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Published in: Current HIV/AIDS Reports 2/2016

Open Access 01-04-2016 | HIV Pathogenesis and Treatment (AL Landay, Section Editor)

How to Define the Latent Reservoir: Tools of the Trade

Authors: Kirston M. Barton, Sarah E. Palmer

Published in: Current HIV/AIDS Reports | Issue 2/2016

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Abstract

HIV is a devastating worldwide epidemic that has had substantial social and economic impacts throughout the globe. Due to the presence of a small pool of latently infected cells that persists during antiretroviral therapy (ART), HIV is not curable. Because of the high cost of ART and the lack of reliable accessibility across the globe, life-long ART is unfortunately not a feasible solution for the epidemic. Therefore, new strategies need to be developed and implemented to address HIV-1 infection. Several approaches toward this end are currently under investigation (Ebina et al. in Sci Rep 3:2510, 2013; Archin et al. in Nature 487:482–5, 2012; Elliott et al. in PLoS Pathog 10:e1004473, 2014; Rasmussen et al. in Lancet HIV 1:e13–e21, 2014; Tebas et al. in N Engl J Med 370:901–10, 2014; Archin et al. in Nat Rev Microbiol 12:750–64, 2014; Barton et al. in PLoS One 9:e102684, 2014; Sogaard et al. in PLoS Pathog 11:e1005142, 2015). Initial studies have proven promising, but have highlighted the need for sensitive and accurate assays to detect changes in very low concentrations of virus to allow confident interpretation of the success of curative approaches. This review will focus on assays that are currently available and the advantages and limitations of each.
Literature
1.
go back to reference Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5(5):512–7. doi:10.1038/8394.CrossRefPubMed Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5(5):512–7. doi:10.​1038/​8394.CrossRefPubMed
3.
go back to reference Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013;3:2510. doi:10.1038/srep02510. Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013;3:2510. doi:10.​1038/​srep02510.
4.
go back to reference Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482–5. doi:10.1038/nature11286. Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482–5. doi:10.​1038/​nature11286.
5.••
go back to reference Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(10):e1004473. doi:10.1371/journal.ppat.1004473. First clinical trial conducted using vorinostat that showed viral reactivation following administration. Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(10):e1004473. doi:10.​1371/​journal.​ppat.​1004473. First clinical trial conducted using vorinostat that showed viral reactivation following administration.
6.••
go back to reference Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014;1(1):e13–21. doi:10.1016/S2352-3018(14)70014-1. This clinical trial demonstrates that panobinostat activates HIV-1 transcription in vivo. Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014;1(1):e13–21. doi:10.​1016/​S2352-3018(14)70014-1. This clinical trial demonstrates that panobinostat activates HIV-1 transcription in vivo.
7.
go back to reference Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. New England J Med. 2014;370(10):901–10. doi:10.1056/NEJMoa1300662. Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. New England J Med. 2014;370(10):901–10. doi:10.​1056/​NEJMoa1300662.
8.
go back to reference Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12(11):750–64. doi:10.1038/nrmicro3352. Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12(11):750–64. doi:10.​1038/​nrmicro3352.
9.
10.••
go back to reference Sogaard OS, Graversen ME, Leth S, Olesen R, Brinkmann CR, Nissen SK, et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015;11(9):e1005142. doi:10.1371/journal.ppat.1005142. A recent clinical trial demonstrating that romidepsin reactivates HIV from latency in vivo. Sogaard OS, Graversen ME, Leth S, Olesen R, Brinkmann CR, Nissen SK, et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015;11(9):e1005142. doi:10.​1371/​journal.​ppat.​1005142. A recent clinical trial demonstrating that romidepsin reactivates HIV from latency in vivo.
