Total HIV-1 DNA, a marker of viral reservoir dynamics with clinical implications

Clinical Microbiology Reviews

Volumn 29, Issue 4, 2016, Pages 859-880

  Avettand Fènoë, Véronique ^a,b   Hocqueloux, Laurent ^c   Ghosn, Jade ^a,d   Cheret, Antoine ^a,e   Frange, Pierre ^a,b   Melard, Adeline ^a   Viard, Jean Paul ^a,d   Rouzioux, Christine ^a,b  

^a UNIVERSITÉ PARIS DESCARTES   (France)

^b HÔPITAL NECKER ENFANTS MALADES   (France)

^c CENTRE HOSPITALIER RÉGIONAL D ORLÉANS   (France)

^d HÔTEL DIEU   (France)

^e BICÊTRE HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIRETROVIRUS AGENT; DARUNAVIR; GAMMA INTERFERON; KI 67 ANTIGEN; LOPINAVIR; RITONAVIR; VIRUS DNA; VIRUS RNA; BIOLOGICAL MARKER;

ARTICLE; CD4 CD8 RATIO; CD4 LYMPHOCYTE COUNT; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; INTESTINE LYMPHATIC TISSUE; LATENT PERIOD; LYMPH NODE; META ANALYSIS (TOPIC); PERIPHERAL BLOOD MONONUCLEAR CELL; PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); VIRUS REPLICATION; GENETICS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; ISOLATION AND PURIFICATION; PHYSIOLOGY; PROVIRUS; VIROLOGY; VIRUS LATENCY; VIRUS LOAD;

BIOMARKERS; DNA, VIRAL; HIV INFECTIONS; HIV-1; HUMANS; PROVIRUSES; VIRAL LOAD; VIRUS LATENCY;

EID: 84986593232     PISSN: 08938512     EISSN: 10986618     Source Type: Journal    
DOI: 10.1128/CMR.00015-16     Document Type: Article

References (268)

1. 4+T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 5:512–517. http://dx.doi.org/10.1038/8394
2. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD. 1997. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278:1291–1295. http://dx.doi.org/10.1126/science.278.5341.1291
3. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, Kuo YH, Brookmeyer R, Zeiger MA, Barditch-Crovo P, Siliciano RF. 1997. Quantification of latent tissue reservoirs and total body viral load inHIV-1infection. Nature 387:183–188. http://dx.doi.org/10.1038/387183a0
4. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, Schneider T, Hofmann J, Kucherer C, Blau O, Blau IW, Hofmann WK, Thiel E. 2009. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med 360:692–698. http://dx.doi.org/10.1056/NEJMoa0802905
5. Trono D, Van Lint C, Rouzioux C, Verdin E, Barre-Sinoussi F, Chun TW, Chomont N. 2010. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 329:174–180. http://dx.doi.org/10.1126/science.1191047
6. Lewin SR, Rouzioux C. 2011. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS 25:885–897. http://dx.doi.org/10.1097/QAD.0b013e3283467041
7. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. 2009. The challenge of finding a cure for HIV infection. Science 323:1304–1307. http://dx.doi.org/10.1126/science.1165706
8. Li JZ, Smith DM, Mellors JW. 2015. The need for treatment interruption studies and biomarker identification in the search for an HIV cure. AIDS 29:1429–1432. http://dx.doi.org/10.1097/QAD.0000000000000658
9. Eriksson S, Graf E, Dahl V, Strain MC, Yukl S, Lysenko E, Bosch RJ, Lai J, Chioma S, Emad F, Abdel-Mohsen M, Hoh R, Hecht FM, Hunt P, Somsouk M, Wong J, Johnston R, Siliciano R, Richman D, O’Doherty U, Palmer S, Deeks S, Siliciano J. 2013. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog 9:e1003174. http://dx.doi.org/10.1371/journal.ppat.1003174
10. Massanella M, Richman DD. 2016. Measuring the latent reservoir in vivo. J Clin Invest 126:464–472. http://dx.doi.org/10.1172/JCI80567
11. Kiselinova M, De Spiegelaere W, Buzon MJ, Malatinkova E, Lichterfeld M, Vandekerckhove L. 2016. Integrated and total HIV-1 DNA predict ex vivo viral outgrowth. PLoS Pathog 12:e1005472. http://dx.doi.org/10.1371/journal.ppat.1005472
12. Banga R, Procopio FA, Perreau M. 2016. Current approaches to assess HIV-1 persistence. Curr Opin HIV AIDS 11:424–431. http://dx.doi.org /10.1097/COH.0000000000000282
13. Blankson JN, Persaud D, Siliciano RF. 2002. The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med 53:557–593. http://dx.doi.org/10.1146/annurev.med.53.082901.104024
14. Douek DC. 2003. Disrupting T-cell homeostasis: how HIV-1 infection causes disease. AIDS Rev 5:172–177
15. 4+T-cells carrying replication-competent virus in HIV-1-infected individuals. Methods Mol Biol 304:3–15. http://dx.doi.org/10.1385/1-59259-907-9:003
16. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, Lloyd AL, Nowak MA, Fauci AS. 1997. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 94:13193–13197. http://dx.doi.org/10.1073/pnas.94.24.13193
17. Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, Lai J, Blankson JN, Siliciano JD, Siliciano RF. 2013. Replicationcompetent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155:540–551. http://dx.doi.org/10.1016/j.cell.2013.09.020
18. 4+ T cells from patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 111:7078–7083. http://dx.doi.org/10.1073/pnas.1402873111
19. 4+T cells. Nat Med 9:727–728. http://dx.doi.org/10.1038/nm880
20. Crooks AM, Bateson R, Cope AB, Dahl NP, Griggs MK, Kuruc JD, Gay CL, Eron JJ, Margolis DM, Bosch RJ, Archin NM. 2015. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J Infect Dis 212:1361–1365. http://dx.doi.org/10.1093/infdis/jiv218
21. Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M, Rainwater-Lovett K, Mellors JW, Rosenbloom D, Persaud D. 2015. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med 372:786–788. http://dx.doi.org/10.1056/NEJMc1413931
22. Pasternak AO, Lukashov VV, Berkhout B. 2013. Cell-associated HIV RNA: a dynamic biomarker of viral persistence. Retrovirology 10:41. http://dx.doi.org/10.1186/1742-4690-10-41
23. Bukrinsky MI, Stanwick TL, Dempsey MP, Stevenson M. 1991. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 254:423–427. http://dx.doi.org/10.1126/science.1925601
24. 4+ T cells in acute human immunodeficiency virus type 1 infection. J Infect Dis 182:1636–1642. http://dx.doi.org/10.1086/317615
25. Persaud D, Pierson T, Ruff C, Finzi D, Chadwick KR, Margolick JB, Ruff A, Hutton N, Ray S, Siliciano RF. 2000. A stable latent reservoir for HIV-1 in resting CD4(+) T lymphocytes in infected children. J Clin Invest 105:995–1003. http://dx.doi.org/10.1172/JCI9006
26. Pierson TC, Zhou Y, Kieffer TL, Ruff CT, Buck C, Siliciano RF. 2002. Molecular characterization of preintegration latency in human immunodeficiency virus type 1 infection. J Virol 76:8518–8531. http://dx.doi.org/10.1128/JVI.76.17.8518-8513.2002
27. 4+ T cells. J Virol 79:2199–2210. http://dx.doi.org/10.1128/JVI.79.4.2199-2210.2005
28. Kilzer JM, Stracker T, Beitzel B, Meek K, Weitzman M, Bushman FD. 2003. Roles of host cell factors in circularization of retroviral DNA. Virology 314:460–467. http://dx.doi.org/10.1016/S0042-6822(03)00455-0
29. Yamamoto N, Tanaka C, Wu Y, Chang MO, Inagaki Y, Saito Y, Naito T, Ogasawara H, Sekigawa I, Hayashida Y. 2006. Analysis of human immunodeficiency virus type 1 integration by using a specific, sensitive and quantitative assay based on real-time polymerase chain reaction. Virus Genes 32:105–113. http://dx.doi.org/10.1007/s11262-005-5851-2
30. Chavez HH, Tran TA, Dembele B, Nasreddine N, Lambotte O, Gubler B, le Nevot E, Delfraissy JF, Taoufik Y. 2007. Lack of evidence for prolonged double-long terminal repeat episomal HIV DNA stability in vivo. J Acquir Immune Defic Syndr 45:247–249. http://dx.doi.org/10.1097/QAI.0b013e3180415dc2
31. Sharkey ME, Teo I, Greenough T, Sharova N, Luzuriaga K, Sullivan JL, Bucy RP, Kostrikis LG, Haase A, Veryard C, Davaro RE, Cheeseman SH, Daly JS, Bova C, Ellison RT, III, Mady B, Lai KK, Moyle G, Nelson M, Gazzard B, Shaunak S, Stevenson M. 2000. Persistence of episomal HIV-1 infection intermediates in patients on highly active antiretroviral therapy. Nat Med 6:76–81. http://dx.doi.org/10.1038/71569
