV AIDS. 2011;6(1):30–6. doi: 10.1097/COH.0b013e3283413775 21242891.

16. Yukl SA, Shergill AK, Ho T, Killian M, Girling V, Epling L, et al. The distribution of HIV DNA and RNA in cell subsets differs in gut and blood of HIV-positive patients on ART: implications for viral persistence. J Infect Dis. 2013;208(8):1212–20. doi: 10.1093/infdis/jit308 23852128; PubMed Central PMCID: PMC3778964.

17. Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z, et al. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med. 2014;20(2):139–42. doi: 10.1038/nm.3445 24412925; PubMed Central PMCID: PMC3959167.

18. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9(3):e1003211. doi: 10.1371/journal.ppat.1003211 23516360; PubMed Central PMCID: PMC3597518.

19. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, et al. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol. 2004;78(3):1160–8. doi: 10.1128/JVI.78.3.1160-1168.2004 14722271; PubMed Central PMCID: PMC321406.

20. Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 2013;9(2):e1003174. doi: 10.1371/journal.ppat.1003174 23459007; PubMed Central PMCID: PMC3573107.

21. Boulassel MR, Chomont N, Pai NP, Gilmore N, Sekaly RP, Routy JP. CD4 T cell nadir independently predicts the magnitude of the HIV reservoir after prolonged suppressive antiretroviral therapy. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2012;53(1):29–32. Epub 2011/10/25. doi: 10.1016/j.jcv.2011.09.018 22019250.

22. Chun TW, Justement JS, Pandya P, Hallahan CW, McLaughlin M, Liu S, et al. Relationship between the size of the human immunodeficiency virus type 1 (HIV-1) reservoir in peripheral blood CD4+ T cells and CD4+:CD8+ T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy. J Infect Dis. 2002;185(11):1672–6. doi: 10.1086/340521 12023777.

23. 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. Nat Med. 2003;9(6):727–8. doi: 10.1038/nm880 12754504.

24. Horsburgh BA, Palmer S. Measuring HIV Persistence on Antiretroviral Therapy. Adv Exp Med Biol. 2018;1075:265–84. Epub 2018/07/22. doi: 10.1007/978-981-13-0484-2_11 30030797.

25. Hong F, Aga E, Cillo AR, Yates AL, Besson G, Fyne E, et al. Novel Assays for Measurement of Total Cell-Associated HIV-1 DNA and RNA. J Clin Microbiol. 2016;54(4):902–11. Epub 2016/01/15. doi: 10.1128/JCM.02904-15 26763968; PubMed Central PMCID: PMC4809955.

26. Pasternak AO, Berkhout B. What do we measure when we measure cell-associated HIV RNA. Retrovirology. 2018;15(1):13. Epub 2018/01/31. doi: 10.1186/s12977-018-0397-2 29378657; PubMed Central PMCID: PMC5789533.

27. Pasternak AO, Lukashov VV, Berkhout B. Cell-associated HIV RNA: a dynamic biomarker of viral persistence. Retrovirology. 2013;10:41. doi: 10.1186/1742-4690-10-41 23587031; PubMed Central PMCID: PMC3637491.

28. Agosto LM, Liszewski MK, Mexas A, Graf E, Pace M, Yu JJ, et al. Patients on HAART often have an excess of unintegrated HIV DNA: implications for monitoring reservoirs. Virology. 2011;409(1):46–53. Epub 2010/10/26. doi: 10.1016/j.virol.2010.08.024 20970154.

29. Brussel A, Sonigo P. Analysis of early human immunodeficiency virus type 1 DNA synthesis by use of a new sensitive assay for quantifying integrated provirus. J Virol. 2003;77(18):10119–24. doi: 10.1128/JVI.77.18.10119-10124.2003 12941923.

30. Rouzioux C, Hubert JB, Burgard M, Deveau C, Goujard C, Bary M, et al. Early levels of HIV-1 DNA in peripheral blood mononuclear cells are predictive of disease progression independently of HIV-1 RNA levels and CD4+ T cell counts. J Infect Dis. 2005;192(1):46–55. Epub 2005/06/09. doi: 10.1086/430610 [pii] 10.1086/430610. 15942893.