11.
go back to reference Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med. 1995;1(12):1284–90.CrossRefPubMed Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med. 1995;1(12):1284–90.CrossRefPubMed
13.
go back to reference Nottet HS, van Dijk SJ, Fanoy EB, Goedegebuure IW, de Jong D, Vrisekoop N, et al. HIV-1 can persist in aged memory CD4+ T lymphocytes with minimal signs of evolution after 8.3 years of effective highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2009;50(4):345–53. doi:10.1097/QAI.0b013e318197eb04.CrossRefPubMed Nottet HS, van Dijk SJ, Fanoy EB, Goedegebuure IW, de Jong D, Vrisekoop N, et al. HIV-1 can persist in aged memory CD4+ T lymphocytes with minimal signs of evolution after 8.3 years of effective highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2009;50(4):345–53. doi:10.​1097/​QAI.​0b013e318197eb04​.CrossRefPubMed
15.••
go back to reference Josefsson L, Palmer S, Faria NR, Lemey P, Casazza J, Ambrozak D, et al. Single cell analysis of lymph node tissue from HIV-1 infected patients reveals that the majority of CD4+ T-cells contain one HIV-1 DNA molecule. PLoS Pathog. 2013;9(6):e1003432. doi:10.1371/journal.ppat.1003432. Important work conclusively demonstrating that each HIV-infected cell generally contains a single integrated HIV-1 genome.CrossRefPubMedPubMedCentral Josefsson L, Palmer S, Faria NR, Lemey P, Casazza J, Ambrozak D, et al. Single cell analysis of lymph node tissue from HIV-1 infected patients reveals that the majority of CD4+ T-cells contain one HIV-1 DNA molecule. PLoS Pathog. 2013;9(6):e1003432. doi:10.​1371/​journal.​ppat.​1003432. Important work conclusively demonstrating that each HIV-infected cell generally contains a single integrated HIV-1 genome.CrossRefPubMedPubMedCentral
16.
go back to reference Josefsson L, von Stockenstrom S, Faria NR, Sinclair E, Bacchetti P, Killian M, et al. The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. Proc Natl Acad Sci U S A. 2013;110(51):E4987–96. doi:10.1073/pnas.1308313110.CrossRefPubMedPubMedCentral Josefsson L, von Stockenstrom S, Faria NR, Sinclair E, Bacchetti P, Killian M, et al. The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. Proc Natl Acad Sci U S A. 2013;110(51):E4987–96. doi:10.​1073/​pnas.​1308313110.CrossRefPubMedPubMedCentral
17.
go back to reference von Stockenstrom S, Odevall L, Lee E, Sinclair E, Bacchetti P, Killian M, et al. Longitudinal genetic characterization reveals that cell proliferation maintains a persistent HIV type 1 DNA pool during effective HIV therapy. J Infect Dis. 2015. doi:10.1093/infdis/jiv092. von Stockenstrom S, Odevall L, Lee E, Sinclair E, Bacchetti P, Killian M, et al. Longitudinal genetic characterization reveals that cell proliferation maintains a persistent HIV type 1 DNA pool during effective HIV therapy. J Infect Dis. 2015. doi:10.​1093/​infdis/​jiv092.
18.•
go back to reference 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. A thorough study demonstrating that the majority of detectable HIV RNA and DNA in individuals on ART is defective.CrossRefPubMedPubMedCentral 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. A thorough study demonstrating that the majority of detectable HIV RNA and DNA in individuals on ART is defective.CrossRefPubMedPubMedCentral
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference Crooks AM, Bateson R, Cope AB, Dahl NP, Griggs MK, Kuruc JD, et al. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J Infect Dis. 2015. doi:10.1093/infdis/jiv218.PubMed Crooks AM, Bateson R, Cope AB, Dahl NP, Griggs MK, Kuruc JD, et al. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J Infect Dis. 2015. doi:10.​1093/​infdis/​jiv218.PubMed
21.
go back to reference 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.PubMed 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.PubMed
23.
go back to reference Lee SKZ S, Archin N, Margolis D, Swanstrom R. Assay to measure replication-competent HIV-1 in supressed patients based on ultra-deep sequencing, IAS. Canada: Vancouver; 2015. Lee SKZ S, Archin N, Margolis D, Swanstrom R. Assay to measure replication-competent HIV-1 in supressed patients based on ultra-deep sequencing, IAS. Canada: Vancouver; 2015.
