How to Define the Latent Reservoir: Tools of the Trade

Current HIV/AIDS Reports

Volumn 13, Issue 2, 2016, Pages 77-84

  Barton, Kirston M ^a   Palmer, Sarah E ^a  

^a WESTMEAD HOSPITAL   (Australia)

Author keywords

HIV biomarkers; HIV pathogenesis; Human immunodeficiency virus; Latent HIV; Persistent HIV; Review; Single copy assay; Viral outgrowth assay

Indexed keywords

ANTIRETROVIRUS AGENT; HLA DR ANTIGEN; HUMAN IMMUNODEFICIENCY VIRUS ANTIBODY; HUMAN IMMUNODEFICIENCY VIRUS ANTIGEN; PROGRAMMED DEATH 1 RECEPTOR; VIRUS DNA; VIRUS RNA; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT;

CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELLULAR IMMUNITY; DRUG COST; ENZYME LINKED IMMUNOSORBENT ASSAY; EPIDEMIC; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN; REAL TIME POLYMERASE CHAIN REACTION; REVIEW; VIREMIA; VIRUS CARRIER; VIRUS DETECTION; VIRUS GENOME; VIRUS LOAD; VIRUS REPLICATION; GENETICS; HIV INFECTIONS; HUMAN IMMUNODEFICIENCY VIRUS 1; VIROLOGY; VIRUS LATENCY;

ANTI-HIV AGENTS; CD4-POSITIVE T-LYMPHOCYTES; HIV INFECTIONS; HIV-1; HUMANS; RNA, VIRAL; VIREMIA; VIRUS LATENCY;

EID: 84957694352     PISSN: 15483568     EISSN: 15483576     Source Type: Journal    
DOI: 10.1007/s11904-016-0304-1     Document Type: Review

References (69)