31. Mexas AM, Graf EH, Pace MJ, Yu JJ, Papasavvas E, Azzoni L, et al. Concurrent measures of total and integrated HIV DNA monitor reservoirs and ongoing replication in eradication trials. AIDS. 2012;26(18):2295–306. doi: 10.1097/QAD.0b013e32835a5c2f 23014521; PubMed Central PMCID: PMC4692807.

32. 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. doi: 10.1038/387183a0 9144289.

33. Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, Bakeman W, et al. Cross-clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies. J Virol. 2014;88(21):12385–96. doi: 10.1128/JVI.00609-14 25122785; PubMed Central PMCID: PMC4248919.

34. Yucha RW, Hobbs KS, Hanhauser E, Hogan LE, Nieves W, Ozen MO, et al. High-throughput Characterization of HIV-1 Reservoir Reactivation Using a Single-Cell-in-Droplet PCR Assay. EBioMedicine. 2017;20:217–29. Epub 2017/05/23. doi: 10.1016/j.ebiom.2017.05.006 28529033; PubMed Central PMCID: PMC5478213.

35. Siliciano JD, Siliciano RF. 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. 2005;304:3–15. doi: 10.1385/1-59259-907-9:003 16061962.

36. 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. doi: 10.1126/science.278.5341.1295 9360927.

37. Laird GM, Eisele EE, Rabi SA, Lai J, Chioma S, Blankson JN, et al. Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS Pathog. 2013;9(5):e1003398. doi: 10.1371/journal.ppat.1003398 23737751; PubMed Central PMCID: PMC3667757.

38. Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014;20(4):425–9. doi: 10.1038/nm.3489 24658076; PubMed Central PMCID: PMC3981911.

39. Sanyal A, Mailliard RB, Rinaldo CR, Ratner D, Ding M, Chen Y, et al. Novel assay reveals a large, inducible, replication-competent HIV-1 reservoir in resting CD4+ T cells. Nat Med. 2017;23(7):885–9. doi: 10.1038/nm.4347 28553933; PubMed Central PMCID: PMC5505781.

40. Bosque A, Planelles V. Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood. 2009;113(1):58–65. doi: 10.1182/blood-2008-07-168393 18849485; PubMed Central PMCID: PMC2614643.

41. Adachi A, Gendelman HE, Koenig S, Folks T, Willey R, Rabson A, et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol. 1986;59(2):284–91. 3016298; PubMed Central PMCID: PMC253077.

42. Tsai P, Wu G, Baker CE, Thayer WO, Spagnuolo RA, Sanchez R, et al. In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection. Retrovirology. 2016;13(1):36. Epub 2016/05/22. doi: 10.1186/s12977-016-0268-7 27206407; PubMed Central PMCID: PMC4875645.

43. Lassen KG, Hebbeler AM, Bhattacharyya D, Lobritz MA, Greene WC. A flexible model of HIV-1 latency permitting evaluation of many primary CD4 T-cell reservoirs. PLoS One. 2012;7(1):e30176. doi: 10.1371/journal.pone.0030176 22291913; PubMed Central PMCID: PMC3265466.

44. Marini A, Harper JM, Romerio F. An in vitro system to model the establishment and reactivation of HIV-1 latency. J Immunol. 2008;181(11):7713–20. doi: 10.4049/jimmunol.181.11.7713 19017960.

45. Cillo AR, Sobolewski MD, Bosch RJ, Fyne E, Piatak M Jr., Coffin JM, et al. Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A. 2014;111(19):7078–83. doi: 10.1073/pnas.1402873111 24706775; PubMed Central PMCID: PMC4024870.

46. Spina CA, Anderson J, Archin NM, Bosque A, Chan J, Famiglietti M, et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog. 2013;9(12):e1003834. doi: 10.1371/journal.ppat.1003834 24385908; PubMed Central PMCID: PMC3873446.

47. Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013;155(3):540–51. doi: 10.1016/j.cell.2013.09.020 24243014; PubMed Central PMCID: PMC3896327.