24.
go back to reference Metcalf Pate KA, Pohlmeyer CW, Walker-Sperling VE, Foote JB, Najarro KM, Cryer CG, et al. A murine viral outgrowth assay to detect residual HIV type 1 in patients with undetectable viral loads. J Infect Dis. 2015. doi:10.1093/infdis/jiv230.PubMed Metcalf Pate KA, Pohlmeyer CW, Walker-Sperling VE, Foote JB, Najarro KM, Cryer CG, et al. A murine viral outgrowth assay to detect residual HIV type 1 in patients with undetectable viral loads. J Infect Dis. 2015. doi:10.​1093/​infdis/​jiv230.PubMed
27.
go back to reference Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol. 2003;41(10):4531–6.CrossRefPubMedPubMedCentral Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol. 2003;41(10):4531–6.CrossRefPubMedPubMedCentral
28.
29.
30.
go back to reference De Bel A, Marissens D, Debaisieux L, Liesnard C, Van den Wijngaert S, Lauwers S, et al. Correction of underquantification of human immunodeficiency virus type 1 load with the second version of the Roche Cobas AmpliPrep/Cobas TaqMan assay. J Clin Microbiol. 2010;48(4):1337–42. doi:10.1128/JCM.01226-09.CrossRefPubMedPubMedCentral De Bel A, Marissens D, Debaisieux L, Liesnard C, Van den Wijngaert S, Lauwers S, et al. Correction of underquantification of human immunodeficiency virus type 1 load with the second version of the Roche Cobas AmpliPrep/Cobas TaqMan assay. J Clin Microbiol. 2010;48(4):1337–42. doi:10.​1128/​JCM.​01226-09.CrossRefPubMedPubMedCentral
31.
go back to reference Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, Hunt PW, et al. Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol. 2009;83(1):329–35. doi:10.1128/JVI.01763-08.CrossRefPubMedPubMedCentral Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, Hunt PW, et al. Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol. 2009;83(1):329–35. doi:10.​1128/​JVI.​01763-08.CrossRefPubMedPubMedCentral
33.
go back to reference Bagnarelli P, Valenza A, Menzo S, Sampaolesi R, Varaldo PE, Butini L, et al. Dynamics and modulation of human immunodeficiency virus type 1 transcripts in vitro and in vivo. J Virol. 1996;70(11):7603–13.PubMedPubMedCentral Bagnarelli P, Valenza A, Menzo S, Sampaolesi R, Varaldo PE, Butini L, et al. Dynamics and modulation of human immunodeficiency virus type 1 transcripts in vitro and in vivo. J Virol. 1996;70(11):7603–13.PubMedPubMedCentral
34.
go back to reference Hermankova M, Siliciano JD, Zhou Y, Monie D, Chadwick K, Margolick JB, et al. Analysis of human immunodeficiency virus type 1 gene expression in latently infected resting CD4+ T lymphocytes in vivo. J Virol. 2003;77(13):7383–92.CrossRefPubMedPubMedCentral Hermankova M, Siliciano JD, Zhou Y, Monie D, Chadwick K, Margolick JB, et al. Analysis of human immunodeficiency virus type 1 gene expression in latently infected resting CD4+ T lymphocytes in vivo. J Virol. 2003;77(13):7383–92.CrossRefPubMedPubMedCentral
35.
go back to reference Vesanen M, Markowitz M, Cao Y, Ho DD, Saksela K. Human immunodeficiency virus type-1 mRNA splicing pattern in infected persons is determined by the proportion of newly infected cells. Virology. 1997;236(1):104–9. doi:10.1006/viro.1997.8718.CrossRefPubMed Vesanen M, Markowitz M, Cao Y, Ho DD, Saksela K. Human immunodeficiency virus type-1 mRNA splicing pattern in infected persons is determined by the proportion of newly infected cells. Virology. 1997;236(1):104–9. doi:10.​1006/​viro.​1997.​8718.CrossRefPubMed
37.