32. Butler SL, Johnson EP, Bushman FD. 2002. Human immunodeficiency virus cDNA metabolism: notable stability of two-long terminal repeat circles. J Virol 76:3739–3747. http://dx.doi.org/10.1128/JVI.76.8.3739-3747.2002
33. Butler SL, Hansen MS, Bushman FD. 2001. A quantitative assay for HIV DNA integration in vivo. Nat Med 7:631–634. http://dx.doi.org/10.1038/87979
34. Pierson TC, Kieffer TL, Ruff CT, Buck C, Gange SJ, Siliciano RF. 2002. Intrinsic stability of episomal circles formed during human immunodeficiency virus type 1 replication. J Virol 76:4138–4144. http://dx.doi.org/10.1128/JVI.76.8.4138-4144.2002
35. Brussel A, Mathez D, Broche-Pierre S, Lancar R, Calvez T, Sonigo P, Leibowitch J. 2003. Longitudinal monitoring of 2-long terminal repeat circles in peripheral blood mononuclear cells from patients with chronic HIV-1 infection. AIDS 17:645–652. http://dx.doi.org/10.1097/00002030-200303280-00001
36. Buzon MJ, Seiss K, Weiss R, Brass AL, Rosenberg ES, Pereyra F, Yu XG, Lichterfeld M. 2011. Inhibition of HIV-1 integration in ex vivo infected CD4 T cells from elite controllers. J Virol 85:9646–9650. http://dx.doi.org/10.1128/JVI.05327-11
37. Graf EH, Mexas AM, Yu JJ, Shaheen F, Liszewski MK, Di Mascio M, Migueles SA, Connors M, O’Doherty U. 2011. Elite suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV_ patients on and off HAART. PLoS Pathog 7:e1001300. http://dx.doi.org/10.1371/journal.ppat.1001300
38. Munir S, Thierry S, Subra F, Deprez E, Delelis O. 2013. Quantitative analysis of the time-course of viral DNA forms during the HIV-1 life cycle. Retrovirology 10:87. http://dx.doi.org/10.1186/1742-4690-10-87
39. 4+ T cells. Virology 441:18–21. http://dx.doi.org/10.1016/j.virol.2013.02.028
40. Bushman F. 2003. Measuring covert HIV replication during HAART: the abundance of 2-LTR circles is not a reliable marker. AIDS 17:749–750. http://dx.doi.org/10.1097/00002030-200303280-00014
41. Sharkey M, Triques K, Kuritzkes DR, Stevenson M. 2005. In vivo evidence for instability of episomal human immunodeficiency virus type 1 cDNA. J Virol 79:5203–5210. http://dx.doi.org/10.1128/JVI.79.8.5203-5210.2005
42. Buzon MJ, Massanella M, Llibre JM, Esteve A, Dahl V, Puertas MC, Gatell JM, Domingo P, Paredes R, Sharkey M, Palmer S, Stevenson M, Clotet B, Blanco J, Martinez-Picado J. 2010. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAARTsuppressed subjects. Nat Med 16:460–465. http://dx.doi.org/10.1038/nm.2111
43. Petitjean G, Al Tabaa Y, Tuaillon E, Mettling C, Baillat V, Reynes J, Segondy M, Vendrell JP. 2007. Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients. Retrovirology 4:60. http://dx.doi.org/10.1186/1742-4690-4-60
44. Cara A, Cereseto A, Lori F, Reitz MS, Jr. 1996. HIV-1 protein expression from synthetic circles of DNA mimicking the extrachromosomal forms of viral DNA. J Biol Chem 271:5393–5397. http://dx.doi.org/10.1074/jbc.271.10.5393
45. Nakajima N, Lu R, Engelman A. 2001. Human immunodeficiency virus type 1 replication in the absence of integrase-mediated DNA recombination: definition of permissive and nonpermissive T-cell lines. J Virol 75:7944–7955. http://dx.doi.org/10.1128/JVI.75.17.7944-7955.2001
46. 4+T lymphocytes: implications for integrase inhibitors. J Gen Virol 86:765–771. http://dx.doi.org/10.1099/vir.0.80570-0
47. Poon B, Chang MA, Chen IS. 2007. Vpr is required for efficient Nef expression from unintegrated human immunodeficiency virus type 1 DNA. J Virol 81:10515–10523. http://dx.doi.org/10.1128/JVI.00947-07
48. Kelly J, Beddall MH, Yu D, Iyer SR, Marsh JW, Wu Y. 2008. Human macrophages support persistent transcription from unintegrated HIV-1 DNA. Virology 372:300–312. http://dx.doi.org/10.1016/j.virol.2007.11.007
49. Gelderblom HC, Vatakis DN, Burke SA, Lawrie SD, Bristol GC, Levy DN. 2008. Viral complementation allows HIV-1 replication without integration. Retrovirology 5:60. http://dx.doi.org/10.1186/1742-4690-5-60
50. Kantor B, Ma H, Webster-Cyriaque J, Monahan PE, Kafri T. 2009. Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection. Proc Natl Acad Sci U S A 106:18786–18791. http://dx.doi.org/10.1073/pnas.0905859106
51. Sloan RD, Wainberg MA. 2011. The role of unintegrated DNA in HIV infection. Retrovirology 8:52. http://dx.doi.org/10.1186/1742-4690-8-52
52. Thierry S, Munir S, Thierry E, Subra F, Leh H, Zamborlini A, Saenz D, Levy DN, Lesbats P, Saib A, Parissi V, Poeschla E, Deprez E, Delelis O. 2015. Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration. Retrovirology 12:24. http://dx.doi.org/10.1186/s12977-015-0153-9
53. Chan CN, Trinite B, Lee CS, Mahajan S, Anand A, Wodarz D, Sabbaj S, Bansal A, Goepfert PA, Levy DN. 2016. HIV-1 latency and virus production from unintegrated genomes following direct infection of resting CD4 T cells. Retrovirology 13:1. http://dx.doi.org/10.1186/s12977-015-0234-9
54. Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. 1995. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1:1284–1290. http://dx.doi.org/10.1038/nm1295-1284
55. 4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. Proc Natl Acad Sci U S A 108:11199–11204. http://dx.doi.org/10.1073/pnas.1107729108
56. Sanchez G, Xu X, Chermann JC, Hirsch I. 1997. Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J Virol 71:2233–2240
57. Buzon MJ, Martin-Gayo E, Pereyra F, Ouyang Z, Sun H, Li JZ, Piovoso M, Shaw A, Dalmau J, Zangger N, Martinez-Picado J, Zurakowski R, Yu XG, Telenti A, Walker BD, Rosenberg ES, Lichterfeld M. 2014. Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells. J Virol 88:10056–10065. http://dx.doi.org/10.1128/JVI.01046-14
58. Noel N, Pena R, David A, Avettand-Fenoel V, Erkizia I, Jimenez E, Lecuroux C, Rouzioux C, Boufassa F, Pancino G, Venet A, Van Lint C, Martinez-Picado J, Lambotte O, Saez-Cirion A, Prado JG. 2016. Long-term spontaneous control of HIV-1 relates to low frequency of infected cells and inefficient viral reactivation. J Virol 90:6148–6158. http://dx.doi.org/10.1128/JVI.00419-16
59. Avettand-Fenoel V, Chaix ML, Blanche S, Burgard M, Floch C, Toure K, Allemon MC, Warszawski J, Rouzioux C. 2009. LTR real-time PCR for HIV-1 DNA quantitation in blood cells for early diagnosis in infants born to seropositive mothers treated in HAART area (ANRS CO 01). J Med Virol 81:217–223. http://dx.doi.org/10.1002/jmv.21390
60. Izopet J, Tamalet C, Pasquier C, Sandres K, Marchou B, Massip P, Puel J. 1998. Quantification of HIV-1 proviral DNA by a standardized colorimetric PCR-based assay. J Med Virol 54:54–59. http://dx.doi.org/10.1002/(SICI)1096-9071(199801)54:1_54::AID-JMV8_3.0.CO;2-O
61. Christopherson C, Kidane Y, Conway B, Krowka J, Sheppard H, Kwok S. 2000. PCR-based assay to quantify human immunodeficiency virus type 1 DNA in peripheral blood mononuclear cells. J Clin Microbiol 38:630–634
62. Desire N, Dehee A, Schneider V, Jacomet C, Goujon C, Girard PM, Rozenbaum W, Nicolas JC. 2001. Quantification of human immunodeficiency virus type 1 proviral load by a TaqMan real-time PCR assay. J Clin Microbiol 39:1303–1310. http://dx.doi.org/10.1128/JCM.39.4.1303-1310.2001
63. 4+ cells. APMIS 111:625–633. http://dx.doi.org/10.1034/j.1600-0463.2003.1110605.x
64. Lillo FB, Grasso MA, Lodini S, Bellotti MG, Colucci G. 2004. Few modifications of the Cobas Amplicor HIV Monitor 1.5 test allow reliable quantitation of HIV-1 proviral load in peripheral blood mononuclear cells. J Virol Methods 120:201–205. http://dx.doi.org/10.1016/j.jviromet.2004.05.008
65. Casabianca A, Gori C, Orlandi C, Forbici F, Federico Perno C, Magnani M. 2007. Fast and sensitive quantitative detection of HIV DNA in whole blood leucocytes by SYBR green I real-time PCR assay. Mol Cell Probes 21:368–376. http://dx.doi.org/10.1016/j.mcp.2007.05.005
