The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy.

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    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
    • Abstract:
      HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART.
    • References:
      Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13193-7. (PMID: 9371822)
      Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):E2575-E2584. (PMID: 29483265)
      Nature. 1997 May 8;387(6629):183-8. (PMID: 9144289)
      Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974-8. (PMID: 2762307)
      Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12955-60. (PMID: 14569007)
      Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8869-73. (PMID: 9671771)
      J Clin Invest. 2020 Jul 1;130(7):3543-3559. (PMID: 32191639)
      J Infect Dis. 2017 Jul 15;216(2):254-262. (PMID: 28838149)
      J Exp Med. 2018 Sep 3;215(9):2311-2324. (PMID: 30072495)
      N Engl J Med. 1997 Sep 11;337(11):725-33. (PMID: 9287227)
      Cell Rep. 2022 Apr 26;39(4):110739. (PMID: 35476994)
      Cell. 2015 Jan 29;160(3):420-32. (PMID: 25635456)
      PLoS Pathog. 2012 Feb;8(2):e1002506. (PMID: 22319447)
      Science. 1997 Nov 14;278(5341):1291-5. (PMID: 9360926)
      Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):E1126-34. (PMID: 25713386)
      Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32066-32077. (PMID: 33239444)
      Nat Med. 2016 Sep;22(9):1043-9. (PMID: 27500724)
      J Virol. 2005 Aug;79(15):9625-34. (PMID: 16014925)
      Cell. 2002 Aug 23;110(4):521-9. (PMID: 12202041)
      J Exp Med. 2017 Apr 3;214(4):959-972. (PMID: 28341641)
      J Infect Dis. 2015 Aug 15;212(4):596-607. (PMID: 25712966)
      Open Forum Infect Dis. 2015 Aug 26;2(4):ofv123. (PMID: 26478893)
      Methods Mol Biol. 2005;304:3-15. (PMID: 16061962)
      Methods Mol Biol. 2016;1354:239-53. (PMID: 26714716)
      J Virol. 2004 Jun;78(12):6122-33. (PMID: 15163705)
      Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18692-18700. (PMID: 32690683)
      Annu Rev Virol. 2017 Sep 29;4(1):261-285. (PMID: 28715973)
      J Exp Med. 2021 Dec 6;218(12):. (PMID: 34636876)
      Cell Host Microbe. 2023 Mar 8;31(3):356-372.e5. (PMID: 36809762)
      J Virol. 2006 Jul;80(13):6441-57. (PMID: 16775332)
      Nature. 2016 Dec 8;540(7632):284-287. (PMID: 27841870)
      J Clin Invest. 2020 Nov 2;130(11):5847-5857. (PMID: 33016926)
      Nat Commun. 2019 Feb 13;10(1):728. (PMID: 30760706)
      PLoS Pathog. 2021 Apr 7;17(4):e1009141. (PMID: 33826675)
      Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):E7908-E7916. (PMID: 27872306)
      Nature. 2014 Aug 7;512(7512):74-7. (PMID: 25042999)
      Curr HIV/AIDS Rep. 2021 Jun;18(3):211-220. (PMID: 33709324)
      N Engl J Med. 1997 Sep 11;337(11):734-9. (PMID: 9287228)
      PLoS Pathog. 2021 Sep 16;17(9):e1009581. (PMID: 34529720)
      Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1883-8. (PMID: 26858442)
      Blood. 2001 Apr 15;97(8):2390-400. (PMID: 11290602)
      EMBO J. 1990 May;9(5):1551-60. (PMID: 2184033)
      Nat Med. 2009 Aug;15(8):893-900. (PMID: 19543283)
      Nat Med. 2003 Jun;9(6):727-8. (PMID: 12754504)
      Nature. 1987 Apr 16-22;326(6114):711-3. (PMID: 3031512)
      Sci Transl Med. 2021 Dec 15;13(624):eabl4097. (PMID: 34910552)
      Science. 1997 Nov 14;278(5341):1295-300. (PMID: 9360927)
      PLoS Pathog. 2007 Apr;3(4):e46. (PMID: 17411338)
      Proc Natl Acad Sci U S A. 2022 Feb 8;119(6):. (PMID: 35110411)