48. Hosmane NN, Kwon KJ, Bruner KM, Capoferri AA, Beg S, Rosenbloom DI, et al. Proliferation of latently infected CD4(+) T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics. J Exp Med. 2017;214(4):959–72. Epub 2017/03/28. doi: 10.1084/jem.20170193 28341641; PubMed Central PMCID: PMC5379987.

49. Kulpa DA, Talla A, Brehm JH, Ribeiro SP, Yuan S, Bebin-Blackwell A-G, et al. Differentiation to an effector memory phenotype potentiates HIV-1 latency reversal in CD4+ T cells. Journal of Virology. 2019;93(24):e00969–19. Epub October 2, 2019.

50. Guerrero S, Batisse J, Libre C, Bernacchi S, Marquet R, Paillart JC. HIV-1 replication and the cellular eukaryotic translation apparatus. Viruses. 2015;7(1):199–218. doi: 10.3390/v7010199 25606970; PubMed Central PMCID: PMC4306834.

51. Romanchikova N, Ivanova V, Scheller C, Jankevics E, Jassoy C, Serfling E. NFAT transcription factors control HIV-1 expression through a binding site downstream of TAR region. Immunobiology. 2003;208(4):361–5. Epub 2004/01/30. doi: 10.1078/0171-2985-00283 14748509.

52. Sarikhani M, Maity S, Mishra S, Jain A, Tamta AK, Ravi V, et al. SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis. J Biol Chem. 2018;293(14):5281–94. Epub 2018/02/15. doi: 10.1074/jbc.RA117.000915 29440391; PubMed Central PMCID: PMC5892579.

53. Selliah N, Zhang M, DeSimone D, Kim H, Brunner M, Ittenbach RF, et al. The gammac-cytokine regulated transcription factor, STAT5, increases HIV-1 production in primary CD4 T cells. Virology. 2006;344(2):283–91. doi: 10.1016/j.virol.2005.09.063 16289657.

54. Luckheeram RV, Zhou R, Verma AD, Xia B. CD4(+)T cells: differentiation and functions. Clin Dev Immunol. 2012;2012:925135. Epub 2012/04/05. doi: 10.1155/2012/925135 22474485; PubMed Central PMCID: PMC3312336.

55. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89. Epub 2010/03/03. doi: 10.1146/annurev-immunol-030409-101212 20192806; PubMed Central PMCID: PMC3502616.

56. Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM. T cell responses: naive to memory and everything in between. Adv Physiol Educ. 2013;37(4):273–83. Epub 2013/12/03. doi: 10.1152/advan.00066.2013 24292902; PubMed Central PMCID: PMC4089090.

57. Bauer I, Grozio A, Lasiglie D, Basile G, Sturla L, Magnone M, et al. The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem. 2012;287(49):40924–37. Epub 2012/10/23. doi: 10.1074/jbc.M112.405837 23086953; PubMed Central PMCID: PMC3510797.

58. Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009;460(7255):587–91. Epub 2009/07/31. doi: 10.1038/nature08197 19641587; PubMed Central PMCID: PMC3727385.

59. Parbin S, Kar S, Shilpi A, Sengupta D, Deb M, Rath SK, et al. Histone deacetylases: a saga of perturbed acetylation homeostasis in cancer. J Histochem Cytochem. 2014;62(1):11–33. Epub 2013/09/21. doi: 10.1369/0022155413506582 24051359; PubMed Central PMCID: PMC3873803.

60. Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713. Epub 2014/04/03. doi: 10.1101/cshperspect.a018713 24691964; PubMed Central PMCID: PMC3970420.

61. Rother MB, van Attikum H. DNA repair goes hip-hop: SMARCA and CHD chromatin remodellers join the break dance. Philos Trans R Soc Lond B Biol Sci. 2017;372(1731). Epub 2017/08/30. doi: 10.1098/rstb.2016.0285 28847822; PubMed Central PMCID: PMC5577463.