1. 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.
2. McMahon JH, Elliott JH, Roney J, Hagenauer M, Lewin SR. Experiences and expectations of participants completing an HIV cure focused clinical trial. Aids. 2015;29(2):248–50. doi:10.1097/QAD.0000000000000534.
3. 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. 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. 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. 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. 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. 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. Barton KM, Archin NM, Keedy KS, Espeseth AS, Zhang YL, Gale J, et al. Selective HDAC inhibition for the disruption of latent HIV-1 infection. PLoS One. 2014;9(8), e102684. doi:10.1371/journal.pone.0102684.
10. 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. 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.
12. Soriano-Sarabia N, Bateson RE, Dahl NP, Crooks AM, Kuruc JD, Margolis DM, et al. Quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells. J Virol. 2014;88(24):14070–7. doi:10.1128/JVI.01900-14.
13. 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.
14. Josefsson L, King MS, Makitalo B, Brannstrom J, Shao W, Maldarelli F, et al. Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. Proc Natl Acad Sci U S A. 2011;108(27):11199–204. doi:10.1073/pnas.1107729108.
15. 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.
16. 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.
17. 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. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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. 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.
25. Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A. 2008;105(10):3879–84. doi:10.1073/pnas.0800050105.
26. Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 2007;3(4), e46. doi:10.1371/journal.ppat.0030046.
27. 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.
28. Cillo AR, Vagratian D, Bedison MA, Anderson EM, Kearney MF, Fyne E, et al. Improved single-copy assays for quantification of persistent HIV-1 viremia in patients on suppressive antiretroviral therapy. J Clin Microbiol. 2014;52(11):3944–51. doi:10.1128/JCM.02060-14.
29. Markowitz M, Evering TH, Garmon D, Caskey M, La Mar M, Rodriguez K, et al. A randomized open-label study of 3- versus 5-drug combination antiretroviral therapy in newly HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2014;66(2):140–7. doi:10.1097/QAI.0000000000000111.
30. 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.
31. 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.
32. Lassen KG, Bailey JR, Siliciano RF. Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J Virol. 2004;78(17):9105–14. doi:10.1128/JVI.78.17.9105-9114.2004.
33. 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.
34. 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.
35. 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.
36. Besson GJ, Lalama CM, Bosch RJ, Gandhi RT, Bedison MA, Aga E, et al. HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis. 2014;59(9):1312–21. doi:10.1093/cid/ciu585.
37. 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.
38. Zhu W, Jiao Y, Lei R, Hua W, Wang R, Ji Y, et al. Rapid turnover of 2-LTR HIV-1 DNA during early stage of highly active antiretroviral therapy. PLoS One. 2011;6(6), e21081. doi:10.1371/journal.pone.0021081.
39. Gandhi RT, Coombs RW, Chan ES, Bosch RJ, Zheng L, Margolis DM, et al. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012;59(3):229–35. doi:10.1097/QAI.0b013e31823fd1f2.
40. Cillo AR, Krishnan A, Mitsuyasu RT, McMahon DK, Li S, Rossi JJ, et al. Plasma viremia and cellular HIV-1 DNA persist despite autologous hematopoietic stem cell transplantation for HIV-related lymphoma. J Acquir Immune Defic Syndr. 2013;63(4):438–41. doi:10.1097/QAI.0b013e31828e6163.
41. 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.
42. Strain MC, Lada SM, Luong T, Rought SE, Gianella S, Terry VH, et al. Highly precise measurement of HIV DNA by droplet digital PCR. PLoS One. 2013;8(4), e55943. doi:10.1371/journal.pone.0055943.
43. Rouzioux C, Melard A, Avettand-Fenoel V. Quantification of total HIV1-DNA in peripheral blood mononuclear cells. Methods Mol Biol. 2014;1087:261–70. doi:10.1007/978-1-62703-670-2_21.
44. 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.
45. Pauza CD, Trivedi P, McKechnie TS, Richman DD, Graziano FM. 2-LTR circular viral DNA as a marker for human immunodeficiency virus type 1 infection in vivo. Virology. 1994;205(2):470–8. doi:10.1006/viro.1994.1667.
46. Sharkey M, Triques K, Kuritzkes DR, Stevenson M. In vivo evidence for instability of episomal human immunodeficiency virus type 1 cDNA. J Virol. 2005;79(8):5203–10. doi:10.1128/JVI.79.8.5203-5210.2005.
47. Cohn LB, Silva IT, Oliveira TY, Rosales RA, Parrish EH, Learn GH, et al. HIV-1 integration landscape during latent and active infection. Cell. 2015;160(3):420–32. doi:10.1016/j.cell.2015.01.020.
48. 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.
49. 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.
50. Yu JJ, Wu TL, Liszewski MK, Dai J, Swiggard WJ, Baytop C, et al. A more precise HIV integration assay designed to detect small differences finds lower levels of integrated DNA in HAART treated patients. Virology. 2008;379(1):78–86. doi:10.1016/j.virol.2008.05.030.
51. 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. EBioMed. 2015;2(8):872–81. doi:10.1016/j.ebiom.2015.06.019.
52. Duong YT, Qiu M, De AK, Jackson K, Dobbs T, Kim AA, et al. Detection of recent HIV-1 infection using a new limiting-antigen avidity assay: potential for HIV-1 incidence estimates and avidity maturation studies. PLoS One. 2012;7(3), e33328. doi:10.1371/journal.pone.0033328.
53. 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.
54. 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.
55. Burbelo PD, Bayat A, Rhodes CS, Hoh R, Martin JN, Fromentin R, et al. HIV antibody characterization as a method to quantify reservoir size during curative interventions. J Infect Dis. 2014;209(10):1613–7. doi:10.1093/infdis/jit667.
56. 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.
57. Hatano H, Jain V, Hunt PW, Lee TH, Sinclair E, Do TD, et al. Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. J Infect Dis. 2013;208(1):50–6. doi:10.1093/infdis/jis630.
58. Cockerham LR, Siliciano JD, Sinclair E, O'Doherty U, Palmer S, Yukl SA, et al. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells. PLoS One. 2014;9(10), e110731. doi:10.1371/journal.pone.0110731.
59. This week’s section. Science. 2015;349(6247):456-8. doi:10.1126/science.349.6247.456.
60. 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.
61. 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.
62. Hatano H, Somsouk M, Sinclair E, Harvill K, Gilman L, Cohen M, et al. Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers. Aids. 2013;27(14):2255–60. doi:10.1097/QAD.0b013e328362692f.
63. 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.
64. Dahl V, Gisslen M, Hagberg L, Peterson J, Shao W, Spudich S, et al. An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy. J Infect Dis. 2014;209(10):1618–22. doi:10.1093/infdis/jit805.
65. 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.
66. 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.
67. 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.
68. Hill AL, Rosenbloom DI, Fu F, Nowak MA, Siliciano RF. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. Proc Natl Acad Sci U S A. 2014;111(37):13475–80. doi:10.1073/pnas.1406663111.
69. 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.