go back to reference Besson GJ, McMahon D, Maldarelli F, Mellors JW. Short-course raltegravir intensification does not increase 2 long terminal repeat episomal HIV-1 DNA in patients on effective antiretroviral therapy. Clin Infect Dis : Off Publ Infect Dis Soc Am. 2012;54(3):451–3. doi:10.1093/cid/cir721.CrossRef Besson GJ, McMahon D, Maldarelli F, Mellors JW. Short-course raltegravir intensification does not increase 2 long terminal repeat episomal HIV-1 DNA in patients on effective antiretroviral therapy. Clin Infect Dis : Off Publ Infect Dis Soc Am. 2012;54(3):451–3. doi:10.​1093/​cid/​cir721.CrossRef
41.
go back to reference Chun TW, Murray D, Justement JS, Hallahan CW, Moir S, Kovacs C, et al. Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy. J Infect Dis. 2011;204(1):135–8. doi:10.1093/infdis/jir208.CrossRefPubMedPubMedCentral Chun TW, Murray D, Justement JS, Hallahan CW, Moir S, Kovacs C, et al. Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy. J Infect Dis. 2011;204(1):135–8. doi:10.​1093/​infdis/​jir208.CrossRefPubMedPubMedCentral
44.
go back to reference Durand CM, Ghiaur G, Siliciano JD, Rabi SA, Eisele EE, Salgado M, et al. HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. 2012;205(6):1014–8. doi:10.1093/infdis/jir884.CrossRefPubMedPubMedCentral Durand CM, Ghiaur G, Siliciano JD, Rabi SA, Eisele EE, Salgado M, et al. HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. 2012;205(6):1014–8. doi:10.​1093/​infdis/​jir884.CrossRefPubMedPubMedCentral
48.
go back to reference O'Doherty U, Swiggard WJ, Jeyakumar D, McGain D, Malim MH. A sensitive, quantitative assay for human immunodeficiency virus type 1 integration. J Virol. 2002;76(21):10942–50.CrossRefPubMedPubMedCentral O'Doherty U, Swiggard WJ, Jeyakumar D, McGain D, Malim MH. A sensitive, quantitative assay for human immunodeficiency virus type 1 integration. J Virol. 2002;76(21):10942–50.CrossRefPubMedPubMedCentral
49.
go back to reference Sanchez G, Xu X, Chermann JC, Hirsch I. Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J Virol. 1997;71(3):2233–40.PubMedPubMedCentral Sanchez G, Xu X, Chermann JC, Hirsch I. Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J Virol. 1997;71(3):2233–40.PubMedPubMedCentral
51.
53.••
go back to reference Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161(5):319–27. doi:10.7326/M14-1027. This manuscript describes the comprehensive analysis of residual viremia in two individuals who underwent an allogeneic stem cell transplant in which no virus was found.CrossRefPubMedPubMedCentral Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med. 2014;161(5):319–27. doi:10.​7326/​M14-1027. This manuscript describes the comprehensive analysis of residual viremia in two individuals who underwent an allogeneic stem cell transplant in which no virus was found.CrossRefPubMedPubMedCentral
54.••
go back to reference Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient detects. PLoS Pathog. 2013;9(5):e1003347. doi:10.1371/journal.ppat.1003347. A comprehensive and collaborative analysis of the Berlin patient detects HIV; however, to date no viral rebound has been detected. Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient detects. PLoS Pathog. 2013;9(5):e1003347. doi:10.​1371/​journal.​ppat.​1003347. A comprehensive and collaborative analysis of the Berlin patient detects HIV; however, to date no viral rebound has been detected.