62. Flaus A, Owen-Hughes T. Mechanisms for ATP-dependent chromatin remodelling: the means to the end. FEBS J. 2011;278(19):3579–95. Epub 2011/08/04. doi: 10.1111/j.1742-4658.2011.08281.x 21810178; PubMed Central PMCID: PMC4162296.

63. Margolis DM. Histone deacetylase inhibitors and HIV latency. Curr Opin HIV AIDS. 2011;6(1):25–9. Epub 2011/01/19. doi: 10.1097/COH.0b013e328341242d 21242890; PubMed Central PMCID: PMC3079555.

64. Procopio FA, Fromentin R, Kulpa DA, Brehm JH, Bebin AG, Strain MC, et al. A Novel Assay to Measure the Magnitude of the Inducible Viral Reservoir in HIV-infected Individuals. EBioMedicine. 2015;2(8):874–83. doi: 10.1016/j.ebiom.2015.06.019 26425694; PubMed Central PMCID: PMC4563128.

65. Geginat J, Sallusto F, Lanzavecchia A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells. J Exp Med. 2001;194(12):1711–9. doi: 10.1084/jem.194.12.1711 11748273; PubMed Central PMCID: PMC2193568.

66. Rosenbloom DI, Elliott O, Hill AL, Henrich TJ, Siliciano JM, Siliciano RF. Designing and Interpreting Limiting Dilution Assays: General Principles and Applications to the Latent Reservoir for Human Immunodeficiency Virus-1. Open Forum Infect Dis. 2015;2(4):ofv123. doi: 10.1093/ofid/ofv123 26478893; PubMed Central PMCID: PMC4602119.

67. Laird GM, Rosenbloom DI, Lai J, Siliciano RF, Siliciano JD. Measuring the Frequency of Latent HIV-1 in Resting CD4(+) T Cells Using a Limiting Dilution Coculture Assay. Methods Mol Biol. 2016;1354:239–53. doi: 10.1007/978-1-4939-3046-3_16 26714716.

68. Fun A, Mok HP, Wills MR, Lever AM. A highly reproducible quantitative viral outgrowth assay for the measurement of the replication-competent latent HIV-1 reservoir. Sci Rep. 2017;7:43231. doi: 10.1038/srep43231 28233807; PubMed Central PMCID: PMC5324126.

69. Rosenbloom DIS, Bacchetti P, Stone M, Deng X, Bosch RJ, Richman DD, et al. Assessing intra-lab precision and inter-lab repeatability of outgrowth assays of HIV-1 latent reservoir size. PLoS Comput Biol. 2019;15(4):e1006849. Epub 2019/04/13. doi: 10.1371/journal.pcbi.1006849 30978183; PubMed Central PMCID: PMC6481870.

70. Norton NJ, Fun A, Bandara M, Wills MR, Mok HP, Lever AML. Innovations in the quantitative virus outgrowth assay and its use in clinical trials. Retrovirology. 2017;14(1):58. Epub 2017/12/23. doi: 10.1186/s12977-017-0381-2 29268753; PubMed Central PMCID: PMC5740843.

71. Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB, Capoferri AA, et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med. 2016. doi: 10.1038/nm.4156 27500724.

72. Jordan A, Defechereux P, Verdin E. The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation. EMBO J. 2001;20(7):1726–38. doi: 10.1093/emboj/20.7.1726 11285236; PubMed Central PMCID: PMC145503.

73. Bosque A, Famiglietti M, Weyrich AS, Goulston C, Planelles V. Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells. PLoS Pathog. 2011;7(10):e1002288. doi: 10.1371/journal.ppat.1002288 21998586; PubMed Central PMCID: PMC3188522.

74. Vandergeeten C, Fromentin R, DaFonseca S, Lawani MB, Sereti I, Lederman MM, et al. Interleukin-7 promotes HIV persistence during antiretroviral therapy. Blood. 2013;121(21):4321–9. doi: 10.1182/blood-2012-11-465625 23589672; PubMed Central PMCID: PMC3663425.

75. Wang FX, Xu Y, Sullivan J, Souder E, Argyris EG, Acheampong EA, 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(1):128–37. doi: 10.1172/JCI22574 15630452; PubMed Central PMCID: PMC539197.