66. Casabianca A, Orlandi C, Canovari B, Scotti M, Acetoso M, Valentini M, Petrelli E, Magnani M. 2014. A real time PCR platform for the simultaneous quantification of total and extrachromosomal HIV DNA forms in blood of HIV-1 infected patients. PLoS One 9:e111919. http://dx.doi.org/10.1371/journal.pone.0111919
67. Beloukas A, Paraskevis D, Haida C, Sypsa V, Hatzakis A. 2009. Development and assessment of a multiplex real-time PCR assay for the quantification of HIV-1 DNA. J Clin Microbiol 47:2194–2199. http://dx.doi.org/10.1128/JCM.01264-08
68. Hong F, Aga E, Cillo AR, Yates AL, Besson G, Fyne E, Koontz DL, Jennings C, Zheng L, Mellors JW. 2016. Novel assays for measurement of total cell-associated HIV-1 DNA and RNA. J Clin Microbiol 54:902–911. http://dx.doi.org/10.1128/JCM.02904-15
69. De Rossi A, Zanchetta M, Vitone F, Antonelli G, Bagnarelli P, Buonaguro L, Capobianchi MR, Clementi M, Abbate I, Canducci F, Monachetti A, Riva E, Rozera G, Scagnolari C, Tagliamonte M, Re MC. 2010. Quantitative HIV-1 proviral DNA detection: a multicentre analysis. New Microbiol 33:293–302
70. Vandergeeten C, Fromentin R, Merlini E, Bramah-Lawani M, DaFonseca S, Bakeman W, McNulty A, Ramgopal M, Michael N, Kim JH, Ananworanich J, Chomont N. 2014. Cross-clade ultrasensitive PCRbased assays to measure HIV persistence in large cohort studies. J Virol 88:12385–12396. http://dx.doi.org/10.1128/JVI.00609-14
71. Henrich TJ, Gallien S, Li JZ, Pereyra F, Kuritzkes DR. 2012. Low-level detection and quantitation of cellular HIV-1 DNA and 2-LTR circles using droplet digital PCR. J Virol Methods 186:68–72. http://dx.doi.org/10.1016/j.jviromet.2012.08.019
72. Strain MC, Lada SM, Luong T, Rought SE, Gianella S, Terry VH, Spina CA, Woelk CH, Richman DD. 2013. Highly precise measurement of HIV DNA by droplet digital PCR. PLoS One 8:e55943. http://dx.doi.org/10.1371/journal.pone.0055943
73. Persaud D, Patel K, Karalius B, Rainwater-Lovett K, Ziemniak C, Ellis A, Chen YH, Richman D, Siberry GK, Van Dyke RB, Burchett S, Seage GR, III, Luzuriaga K. 2014. Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA Pediatr 168:1138–1146. http://dx.doi.org/10.1001/jamapediatrics.2014.1560
74. Jones M, Williams J, Gartner K, Phillips R, Hurst J, Frater J. 2014. Low copy target detection by Droplet Digital PCR through application of a novel open access bioinformatic pipeline, definetherain. J Virol Methods 202:46–53. http://dx.doi.org/10.1016/j.jviromet.2014.02.020
75. Luzuriaga K, Tabak B, Garber M, Chen YH, Ziemniak C, McManus MM, Murray D, Strain MC, Richman DD, Chun TW, Cunningham CK, Persaud D. 2014. HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment. J Infect Dis 210:1529–1538. http://dx.doi.org/10.1093/infdis/jiu297
76. Bosman KJ, Nijhuis M, van Ham PM, Wensing AM, Vervisch K, Vandekerckhove L, De Spiegelaere W. 2015. Comparison of digital PCR platforms and semi-nested qPCR as a tool to determine the size of the HIV reservoir. Sci Rep 5:13811. http://dx.doi.org/10.1038/srep13811
77. Martinez-Bonet M, Puertas MC, Fortuny C, Ouchi D, Mellado MJ, Rojo P, Noguera-Julian A, Munoz-Fernandez MA, Martinez-Picado J. 2015. Establishment and replenishment of the viral reservoir in perinatally HIV-1-infected children initiating very early antiretroviral therapy. Clin Infect Dis 61:1169–1178. http://dx.doi.org/10.1093/cid/civ456
78. Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, Dewar R, Marovich M, van Griensven F, Sekaly R, Pinyakorn S, Phanuphak N, Trichavaroj R, Rutvisuttinunt W, Chomchey N, Paris R, Peel S, Valcour V, Maldarelli F, Chomont N, Michael N, Phanuphak P, Kim JH, RV254/SEARCH 010 Study Group. 2012. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One 7:e33948. http://dx.doi.org/10.1371/journal.pone.0033948
79. Ananworanich J, Sacdalan CP, Pinyakorn S, Chomont N, de Souza M, Luekasemsuk T, Schuetz A, Krebs SJ, Dewar R, Jagodzinski L, Ubolyam S, Trichavaroj R, Tovanabutra S, Spudich S, Valcour V, Sereti I, Michael N, Robb M, Phanuphak P, Kim JH, Phanuphak N. 2016. Virological and immunological characteristics of HIV-infected individuals at the earliest stage of infection. J Virus Erad 2:43–48
80. Ghosn J, Deveau C, Chaix ML, Goujard C, Galimand J, Zitoun Y, Allegre T, Delfraissy JF, Meyer L, Rouzioux C. 2010. Despite being highly diverse, immunovirological status strongly correlates with clinical symptoms during primary HIV-1 infection: a cross-sectional study based on 674 patients enrolled in the ANRS CO 06 PRIMO cohort. J Antimicrob Chemother 65:741–748. http://dx.doi.org/10.1093/jac/dkq035
81. Goujard C, Bonarek M, Meyer L, Bonnet F, Chaix ML, Deveau C, Sinet M, Galimand J, Delfraissy JF, Venet A, Rouzioux C, Morlat P. 2006. CD4 cell count and HIV DNA level are independent predictors of disease progression after primary HIV type 1 infection in untreated patients. Clin Infect Dis 42:709–715. http://dx.doi.org/10.1086/500213
82. Ngo-Giang-Huong N, Deveau C, Da Silva I, Pellegrin I, Venet A, Harzic M, Sinet M, Delfraissy JF, Meyer L, Goujard C, Rouzioux C. 2001. Proviral HIV-1 DNA in subjects followed since primary HIV-1 infection who suppress plasma viral load after one year of highly active antiretroviral therapy. AIDS 15:665–673. http://dx.doi.org/10.1097/00002030-200104130-00001
83. Minga AK, Anglaret X, d’ Aquin Toni T, Chaix ML, Dohoun L, Abo Y, Coulibaly A, Duvignac J, Gabillard D, Rouet F, Rouzioux C. 2008. HIV-1DNAin peripheral blood mononuclear cells is strongly associated with HIV-1 disease progression in recently infected West African adults. J Acquir Immune Defic Syndr 48:350–354. http://dx.doi.org/10.1097/QAI.0b013e3181775e55
84. 4+ T cell counts. J Infect Dis 192:46–55. http://dx.doi.org/10.1086/430610
85. Kostrikis LG, Touloumi G, Karanicolas R, Pantazis N, Anastassopoulou C, Karafoulidou A, Goedert JJ, Hatzakis A. 2002. Quantitation of human immunodeficiency virus type 1DNAforms with the second template switch in peripheral blood cells predicts disease progression independently of plasma RNA load. J Virol 76:10099–10108. http://dx.doi.org/10.1128/JVI.76.20.10099-10108.2002
86. Persaud D, Zhou Y, Siliciano JM, Siliciano RF. 2003. Latency in human immunodeficiency virus type 1 infection: no easy answers. J Virol 77: 1659–1665. http://dx.doi.org/10.1128/JVI.77.3.1659-1665.2003
87. Cone RW, Gowland P, Opravil M, Grob P, Ledergerber B. 1998. Levels of HIV-infected peripheral blood cells remain stable throughout the natural history of HIV-1 infection. Swiss HIV Cohort Study. AIDS 12:2253–2260
88. Martinez V, Costagliola D, Bonduelle O, Ngo N, Schnuriger A, Theodorou I, Clauvel JP, Sicard D, Agut H, Debre P, Rouzioux C, Autran B. 2005. Combination of HIV-1-specific CD4 Th1 cell responses and IgG2 antibodies is the best predictor for persistence of long-term nonprogression. J Infect Dis 191:2053–2063. http://dx.doi.org/10.1086/430320
89. Lambotte O, Boufassa F, Madec Y, Nguyen A, Goujard C, Meyer L, Rouzioux C, Venet A, Delfraissy JF. 2005. HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 41:1053–1056. http://dx.doi.org/10.1086/433188
90. Sajadi MM, Heredia A, Le N, Constantine NT, Redfield RR. 2007. HIV-1 natural viral suppressors: control of viral replication in the absence of therapy. AIDS 21:517–519. http://dx.doi.org/10.1097/QAD.0b013e328013d9eb
91. Hocqueloux L, Prazuck T, Avettand-Fenoel V, Lafeuillade A, Cardon B, Viard JP, Rouzioux C. 2010. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 24:1598–1601. http://dx.doi.org/10.1097/QAD.0b013e32833b61ba
92. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard J, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C, ANRS VISCONTI Study Group. 2013. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy. PLoS Pathog 9:e1003211. http://dx.doi.org/10.1371/journal.ppat.1003211