56.
go back to reference Olesen R, Vigano S, Rasmussen TA, Sogaard OS, Ouyang Z, Buzon M, et al. Innate immune activity correlates with CD4 T cell-associated HIV-1 DNA decline during latency-reversing treatment with panobinostat. J Virol. 2015;89(20):10176–89. doi:10.1128/JVI.01484-15.CrossRefPubMed Olesen R, Vigano S, Rasmussen TA, Sogaard OS, Ouyang Z, Buzon M, et al. Innate immune activity correlates with CD4 T cell-associated HIV-1 DNA decline during latency-reversing treatment with panobinostat. J Virol. 2015;89(20):10176–89. doi:10.​1128/​JVI.​01484-15.CrossRefPubMed
57.
60.
go back to reference Kotler DP, Reka S, Borcich A, Cronin WJ. Detection, localization, and quantitation of HIV-associated antigens in intestinal biopsies from patients with HIV. Am J Pathol. 1991;139(4):823–30.PubMedPubMedCentral Kotler DP, Reka S, Borcich A, Cronin WJ. Detection, localization, and quantitation of HIV-associated antigens in intestinal biopsies from patients with HIV. Am J Pathol. 1991;139(4):823–30.PubMedPubMedCentral
61.
go back to reference Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197(5):714–20. doi:10.1086/527324.CrossRefPubMed Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197(5):714–20. doi:10.​1086/​527324.CrossRefPubMed
63.
go back to reference Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis. 2010;202(10):1553–61. doi:10.1086/656722.CrossRefPubMedPubMedCentral Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis. 2010;202(10):1553–61. doi:10.​1086/​656722.CrossRefPubMedPubMedCentral
65.
go back to reference Strategies for Management of Antiretroviral Therapy Study G, El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96. doi:10.1056/NEJMoa062360.CrossRef Strategies for Management of Antiretroviral Therapy Study G, El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96. doi:10.​1056/​NEJMoa062360.CrossRef
66.
go back to reference Strategies for Management of Antiretroviral Therapy Study G, Lundgren JD, Babiker A, El-Sadr W, Emery S, Grund B, et al. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up. J Infect Dis. 2008;197(8):1145–55. doi:10.1086/529523.CrossRef Strategies for Management of Antiretroviral Therapy Study G, Lundgren JD, Babiker A, El-Sadr W, Emery S, Grund B, et al. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up. J Infect Dis. 2008;197(8):1145–55. doi:10.​1086/​529523.CrossRef
67.•
go back to reference Pinkevych M, Cromer D, Tolstrup M, Grimm AJ, Cooper DA, Lewin SR, et al. HIV reactivation from latency after treatment interruption occurs on average every 5–8 days—implications for HIV remission. PLoS Pathog. 2015;11(7):e1005000. doi:10.1371/journal.ppat.1005000. Modelling study that estimates that a 50–70-fold reduction in the reservoir may be required for a one-year ART remission.CrossRefPubMedPubMedCentral Pinkevych M, Cromer D, Tolstrup M, Grimm AJ, Cooper DA, Lewin SR, et al. HIV reactivation from latency after treatment interruption occurs on average every 5–8 days—implications for HIV remission. PLoS Pathog. 2015;11(7):e1005000. doi:10.​1371/​journal.​ppat.​1005000. Modelling study that estimates that a 50–70-fold reduction in the reservoir may be required for a one-year ART remission.CrossRefPubMedPubMedCentral
69.••
go back to reference 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. A very thorough comparative analysis of measures of viral DNA and RNA compared to the viral outgrowth assay.CrossRefPubMedPubMedCentral 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. A very thorough comparative analysis of measures of viral DNA and RNA compared to the viral outgrowth assay.CrossRefPubMedPubMedCentral
Metadata
Title
How to Define the Latent Reservoir: Tools of the Trade
Authors
Kirston M. Barton
Sarah E. Palmer
Publication date
01-04-2016
Publisher
Springer US
Published in
Current HIV/AIDS Reports / Issue 2/2016
Print ISSN: 1548-3568
Electronic ISSN: 1548-3576
DOI
https://doi.org/10.1007/s11904-016-0304-1

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