76. Jones RB, Mueller S, O'Connor R, Rimpel K, Sloan DD, Karel D, et al. A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes. PLoS Pathog. 2016;12(4):e1005545. doi: 10.1371/journal.ppat.1005545 27082643; PubMed Central PMCID: PMC4833318.

77. Hiener B, Horsburgh BA, Eden JS, Barton K, Schlub TE, Lee E, et al. Identification of Genetically Intact HIV-1 Proviruses in Specific CD4+ T Cells from Effectively Treated Participants. Cell Rep. 2017;21(3):813–22. doi: 10.1016/j.celrep.2017.09.081 29045846.

78. Palmer S, Kearney M, Maldarelli F, Halvas EK, Bixby CJ, Bazmi H, et al. Multiple, linked human immunodeficiency virus type 1 drug resistance mutations in treatment-experienced patients are missed by standard genotype analysis. J Clin Microbiol. 2005;43(1):406–13. Epub 2005/01/07. doi: 10.1128/JCM.43.1.406-413.2005 15635002; PubMed Central PMCID: PMC540111.

79. Laskey SB, Pohlmeyer CW, Bruner KM, Siliciano RF. Evaluating Clonal Expansion of HIV-Infected Cells: Optimization of PCR Strategies to Predict Clonality. PLoS Pathog. 2016;12(8):e1005689. Epub 2016/08/06. doi: 10.1371/journal.ppat.1005689 27494508; PubMed Central PMCID: PMC4975415.

80. Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, Hill S, et al. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science. 2014;345(6193):179–83. doi: 10.1126/science.1254194 24968937; PubMed Central PMCID: PMC4262401.

81. Wiegand A, Spindler J, Hong FF, Shao W, Cyktor JC, Cillo AR, et al. Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc Natl Acad Sci U S A. 2017;114(18):E3659–E68. doi: 10.1073/pnas.1617961114 28416661; PubMed Central PMCID: PMC5422779.

82. Wang Z, Gurule EE, Brennan TP, Gerold JM, Kwon KJ, Hosmane NN, et al. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc Natl Acad Sci U S A. 2018;115(11):E2575–E84. Epub 2018/02/28. doi: 10.1073/pnas.1720665115 29483265; PubMed Central PMCID: PMC5856552.

83. Salantes DB, Zheng Y, Mampe F, Srivastava T, Beg S, Lai J, et al. HIV-1 latent reservoir size and diversity are stable following brief treatment interruption. J Clin Invest. 2018;128(7):3102–15. Epub 2018/06/19. doi: 10.1172/JCI120194 29911997; PubMed Central PMCID: PMC6026010.

84. Pinzone MR, VanBelzen DJ, Weissman S, Bertuccio MP, Cannon L, Venanzi-Rullo E, et al. Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion. Nat Commun. 2019;10(1):728. Epub 2019/02/15. doi: 10.1038/s41467-019-08431-7 30760706; PubMed Central PMCID: PMC6374386.

85. Lu CL, Pai JA, Nogueira L, Mendoza P, Gruell H, Oliveira TY, et al. Relationship between intact HIV-1 proviruses in circulating CD4(+) T cells and rebound viruses emerging during treatment interruption. Proc Natl Acad Sci U S A. 2018. Epub 2018/11/14. doi: 10.1073/pnas.1813512115 30420517.

86. Cohen YZ, Lorenzi JCC, Krassnig L, Barton JP, Burke L, Pai J, et al. Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117. J Exp Med. 2018;215(9):2311–24. Epub 2018/08/04. doi: 10.1084/jem.20180936 30072495; PubMed Central PMCID: PMC6122972.

87. Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nat Immunol. 2011;12(6):467–71. doi: 10.1038/ni.2038 21739668; PubMed Central PMCID: PMC4212218.

88. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63. Epub 2004/03/23. doi: 10.1146/annurev.immunol.22.012703.104702 15032595.

89. Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes. Nat Immunol. 2003;4(1):78–86. Epub 2002/11/26. doi: 10.1038/ni872 12447360.