93. Avettand-Fenoel V, Blanche S, Le Chenadec J, Scott-Algara D, Dollfus C, Viard JP, Bouallag N, Benmebarek Y, Riviere Y, Warszawski J, Rouzioux C, Buseyne F. 2012. Relationships between HIV disease history and blood HIV-1 DNA load in perinatally infected adolescents and young adults: the ANRS-EP38-IMMIP study. J Infect Dis 205:1520–1528. http://dx.doi.org/10.1093/infdis/jis233
94. Boulle C, Rouet F, Fassinou P, Msellati P, Debeaudrap P, Chaix ML, Rouzioux C, Avettand-Fenoel V. 2014. HIV-1 DNA concentrations and evolution among African HIV-1-infected children under antiretroviral treatment (ANRS 1244/1278). J Antimicrob Chemother 69:3047–3050. http://dx.doi.org/10.1093/jac/dku274
95. Izopet J, Salama G, Pasquier C, Sandres K, Marchou B, Massip P, Puel J. 1998. Decay of HIV-1 DNA in patients receiving suppressive antiretroviral therapy. J Acquir Immune Defic Syndr Hum Retrovirol 19:478–483. http://dx.doi.org/10.1097/00042560-199812150-00006
96. Garrigue I, Pellegrin I, Hoen B, Dumon B, Harzic M, Schrive MH, Sereni D, Fleury H. 2000. Cell-associated HIV-1-DNA quantitation after highly active antiretroviral therapy-treated primary infection in patients with persistently undetectable plasma HIV-1 RNA. AIDS 14:2851–2855. http://dx.doi.org/10.1097/00002030-200012220-00006
97. Yerly S, Perneger TV, Vora S, Hirschel B, Perrin L. 2000. Decay of cell-associated HIV-1 DNA correlates with residual replication in patients treated during acute HIV-1 infection. AIDS 14:2805–2812. http://dx.doi.org/10.1097/00002030-200012220-00001
98. Karlsson AC, Birk M, Lindback S, Gaines H, Mittler JE, Sonnerborg A. 2001. Initiation of therapy during primary HIV type 1 infection results in a continuous decay of proviral DNA and a highly restricted viral evolution. AIDS Res Hum Retroviruses 17:409–416. http://dx.doi.org/10.1089/088922201750102463
99. De Rossi A, Walker AS, De Forni D, Gibb DM. 2002. Biphasic decay of cell-associated HIV-1 DNA in HIV-1-infected children on antiretroviral therapy. AIDS 16:1961–1963. http://dx.doi.org/10.1097/00002030-200209270-00015
100. Viard JP, Burgard M, Hubert JB, Aaron L, Rabian C, Pertuiset N, Lourenco M, Rothschild C, Rouzioux C. 2004. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 18:45–49. http://dx.doi.org/10.1097/00002030-200401020-00005
101. Strain MC, Little SJ, Daar ES, Havlir DV, Gunthard HF, Lam RY, Daly OA, Nguyen J, Ignacio CC, Spina CA, Richman DD, Wong JK. 2005. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis 191:1410–1418. http://dx.doi.org/10.1086/428777
102. Morand-Joubert L, Marcellin F, Launay O, Guiramand-Hugon S, Gerard L, Yeni P, Aboulker JP. 2005. Contribution of cellular HIV-1 DNA quantification to the efficacy analysis of antiretroviral therapy: a randomized comparison of 2 regimens, including 3 drugs from 2 or 3 classes (TRIANON, ANRS 081). J Acquir Immune Defic Syndr 38: 268–276
103. Hoen B, Cooper DA, Lampe FC, Perrin L, Clumeck N, Phillips AN, Goh LE, Lindback S, Sereni D, Gazzard B, Montaner J, Stellbrink HJ, Lazzarin A, Ponscarme D, Staszewski S, Mathiesen L, Smith D, Finlayson R, Weber R, Wegmann L, Janossy G, Kinloch-de Loes S. 2007. Predictors of virological outcome and safety in primary HIV type 1-infected patients initiating quadruple antiretroviral therapy: QUEST GW PROB3005. Clin Infect Dis 45:381–390. http://dx.doi.org/10.1086/519428
104. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy JP, Haddad EK, Sekaly RP. 2009. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15:893–900. http://dx.doi.org/10.1038/nm.1972
105. Jain V, Hartogensis W, Bacchetti P, Hunt PW, Hatano H, Sinclair E, Epling L, Lee TH, Busch MP, McCune JM, Pilcher CD, Hecht FM, Deeks SG. 2013. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. J Infect Dis 208:1202–1211. http://dx.doi.org/10.1093/infdis/jit311
106. Williams JP, Hurst J, Stohr W, Robinson N, Brown H, Fisher M, Kinloch S, Cooper D, Schechter M, Tambussi G, Fidler S, Carrington M, Babiker A, Weber J, Koelsch KK, Kelleher AD, Phillips RE, Frater J. 2014. HIV-1 DNA predicts disease progression and post-treatment virological control. eLife 3:e03821. http://dx.doi.org/10.7554/eLife.03821
107. Parisi SG, Andreis S, Mengoli C, Scaggiante R, Ferretto R, Manfrin V, Cruciani M, Giobbia M, Boldrin C, Basso M, Andreoni M, Palu G, Sarmati L. 2012. Baseline cellular HIV DNA load predicts HIV DNA decline and residual HIV plasma levels during effective antiretroviral therapy. J Clin Microbiol 50:258–263. http://dx.doi.org/10.1128/JCM.06022-11
108. Besson GJ, Lalama CM, Bosch RJ, Gandhi RT, Bedison MA, Aga E, Riddler SA, McMahon DK, Hong F, Mellors JW. 2014. HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis 59:1312–1321. http://dx.doi.org/10.1093/cid/ciu585
109. Cheret A, Nembot G, Melard A, Lascoux C, Slama L, Miailhes P, Yeni P, Abel S, Avettand-Fenoel V, Venet A, Chaix ML, Molina JM, Katlama C, Goujard C, Tamalet C, Raffi F, Lafeuillade A, Reynes J, Ravaux I, Hoen B, Delfraissy JF, Meyer L, Rouzioux C. 2015. Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a ran-domised, open-label, phase 3 trial. Lancet Infect Dis 15:387–396. http://dx.doi.org/10.1016/S1473-3099(15)70021-6
110. Saitoh A, Hsia K, Fenton T, Powell CA, Christopherson C, Fletcher CV, Starr SE, Spector SA. 2002. Persistence of human immunodeficiency virus (HIV) type 1 DNA in peripheral blood despite prolonged suppression of plasma HIV-1 RNA in children. J Infect Dis 185:1409–1416. http://dx.doi.org/10.1086/340614
111. Uprety P, Chadwick EG, Rainwater-Lovett K, Ziemniak C, Luzuriaga K, Capparelli EV, Yenokyan G, Persaud D. 2015. Cell-associated HIV-1 DNA and RNA decay dynamics during early combination antiretroviral therapy in HIV-1-infected infants. Clin Infect Dis 61:1862–1870. http://dx.doi.org/10.1093/cid/civ688
112. Vitone F, Gibellini D, Schiavone P, Re MC. 2005. Quantitative DNA proviral detection in HIV-1 patients treated with antiretroviral therapy. J Clin Virol 33:194–200. http://dx.doi.org/10.1016/j.jcv.2004.11.003
113. Kiselinova M, Geretti AM, Malatinkova E, Vervisch K, Beloukas A, Messiaen P, Bonczkowski P, Trypsteen W, Callens S, Verhofstede C, De Spiegelaere W, Vandekerckhove L. 2015. HIV-1 RNA and HIV-1 DNA persistence during suppressive ART with PI-based or nevirapinebased regimens. J Antimicrob Chemother 70:3311–3316. http://dx.doi.org/10.1093/jac/dkv250
114. Koelsch KK, Liu L, Haubrich R, May S, Havlir D, Gunthard HF, Ignacio CC, Campos-Soto P, Little SJ, Shafer R, Robbins GK, D’Aquila RT, Kawano Y, Young K, Dao P, Spina CA, Richman DD, Wong JK. 2008. Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis 197:411–419. http://dx.doi.org/10.1086/525283
115. 4+ T cells during antiretroviral therapy. J Virol 88:3516–3526. http://dx.doi.org/10.1128/JVI.03331-13
116. Furtado MR, Callaway DS, Phair JP, Kunstman KJ, Stanton JL, Macken CA, Perelson AS, Wolinsky SM. 1999. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. NEngl J Med 340:1614–1622. http://dx.doi.org/10.1056/NEJM199905273402102
117. Ibanez A, Puig T, Elias J, Clotet B, Ruiz L, Martinez MA. 1999. Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients. AIDS 13:1045–1049. http://dx.doi.org/10.1097/00002030-199906180-00007
118. Koelsch KK, Boesecke C, McBride K, Gelgor L, Fahey P, Natarajan V, Baker D, Bloch M, Murray JM, Zaunders J, Emery S, Cooper DA, Kelleher AD. 2011. Impact of treatment with raltegravir during primary or chronic HIV infection on RNA decay characteristics and the HIV viral reservoir. AIDS 25:2069–2078. http://dx.doi.org/10.1097/QAD.0b013e32834b9658
119. Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. 1998. Early establishment of a pool of latently infected, resting CD4(_) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A 95:8869–8873. http://dx.doi.org/10.1073/pnas.95.15.8869
120. Calcaterra S, Cappiello G, Di Caro A, Garbuglia AR, Benedetto A. 2001. Comparative analysis of total and integrated HIV-1 DNA in peripheral CD4 lymphocytes and monocytes after long treatment with HAART. J Infect 43:239–245. http://dx.doi.org/10.1053/jinf.2001.0875
121. Yu JJ, Wu TL, Liszewski MK, Dai J, Swiggard WJ, Baytop C, Frank I, Levine BL, Yang W, Theodosopoulos T, O’Doherty U. 2008. A more precise HIV integration assay designed to detect small differences finds lower levels of integrated DNA in HAART treated patients. Virology 379:78–86. http://dx.doi.org/10.1016/j.virol.2008.05.030
122. Pires A, Hardy G, Gazzard B, Gotch F, Imami N. 2004. Initiation of antiretroviral therapy during recent HIV-1 infection results in lower residual viral reservoirs. J Acquir Immune Defic Syndr 36:783–790. http://dx.doi.org/10.1097/00126334-200407010-00004
123. Hocqueloux L, Avettand-Fenoel V, Jacquot S, Prazuck T, Legac E, Melard A, Niang M, Mille C, Le Moal G, Viard JP, Rouzioux C. 2013. Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts. J Antimicrob Chemother 68:1169–1178. http://dx.doi.org/10.1093/jac/dks533
124. Laanani M, Ghosn J, Essat A, Melard A, Seng R, Gousset M, Panjo H, Mortier E, Girard PM, Goujard C, Meyer L, Rouzioux C. 2015. Impact of the timing of initiation of antiretroviral therapy during primary HIV-1 infection on the decay of cell-associated HIV-DNA. Clin Infect Dis 60: 1715–1721. http://dx.doi.org/10.1093/cid/civ171
125. Burgard M, Blanche S, Jasseron C, Descamps P, Allemon MC, Ciraru-Vigneron N, Floch C, Heller-Roussin B, Lachassinne E, Mazy F, Warszawski J, Rouzioux C. 2012. Performance of HIV-1 DNA or HIV-1 RNA tests for early diagnosis of perinatal HIV-1 infection during antiretroviral prophylaxis. J Pediatr 160:60–6.e61. http://dx.doi.org/10.1016/j.jpeds.2011.06.053
126. Laure F, Courgnaud V, Rouzioux C, Blanche S, Veber F, Burgard M, Jacomet C, Griscelli C, Brechot C. 1988. Detection of HIV1 DNA in infants and children by means of the polymerase chain reaction. Lancet ii:538–541
127. Mitchell C, Dross S, Beck IA, Micek MA, Frenkel LM. 2014. Low concentrations of HIV-1 DNA at birth delays diagnosis, complicating identification of infants for antiretroviral therapy to potentially prevent the establishment of viral reservoirs. Clin Infect Dis 58:1190–1193. http://dx.doi.org/10.1093/cid/ciu068
128. Cortes FH, Passaes CP, Bello G, Teixeira SL, Vorsatz C, Babic D, Sharkey M, Grinsztejn B, Veloso V, Stevenson M, Morgado MG. 2015. HIV controllers with different viral load cutoff levels have distinct virologic and immunologic profiles. J Acquir Immune Defic Syndr 68:377–385. http://dx.doi.org/10.1097/QAI.0000000000000500
129. Xu H, Wang X, Malam N, Aye PP, Alvarez X, Lackner AA, Veazey RS. 2015. Persistent simian immunodeficiency virus infection drives differentiation, aberrant accumulation, and latent infection of germinal center follicular T helper cells. J Virol 90:1578–1587. http://dx.doi.org/10.1128/JVI.02471-15
130. Fukazawa Y, Lum R, Okoye AA, Park H, Matsuda K, Bae JY, Hagen SI, Shoemaker R, Deleage C, Lucero C, Morcock D, Swanson T, Legasse AW, Axthelm MK, Hesselgesser J, Geleziunas R, Hirsch VM, Edlefsen PT, Piatak M, Jr, Estes JD, Lifson JD, Picker LJ. 2015. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med 21:132–139. http://dx.doi.org/10.1038/nm.3781
131. Fletcher CV, Staskus K, Wietgrefe SW, Rothenberger M, Reilly C, Chipman JG, Beilman GJ, Khoruts A, Thorkelson A, Schmidt TE, Anderson J, Perkey K, Stevenson M, Perelson AS, Douek DC, Haase AT, Schacker TW. 2014. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A 111: 2307–2312. http://dx.doi.org/10.1073/pnas.1318249111
132. Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J, Kosakovsky Pond SL, Chung YS, Penugonda S, Chipman JG, Fletcher CV, Schacker TW, Malim MH, Rambaut A, Haase AT, McLean AR, Wolinsky SM. 2016. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530:51–56. http://dx.doi.org/10.1038/nature16933
133. Rothenberger MK, Keele BF, Wietgrefe SW, Fletcher CV, Beilman GJ, Chipman JG, Khoruts A, Estes JD, Anderson J, Callisto SP, Schmidt TE, Thorkelson A, Reilly C, Perkey K, Reimann TG, Utay NS, Nganou Makamdop K, Stevenson M, Douek DC, Haase AT, Schacker TW. 2015. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc Natl Acad Sci U S A 112:E1126–E1134. http://dx.doi.org/10.1073/pnas.1414926112
134. Pallikkuth S, Sharkey M, Babic DZ, Gupta S, Stone GW, Fischl MA, Stevenson M, Pahwa S. 2015. Peripheral T follicular helper cells are the major HIV reservoir within central memory CD4 T cells in peripheral blood from chronically HIV-infected individuals on combination antiretroviral therapy. J Virol 90:2718–2728. http://dx.doi.org/10.1128/JVI.02883-15
135. Clayton F, Snow G, Reka S, Kotler DP. 1997. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin Exp Immunol 107:288–292. http://dx.doi.org/10.1111/j.1365-2249.1997.236-ce1111.x
136. 4+ T cell depletion and viral replication in SIV infection. Science 280:427–431. http://dx.doi.org/10.1126/science.280.5362.427
137. Veazey RS, Marx PA, Lackner AA. 2001. The mucosal immune system: primary target for HIV infection and AIDS. Trends Immunol 22:626–633. http://dx.doi.org/10.1016/S1471-4906(01)02039-7
138. Poles MA, Elliott J, Taing P, Anton PA, Chen IS. 2001. A preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. J Virol 75:8390–8399. http://dx.doi.org/10.1128/JVI.75.18.8390-8399.2001
139. Anton PA, Mitsuyasu RT, Deeks SG, Scadden DT, Wagner B, Huang C, Macken C, Richman DD, Christopherson C, Borellini F, Lazar R, Hege KM. 2003. Multiple measures of HIV burden in blood and tissue are correlated with each other but not with clinical parameters in aviremic subjects. AIDS 17:53–63. http://dx.doi.org/10.1097/00002030-200301030-00008
140. 4+T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 77:11708–11717. http://dx.doi.org/10.1128/JVI.77.21.11708-11717.2003
141. 4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200:749–759. http://dx.doi.org/10.1084/jem.20040874
142. Veazey RS, Lackner AA. 2004. Getting to the guts of HIV pathogenesis. J Exp Med 200:697–700. http://dx.doi.org/10.1084/jem.20041464
143. Veazey RS, Lackner AA. 2005. HIV swiftly guts the immune system. Nat Med 11:469–470. http://dx.doi.org/10.1038/nm0505-469
144. 4+T cells in multiple tissues during acute SIV infection. Nature 434:1093–1097. http://dx.doi.org/10.1038/nature03501
145. 4+ T cells. Nature 434: 1148–1152. http://dx.doi.org/10.1038/nature03513
146. Mehandru S, Tenner-Racz K, Racz P, Markowitz M. 2005. The gastrointestinal tract is critical to the pathogenesis of acute HIV-1 infection. J Allergy Clin Immunol 116:419–422. http://dx.doi.org/10.1016/j.jaci.2005.05.040
147. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC. 2006. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371. http://dx.doi.org/10.1038/nm1511
148. Brenchley JM, Price DA, Douek DC. 2006. HIV disease: fallout from a mucosal catastrophe? Nat Immunol 7:235–239. http://dx.doi.org/10.1038/ni1316
149. Dandekar S. 2007. Pathogenesis of HIV in the gastrointestinal tract. Curr HIV/AIDS Rep 4:10–15. http://dx.doi.org/10.1007/s11904-007-0002-0
150. Belmonte L, Olmos M, Fanin A, Parodi C, Bare P, Concetti H, Perez H, de Bracco MM, Cahn P. 2007. The intestinal mucosa as a reservoir of HIV-1 infection after successful HAART. AIDS 21:2106–2108. http://dx.doi.org/10.1097/QAD.0b013e3282efb74b
151. 4+ T-cell depletion during acute and early human immunodeficiency virus type 1 infection. J Virol 81:599–612. http://dx.doi.org/10.1128/JVI.01739-06