      J Clin Invest. 2021 Feb 1;131(3):. (PMID: 33301425)
      Nature. 2020 Feb;578(7793):160-165. (PMID: 31969707)
      Cancer Res. 1960 May;20:462-6. (PMID: 14427849)
      Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15109-14. (PMID: 10611346)
      JCI Insight. 2020 Feb 27;5(4):. (PMID: 32045386)
      Cell. 2013 Oct 24;155(3):540-51. (PMID: 24243014)
      Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3704-3710. (PMID: 32029589)
      Nature. 1997 May 8;387(6629):188-91. (PMID: 9144290)
      AIDS Res Hum Retroviruses. 2000 Jul 1;16(10):935-41. (PMID: 10890354)
      Sci Transl Med. 2020 Jan 29;12(528):. (PMID: 31996465)
      Nature. 2018 Sep;561(7723):E17-E19. (PMID: 30232425)
      PLoS Pathog. 2017 Mar 22;13(3):e1006283. (PMID: 28328934)
      Science. 2014 Jul 11;345(6193):179-83. (PMID: 24968937)
      PLoS Pathog. 2013;9(5):e1003398. (PMID: 23737751)
      JAMA. 2005 Feb 16;293(7):817-29. (PMID: 15713771)
      J Virol. 2013 Jan;87(2):1211-20. (PMID: 23152527)
      Nature. 2012 Jul 25;487(7408):482-5. (PMID: 22837004)
      Trends Immunol. 2023 Jan;44(1):60-71. (PMID: 36503686)
      Cell. 2022 Jan 20;185(2):266-282.e15. (PMID: 35026153)
      J Exp Med. 2020 Jul 6;217(7):. (PMID: 32311008)
      Immunity. 2022 Jun 14;55(6):1013-1031.e7. (PMID: 35320704)
      Nature. 2019 Feb;566(7742):120-125. (PMID: 30700913)
      Nat Med. 1995 Dec;1(12):1284-90. (PMID: 7489410)
      Nat Med. 2022 Nov;28(11):2424-2435. (PMID: 36253609)
      Science. 2014 Aug 1;345(6196):570-3. (PMID: 25011556)
      J Virol. 2013 Feb;87(3):1770-8. (PMID: 23175380)
      Nat Med. 1999 May;5(5):512-7. (PMID: 10229227)
      Nat Commun. 2018 Nov 16;9(1):4811. (PMID: 30446650)
      Cell Host Microbe. 2023 Jan 11;31(1):83-96.e5. (PMID: 36596305)
      Nature. 2018 Sep;561(7724):479-484. (PMID: 30258136)
      J Clin Invest. 2018 Jul 2;128(7):3102-3115. (PMID: 29911997)
      Immunity. 1997 Mar;6(3):235-44. (PMID: 9075924)
      J Infect Dis. 2021 Feb 3;223(2):225-233. (PMID: 32823274)
      Nature. 2020 Sep;585(7824):261-267. (PMID: 32848246)
      J Infect Dis. 2015 Nov 1;212(9):1361-5. (PMID: 25877550)
      PLoS Pathog. 2013 Feb;9(2):e1003174. (PMID: 23459007)
      PLoS Pathog. 2022 Aug 31;18(8):e1010726. (PMID: 36044447)
      J Infect Dis. 2023 Jun 15;227(12):1376-1380. (PMID: 36763044)
      Nat Med. 2018 Jul;24(7):923-926. (PMID: 29892063)
      Genes Dev. 1997 Oct 15;11(20):2622-32. (PMID: 9334325)
    • Grant Information:
      R01 OD011095 United States OD NIH HHS; U24 AI143502 United States AI NIAID NIH HHS; UM1 AI126620 United States AI NIAID NIH HHS; R01 AI152703 United States AI NIAID NIH HHS; UM1 AI164561 United States AI NIAID NIH HHS; UM1 AI164570 United States AI NIAID NIH HHS; United States HHMI Howard Hughes Medical Institute; R01 AI028433 United States AI NIAID NIH HHS; UM1 AI164560 United States AI NIAID NIH HHS; DP5 OD031834 United States OD NIH HHS; P01 AI169615 United States AI NIAID NIH HHS; UM1 AI164556 United States AI NIAID NIH HHS; P30 AI094189 United States AI NIAID NIH HHS; UM1 AI164566 United States AI NIAID NIH HHS
    • Contributed Indexing:
      Keywords: AIDS/HIV; Molecular biology; T cells; Virology
    • Accession Number:
      0 (Anti-Retroviral Agents)
    • Publication Date:
      Date Created: 20230718 Date Completed: 20230904 Latest Revision: 20240714
    • Publication Date:
      20240714
    • Accession Number:
      PMC10471168
    • Accession Number:
      10.1172/JCI171554
    • Accession Number:
      37463049