90. Cantrell DA, Smith KA. Transient expression of interleukin 2 receptors. Consequences for T cell growth. J Exp Med. 1983;158(6):1895–911. Epub 1983/12/01. doi: 10.1084/jem.158.6.1895 6606011; PubMed Central PMCID: PMC2187178.

91. Nakarai T, Robertson MJ, Streuli M, Wu Z, Ciardelli TL, Smith KA, et al. Interleukin 2 receptor gamma chain expression on resting and activated lymphoid cells. J Exp Med. 1994;180(1):241–51. Epub 1994/07/01. doi: 10.1084/jem.180.1.241 8006584; PubMed Central PMCID: PMC2191535.

92. Cohen SB, Crawley JB, Kahan MC, Feldmann M, Foxwell BM. Interleukin-10 rescues T cells from apoptotic cell death: association with an upregulation of Bcl-2. Immunology. 1997;92(1):1–5. Epub 1997/11/26. doi: 10.1046/j.1365-2567.1997.00348.x 9370916; PubMed Central PMCID: PMC1363973.

93. Teigler JE, Leyre L, Chomont N, Slike B, Jian N, Eller MA, et al. Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size. JCI Insight. 2018;3(10). Epub 2018/05/18. doi: 10.1172/jci.insight.98420 29769442; PubMed Central PMCID: PMC6018979.

94. Bosque A, Planelles V. Studies of HIV-1 latency in an ex vivo model that uses primary central memory T cells. Methods. 2011;53(1):54–61. doi: 10.1016/j.ymeth.2010.10.002 20970502; PubMed Central PMCID: PMC3031099.

95. Zerbato JM, McMahon DK, Sobolewski MD, Mellors JW, Sluis-Cremer N. Naive CD4+ T Cells Harbor a Large Inducible Reservoir of Latent, Replication-Competent HIV-1. Clin Infect Dis. 2019. Epub 2019/02/13. doi: 10.1093/cid/ciz108 30753360.

96. Venanzi Rullo E, Cannon L, Pinzone MR, Ceccarelli M, Nunnari G, O'Doherty U. "Genetic evidence that Naive T cells can contribute significantly to the HIV intact reservoir: time to re-evaluate their role". Clin Infect Dis. 2019. Epub 2019/05/08. doi: 10.1093/cid/ciz378 31063189.

97. Moso MA, Anderson JL, Adikari S, Gray LR, Khoury G, Chang JJ, et al. HIV latency can be established in proliferating and nonproliferating resting CD4+ T cells in vitro: implications for latency reversal. AIDS. 2019;33(2):199–209. Epub 2018/12/19. doi: 10.1097/QAD.0000000000002075 30562171; PubMed Central PMCID: PMC6319264.

98. Lakkis FG, Lechler RI. Origin and biology of the allogeneic response. Cold Spring Harb Perspect Med. 2013;3(8). Epub 2013/08/03. doi: 10.1101/cshperspect.a014993 23906882; PubMed Central PMCID: PMC3721272.

99. Nabel G, Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987;326(6114):711–3. doi: 10.1038/326711a0 3031512.

100. Roebuck KA, Saifuddin M. Regulation of HIV-1 transcription. Gene Expr. 1999;8(2):67–84. Epub 1999/11/07. 10551796; PubMed Central PMCID: PMC6157391.

101. Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010;238(1):247–62. Epub 2010/10/26. doi: 10.1111/j.1600-065X.2010.00951.x 20969597; PubMed Central PMCID: PMC2975272.

102. Bruner KM, Wang Z, Simonetti FR, Bender AM, Kwon KJ, Sengupta S, et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature. 2019;566(7742):120–5. Epub 2019/02/01. doi: 10.1038/s41586-019-0898-8 30700913; PubMed Central PMCID: PMC6447073.

103. Wonderlich E, Subramanian K, Lackman-Smith C, Ptak RG, Kulpa DA. Ex vivo differentiation of resting CD4+ T cells coupled with the QVOA (dQVOA). protocolsio. 2019:protocols.io doi: dx.doi.org/10.17504/protocols.io.5h2g38e

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