152. Nilsson J, Kinloch-de-Loes S, Granath A, Sonnerborg A, Goh LE, Andersson J. 2007. Early immune activation in gut-associated and peripheral lymphoid tissue during acute HIV infection. AIDS 21:565–574. http://dx.doi.org/10.1097/QAD.0b013e3280117204
153. 4+ T-cell restoration during antiretroviral therapy. J Med Primatol 36:219–227. http://dx.doi.org/10.1111/j.1600-0684.2007.00239.x
154. Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, Scheinberg P, Price DA, Hage CA, Kholi LM, Khoruts A, Frank I, Else J, Schacker T, Silvestri G, Douek DC. 2008. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112: 2826–2835. http://dx.doi.org/10.1182/blood-2008-05-159301
155. Yukl S, Wong JK. 2008. Blood and guts and HIV: preferential HIV persistence in GI mucosa. J Infect Dis 197:640–642. http://dx.doi.org/10.1086/527325
156. Chege D, Sheth PM, Kain T, Kim CJ, Kovacs C, Loutfy M, Halpenny R, Kandel G, Chun TW, Ostrowski M, Kaul R. 2011. Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy. AIDS 25:741–749. http://dx.doi.org/10.1097/QAD.0b013e328344cefb
157. Douek DC, Roederer M, Koup RA. 2009. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med 60:471–484. http://dx.doi.org/10.1146/annurev.med.60.041807.123549
158. Avettand-Fenoel V, Prazuck T, Hocqueloux L, Melard A, Michau C, Kerdraon R, Agoute E, Rouzioux C. 2008. HIV-DNA in rectal cells is well correlated with HIV-DNA in blood in different groups of patients, including long-term non-progressors. AIDS 22:1880–1882. http://dx.doi.org/10.1097/QAD.0b013e32830fbdbc
159. Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, Kottilil S, Moir S, Mican JM, Mullins JI, Ward DJ, Kovacs JA, Mannon PJ, Fauci AS. 2008. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis 197: 714–720. http://dx.doi.org/10.1086/527324
160. Yukl SA, Gianella S, Sinclair E, Epling L, Li Q, Duan L, Choi ALM, Girling V, Ho T, Li P, Fujimoto K, Lampiris H, Hare CB, Pandori M, Haase AT, Günthard HF, Fischer M, Shergill AK, McQuaid K, Havlir DV, Wong JK. 2010. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J Infect Dis 202:1553–1561. http://dx.doi.org/10.1086/656722
161. Yukl SA, Shergill AK, Ho T, Killian M, Girling V, Epling L, Li P, Wong LK, Crouch P, Deeks SG, Havlir DV, McQuaid K, Sinclair E, Wong JK. 2013. The distribution of HIVDNAand RNA in cell subsets differs in gut and blood of HIV-positive patients on ART: implications for viral persistence. J Infect Dis 208:1212–1220. http://dx.doi.org/10.1093/infdis/jit308
162. 4+ T cells, including myeloid cells. AIDS 28:439–442. http://dx.doi.org/10.1097/QAD.0000000000000166
163. Lampinen TM, Critchlow CW, Kuypers JM, Hurt CS, Nelson PJ, Hawes SE, Coombs RW, Holmes KK, Kiviat NB. 2000. Association of antiretroviral therapy with detection of HIV-1 RNA and DNA in the anorectal mucosa of homosexual men. AIDS 14:F69–F75. http://dx.doi.org/10.1097/00002030-200003310-00001
164. Anton PA, Poles MA, Elliott J, Mao SH, McGowan I, Lenz HJ, Chen IS. 2001. Sensitive and 7reproducible quantitation of mucosal HIV-1 RNA and DNA viral burden in patients with detectable and undetectable plasma viral HIV-1 RNA using endoscopic biopsies. J Virol Methods 95:65–79. http://dx.doi.org/10.1016/S0166-0934(01)00295-6
165. Hatano H, Somsouk M, Sinclair E, Harvill K, Gilman L, Cohen M, Hoh R, Hunt PW, Martin JN, Wong JK, Deeks SG, Yukl SA. 2013. Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers. AIDS 27:2255–2260. http://dx.doi.org/10.1097/QAD.0b013e328362692f
166. Valcour VG, Shiramizu BT, Shikuma CM. 2010. HIV DNA in circulating monocytes as a mechanism to dementia and other HIV complications. J Leukoc Biol 87:621–626. http://dx.doi.org/10.1189/jib.0809571
167. Churchill MJ, Wesselingh SL, Cowley D, Pardo CA, McArthur JC, Brew BJ, Gorry PR. 2009. Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol 66: 253–258. http://dx.doi.org/10.1002/ana.21697
168. Zhao L, Galligan DC, Lamers SL, Yu S, Shagrun L, Salemi M, McGrath MS. 2009. High level HIV-1 DNA concentrations in brain tissues differentiate patients with post-HAART AIDS dementia complex or cardiovascular disease from those with AIDS. Sci China C Life Sci 52:651–656. http://dx.doi.org/10.1007/s11427-009-0085-5
169. Zink MC, Brice AK, Kelly KM, Queen SE, Gama L, Li M, Adams RJ, Bartizal C, Varrone J, Rabi SA, Graham DR, Tarwater PM, Mankowski JL, Clements JE. 2010. Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA. J Infect Dis 202:161–170. http://dx.doi.org/10.1086/653213
170. Ball JK, Curran R, Irving WL, Dearden AA. 1999. HIV-1 in semen: determination of proviral and viral titres compared to blood, and quantification of semen leukocyte populations. J Med Virol 59:356–363. http://dx.doi.org/10.1002/(SICI)1096-9071(199911)59:3_356::AID-JMV16_3.0.CO;2-Z
171. Ghosn J, Viard JP, Katlama C, de Almeida M, Tubiana R, Letourneur F, Aaron L, Goujard C, Salmon D, Leruez-Ville M, Rouzioux C, Chaix ML. 2004. Evidence of genotypic resistance diversity of archived and circulating viral strains in blood and semen of pre-treated HIV-infected men. AIDS 18:447–457. http://dx.doi.org/10.1097/00002030-200402200-00011
172. Prazuck T, Chaillon A, Avettand-Fenoel V, Caplan AL, Sayang C, Guigon A, Niang M, Barin F, Rouzioux C, Hocqueloux L. 2013. HIV-DNA in the genital tract of women on long-term effective therapy is associated to residual viremia and previous AIDS-defining illnesses. PLoS One 8:e69686. http://dx.doi.org/10.1371/journal.pone.0069686
173. Canaud G, Dejucq-Rainsford N, Avettand-Fenoel V, Viard JP, Anglicheau D, Bienaime F, Muorah M, Galmiche L, Gribouval O, Noel LH, Satie AP, Martinez F, Sberro-Soussan R, Scemla A, Gubler MC, Friedlander G, Antignac C, Timsit MO, Onetti Muda A, Terzi F, Rouzioux C, Legendre C. 2014. The kidney as a reservoir for HIV-1 after renal transplantation. J Am Soc Nephrol 25:407–419. http://dx.doi.org/10.1681/ASN.2013050564
174. Canaud G, Avettand-Fenoel V, Legendre C. 2015. HIV-positive-to-HIV-positive kidney transplantation. N Engl J Med 372:2069. http://dx.doi.org/10.1056/NEJMc1503288
175. Zanussi S, Bortolin MT, Pratesi C, Tedeschi R, Basaglia G, Abbruzzese L, Mazzucato M, Spina M, Vaccher E, Tirelli U, Rupolo M, Michieli M, Di Mascio M, De Paoli P. 2015. Autograft HIV-DNA load predicts HIV-1 peripheral reservoir after stem cell transplantation for AIDSrelated lymphoma patients. AIDS Res Hum Retroviruses 31:150–159. http://dx.doi.org/10.1089/aid.2014.0157
176. 4+T cells and HIV. AIDS 29:667–674. http://dx.doi.org/10.1097/QAD.0000000000000599
177. Damouche A, Lazure T, Avettand-Fenoel V, Huot N, Dejucq-Rainsford N, Satie AP, Melard A, David L, Gommet C, Ghosn J, Noel N, Pourcher G, Martinez V, Benoist S, Bereziat V, Cosma A, Favier B, Vaslin B, Rouzioux C, Capeau J, Muller-Trutwin M, Dereuddre-Bosquet N, Le Grand R, Lambotte O, Bourgeois C. 2015. Adipose tissue is a neglected viral reservoir and an inflammatory site during chronic HIV and SIV infection. PLoS Pathog 11:e1005153. http://dx.doi.org/10.1371/journal.ppat.1005153
178. Hatzakis AE, Touloumi G, Pantazis N, Anastassopoulou CG, Katsarou O, Karafoulidou A, Goedert JJ, Kostrikis LG. 2004. Cellular HIV-1 DNA load predicts HIV-RNA rebound and the outcome of highly active antiretroviral therapy. AIDS 18:2261–2267. http://dx.doi.org/10.1097/00002030-200411190-00006
179. Tierney C, Lathey JL, Christopherson C, Bettendorf DM, D’Aquila RT, Hammer SM, Katzenstein DA. 2003. Prognostic value of baseline human immunodeficiency virus type 1 DNA measurement for disease progression in patients receiving nucleoside therapy. J Infect Dis 187: 144–148. http://dx.doi.org/10.1086/345870
180. Katzenstein TL, Oliveri RS, Benfield T, Eugen-Olsen J, Nielsen C, Gerstoft J. 2002. Cell-associated HIV DNA measured early during infection has prognostic value independent of serum HIV RNA measured concomitantly. Scand J Infect Dis 34:529–533. http://dx.doi.org/10.1080/00365540110080845
181. Madec Y, Boufassa F, Rouzioux C, Delfraissy JF, Meyer L. 2005. Undetectable viremia without antiretroviral therapy in patients with HIV seroconversion: an uncommon phenomenon? Clin Infect Dis 40: 1350–1354. http://dx.doi.org/10.1086/429318
182. Madec Y, Boufassa F, Avettand-Fenoel V, Hendou S, Melard A, Boucherit S, Surzyn J, Meyer L, Rouzioux C. 2009. Early control of HIV-1 infection in long-term nonprogressors followed since diagnosis in the ANRS SEROCO/HEMOCO cohort. J Acquir Immune Defic Syndr 50:19–26. http://dx.doi.org/10.1097/QAI.0b013e31818ce709
183. Tsiara CG, Nikolopoulos GK, Bagos PG, Goujard C, Katzenstein TL, Minga AK, Rouzioux C, Hatzakis A. 2012. Impact of HIV type 1 DNA levels on spontaneous disease progression: a meta-analysis. AIDS Res Hum Retroviruses 28:366–373. http://dx.doi.org/10.1089/aid.2011.0032
184. McDermott JL, Giri AA, Martini I, Bono M, Giacomini M, Campelli A, Tagliaferro L, Cara A, Varnier OE. 1999. Level of human immunodeficiency virus DNA in peripheral blood mononuclear cells correlates with efficacy of antiretroviral therapy. J Clin Microbiol 37:2361–2365
185. Havlir DV, Strain MC, Clerici M, Ignacio C, Trabattoni D, Ferrante P, Wong JK. 2003. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol 77: 11212–11219. http://dx.doi.org/10.1128/JVI.77.20.11212-11219.2003
186. Havlir DV, Koelsch KK, Strain MC, Margot N, Lu B, Ignacio CC, Miller MD, Wong JK. 2005. Predictors of residual viremia in HIVinfected patients successfully treated with efavirenz and lamivudine plus either tenofovir or stavudine. J Infect Dis 191:1164–1168. http://dx.doi.org/10.1086/428588
187. Weiss L, Chevalier MF, Assoumou L, Didier C, Girard PM, Piketty C, Costagliola D, Rouzioux C. 2014. T-cell activation positively correlates with cell-associated HIV-DNA level in viremic patients with primary or chronic HIV-1 infection. AIDS 28:1683–1687. http://dx.doi.org/10.1097/QAD.0000000000000319
188. Bortolin MT, Zanussi S, Talamini R, Simonelli C, Pratesi C, Tedeschi R, Abbruzzese L, Manuele R, Rupolo M, Tirelli U, De Paoli P. 2010. Predictive value of HIV type 1 DNA levels on overall survival in HIVrelated lymphoma patients treated with high-dose chemotherapy (HDC) plus autologous stem cell transplantation (ASCT). AIDS Res Hum Retroviruses 26:245–251. http://dx.doi.org/10.1089/aid.2009.0081
189. Burgard M, Boufassa F, Viard JP, Garrigue I, Ruffault A, Izopet J, Vabret A, Descamps D, Colson P, Seigneurin JM, Rouzioux C. 2009. Factors influencing peripheral blood mononuclear cellassociated HIV-1 DNA level after long-term suppressive antiretroviral therapy in 236 patients. AIDS 23:2165–2171. http://dx.doi.org/10.1097/QAD.0b013e32833032d4
190. Lambert-Niclot S, Flandre P, Valantin MA, Soulie C, Fourati S, Wirden M, Sayon S, Pakianather S, Bocket L, Masquelier B, Dos Santos G, Katlama C, Calvez V, Marcelin AG. 2012. Similar evolution of cellular HIV-1 DNA level in darunavir/ritonavir monotherapy versus triple therapy in MONOI-ANRS136 trial over 96 weeks. PLoS One 7:e41390. http://dx.doi.org/10.1371/journal.pone.0041390
191. Fourati S, Flandre P, Calin R, Carcelain G, Soulie C, Lambert-Niclot S, Maiga A, Ait-Arkoub Z, Tubiana R, Valantin MA, Autran B, Katlama C, Calvez V, Marcelin AG. 2014. Factors associated with a low HIV reservoir in patients with prolonged suppressive antiretroviral therapy. J Antimicrob Chemother 69:753–756. http://dx.doi.org/10.1093/jac.dkt428
192. Cuzin L, Pugliese P, Saune K, Allavena C, Ghosn J, Cottalorda J, Rodallec A, Chaix ML, Fafi-Kremer S, Soulie C, Ouka M, Charpentier C, Bocket L, Mirand A, Guiguet M. 2015. Levels of intracellular HIVDNA in patients with suppressive antiretroviral therapy. AIDS 29:1665–1671. http://dx.doi.org/10.1097/QAD.0000000000000723
193. Rodriguez-Sainz C, Ramos R, Valor L, Lopez F, Santamaria B, Hernandez DC, Cruz JS, Navarro J, Modrego J, Alecsandru D, Fernandez-Cruz E. 2010. Prognostic value of peripheral blood mononuclear cellassociated HIV-1 DNA for virological outcome in asymptomatic HIV-1 chronic infection. J Clin Virol 48:168–172. http://dx.doi.org/10.1016/j.jcv.2010.03.020
194. Sarmati L, Parisi SG, Nicastri E, d’Ettorre G, Palmisano L, Andreotti M, Andreoni C, Giuliano M, Gatti F, Boldrin C, Palu G, Vullo V, Vella S, Andreoni M. 2005. Association between cellular human immunodeficiency virus DNA level and immunological parameters in patients with undetectable plasma viremia level during highly active antiretroviral therapy. J Clin Microbiol 43:6183–6185. http://dx.doi.org/10.1128/JCM.43.12.6183-6185.2005
195. Chun TW, Murray D, Justement JS, Hallahan CW, Moir S, Kovacs C, Fauci AS. 2011. Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy. J Infect Dis 204:135–138. http://dx.doi.org/10.1093/infdis/jir208
196. Guihot A, Tubiana R, Breton G, Marcelin AG, Samri A, Assoumou L, Goncalves E, Bricaire F, Costagliola D, Calvez V, Rouzioux C, Autran B, Katlama C, Carcelain G. 2010. Immune and virological benefits of 10 years of permanent viral control with antiretroviral therapy. AIDS 24: 614–617. http://dx.doi.org/10.1097/QAD.0b013e32833556f3
197. Avettand-Fenoel V, Bouteloup V, Melard A, Fagard C, Chaix ML, Leclercq P, Chene G, Viard JP, Rouzioux C. 2010. Higher HIV-1 DNA Avettand-Fenoel et al. associated with lower gains in CD4 cell count among patients with advanced therapeutic failure receiving optimized treatment (ANRS 123-ETOILE). J Antimicrob Chemother 65:2212–2214. http://dx.doi.org/10.1093/jac/dkq282
198. Soulie C, Marcelin AG, Ghosn J, Amellal B, Assoumou L, Lambert S, Duvivier C, Costagliola D, Katlama C, Calvez V. 2007. HIV-1 X4/R5 co-receptor in viral reservoir during suppressive HAART. AIDS 21: 2243–2245. http://dx.doi.org/10.1097/QAD.0b013e3282f0e3d0
199. Ghosn J, Leruez-Ville M, Blanche J, Delobelle A, Beaudoux C, Mascard L, Lecuyer H, Canestri A, Landman R, Zucman D, Ponscarme D, Rami A, Viard JP, Spire B, Rouzioux C, Costagliola D, Suzan-Monti M. 2014. HIV-1 DNA levels in peripheral blood mononuclear cells and cannabis use are associated with intermittent HIV shedding in semen of men who have sex with men on successful antiretroviral regimens. Clin Infect Dis 58:1763–1770. http://dx.doi.org/10.1093/cid/ciu187
200. 4+:CD8_ T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy. J Infect Dis 185:1672–1676. http://dx.doi.org/10.1086/340521
201. Ostrowski SR, Katzenstein TL, Thim PT, Pedersen BK, Gerstoft J, Ullum H. 2005. Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy. J Infect Dis 191:348–357. http://dx.doi.org/10.1086/427340
202. Ometto L, De Forni D, Patiri F, Trouplin V, Mammano F, Giacomet V, Giaquinto C, Douek D, Koup R, De Rossi A. 2002. Immune reconstitution in HIV-1-infected children on antiretroviral therapy: role of thymic output and viral fitness. AIDS 16:839–849. http://dx.doi.org/10.1097/00002030-200204120-00003
203. 4+ T-cell counts following antiretroviral cessation in patients with HIV. AIDS 26:711–720. http://dx.doi.org/10.1097/QAD.0b013e3283519214
204. 4+ T cells. J Infect Dis 208:50–56. http://dx.doi.org/10.1093/infdis/jis630
205. Gantner P, Morand-Joubert L, Raffi F, Sueur C, Fagard C, Lascoux-Combe C, Salmon D, Amiel C, Lambert-Niclot S, Fofana D, Viard JP, Fafi-Kremer S, Rouzioux C, Avettand-Fenoel V, Ghosn J. 2016. Drug resistance and tropism as markers of the dynamics of HIV-1 DNA quasispecies in blood cells of heavily pretreated patients who achieved sustained virological suppression. J Antimicrob Chemother 71:751–761. http://dx.doi.org/10.1093/jac/dkv395
206. Delaugerre C, Braun J, Charreau I, Delarue S, Nere ML, de Castro N, May T, Marchou B, Simon F, Molina JM, Aboulker JP. 2012. Comparison of resistance mutation patterns in historical plasma HIV RNA genotypes with those in current proviral HIV DNA genotypes among extensively treated patients with suppressed replication. HIV Med 13: 517–525. http://dx.doi.org/10.1111/j.1468-1293.2012.01002.x
207. Wirden M, Soulie C, Valantin MA, Fourati S, Simon A, Lambert-Niclot S, Bonmarchand M, Clavel-Osorio C, Marcelin AG, Katlama C, Calvez V. 2011. Historical HIV-RNA resistance test results are more informative than proviral DNA genotyping in cases of suppressed or residual viraemia. J Antimicrob Chemother 66:709–712. http://dx.doi.org/10.1093/jac/dkq544
208. Shiramizu B, Paul R, Williams A, Shikuma C, Watters M, Grove J, Valcour V. 2007. HIV proviral DNA associated with decreased neuropsychological function. J Neuropsychiatry Clin Neurosci 19:157–163. http://dx.doi.org/10.1176/jnp.2007.19.2.157
209. Shiramizu B, Williams AE, Shikuma C, Valcour V. 2009. Amount of HIV DNA in peripheral blood mononuclear cells is proportional to the severity of HIV-1-associated neurocognitive disorders. J Neuropsychiatry Clin Neurosci 21:68–74. http://dx.doi.org/10.1176/jnp.2009.21.1.68
210. Valcour VG, Shiramizu BT, Sithinamsuwan P, Nidhinandana S, Ratto-Kim S, Ananworanich J, Siangphoe U, Kim JH, de Souza M, Degruttola V, Paul RH, Shikuma CM. 2009. HIV DNA and cognition in a Thai longitudinal HAART initiation cohort: the SEARCH 001 Cohort Study. Neurology 72:992–998. http://dx.doi.org/10.1212/01.wnl.0000344404.12759.83
211. Avettand-Fenoel V, Flandre P, Chaix ML, Ghosn J, Delaugerre C, Raffi F, Ngovan P, Cohen-Codar I, Delfraissy JF, Rouzioux C. 2010. Impact of 48 week lopinavir/ritonavir monotherapy on blood cell-associated HIV-1-DNA in the MONARK trial. J Antimicrob Chemother 65:1005–1007. http://dx.doi.org/10.1093/jac/dkq084
212. Lambert-Niclot S, Flandre P, Valantin MA, Peytavin G, Duvivier C, Haim-Boukobza S, Algarte-Genin M, Yazdanpanah Y, Girard PM, Katlama C, Calvez V, Marcelin AG. 2011. Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ ritonavir monotherapy. J Infect Dis 204:1211–1216. http://dx.doi.org/10.1093/infdis/jir518
213. Geretti AM, Arribas JR, Lathouwers E, Foster GM, Yakoob R, Kinloch S, Hill A, van Delft Y, Moecklinghoff C. 2013. Dynamics of cellular HIV-1 DNA levels over 144 weeks of darunavir/ritonavir monotherapy versus triple therapy in theMONETtrial. HIV Clin Trials 14:45–50. http://dx.doi.org/10.1310/hct1401-45
214. Perez-Valero I, Arribas JR. 2011. Protease inhibitor monotherapy. Curr Opin Infect Dis 24:7–11. http://dx.doi.org/10.1097/QCO.0b013e3283422cdf
215. Morlat P, Groupe des Experts Prise en Charge Médicale des Personnes Infectées par le VIH. 2015. Prise en charge médicale des personnes vivant avec le VIH. Actualisation 2015 du rapport 2013. CNS/ANRS, Paris, France. http://cns.sante.fr/wp-content/uploads/2015/10/experts-vih_actualisation2015.pdf
216. Sarmati L, Parisi SG, Nicastri E, d’Ettorre G, Andreoni C, Dori L, Gatti F, Montano M, Buonomini AR, Boldrin C, Palu G, Vullo V, Andreoni M. 2007. Cellular HIV-1 DNA quantitation in patients during simplification therapy with protease inhibitor-sparing regimens. J Med Virol 79:880–886. http://dx.doi.org/10.1002/jmv.20914
217. Prazuck T, Zucman D, Avettand-Fenoel V, Ducasse E, Bornarel D, Mille C, Rouzioux C, Hocqueloux L. 2013. Long-term HIV-1 virologic control in patients on a dual NRTI regimen. HIV Clin Trials 14:120–126. http://dx.doi.org/10.1310/hct1403-120
218. Lafeuillade A, Poggi C, Hittinger G, Counillon E, Emilie D. 2003. Predictors of plasma human immunodeficiency virus type 1 RNA control after discontinuation of highly active antiretroviral therapy initiated at acute infection combined with structured treatment interruptions and immune-based therapies. J Infect Dis 188:1426–1432. http://dx.doi.org/10.1086/379251
219. Yerly S, Gunthard HF, Fagard C, Joos B, Perneger TV, Hirschel B, Perrin L. 2004. Proviral HIV-DNA predicts viral rebound and viral setpoint after structured treatment interruptions. AIDS 18:1951–1953. http://dx.doi.org/10.1097/00002030-200409240-00011
220. Piketty C, Weiss L, Assoumou L, Burgard M, Melard A, Ragnaud JM, Bentata M, Girard PM, Rouzioux C, Costagliola D. 2010. A high HIV DNA level in PBMCs at antiretroviral treatment interruption predicts a shorter time to treatment resumption, independently of the CD4 nadir. J Med Virol 82:1819–1828. http://dx.doi.org/10.1002/jmv.21907
221. Assoumou L, Weiss L, Piketty C, Burgard M, Melard A, Girard PM, Rouzioux C, Costagliola D. 2015. A low HIV-DNA level in peripheral blood mononuclear cells at antiretroviral treatment interruption predicts a higher probability of maintaining viral control. AIDS 29:2003–2007. http://dx.doi.org/10.1097/QAD.0000000000000734
222. Gianella S, von Wyl V, Fischer M, Niederoest B, Battegay M, Bernasconi E, Cavassini M, Rauch A, Hirschel B, Vernazza P, Weber R, Joos B, Gunthard HF. 2011. Effect of early antiretroviral therapy during primary HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA. Antivir Ther 16:535–545. http://dx.doi.org/10.3851/IMP1776
223. Boue F, Reynes J, Rouzioux C, Emilie D, Souala F, Tubiana R, Goujard C, Lancar R, Costagliola D. 2011. Alpha interferon administration during structured interruptions of combination antiretroviral therapy in patients with chronic HIV-1 infection: INTERVAC ANRS 105 trial. AIDS 25:115–118. http://dx.doi.org/10.1097/QAD.0b013e328340a1e7
224. Li JZ, Heisey A, Ahmed H, Wang H, Zheng L, Carrington M, Wrin T, Schooley RT, Lederman MM, Kuritzkes DR. 2014. Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study. AIDS 28:2649–2657. http://dx.doi.org/10.1097/QAD.0000000000000478
225. Delaugerre C, Charreau I, Braun J, Nere ML, de Castro N, Yeni P, Ghosn J, Aboulker JP, Molina JM, Simon F. 2010. Time course of total HIV-1 DNA and 2-long-terminal repeat circles in patients with controlled plasma viremia switching to a raltegravir-containing regimen. AIDS 24:2391–2395. http://dx.doi.org/10.1097/QAD.0b013e32833d214c
226. Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, Eisele E, Haase A, Ho YC, Hutter G, Justement JS, Keating S, Lee TH, Li P, Murray D, Palmer S, Pilcher C, Pillai S, Price RW, Rothenberger M, Schacker T, Siliciano J, Siliciano R, Sinclair E, Strain M, Wong J, Richman D, Deeks SG. 2013. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog 9:e1003347. http://dx.doi.org/10.1371/journal.ppat.1003347
227. Cillo AR, Krishnan S, McMahon DK, Mitsuyasu RT, Para MF, Mellors JW. 2014. Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy. PLoS One 9:e92118. http://dx.doi.org/10.1371/journal.pone.0092118
228. Bouchat S, Delacourt N, Kula A, Darcis G, Van Driessche B, Corazza F, Gatot JS, Melard A, Vanhulle C, Kabeya K, Pardons M, Avettand-Fenoel V, Clumeck N, De Wit S, Rohr O, Rouzioux C, Van Lint C. 2015. Sequential treatment with 5-aza-2=-deoxycytidine and deacetylase inhibitors reactivates HIV-1. EMBO Mol Med 8:117–138. http://dx.doi.org/10.15252/emmm.201505557
229. Darcis G, Kula A, Bouchat S, Fujinaga K, Corazza F, Ait-Ammar A, Delacourt N, Melard A, Kabeya K, Vanhulle C, Van Driessche B, Gatot JS, Cherrier T, Pianowski LF, Gama L, Schwartz C, Vila J, Burny A, Clumeck N, Moutschen M, De Wit S, Peterlin BM, Rouzioux C, Rohr O, Van Lint C. 2015. An in-depth comparison of latency-reversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified bryostatin-1+JQ1 and Ingenol-B+JQ1 to potently reactivate viral gene expression. PLoS Pathog 11:e1005063. http://dx.doi.org/10.1371/journal.ppat.1005063
230. Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelievre JD, Boue F, Molina JM, Rouzioux C, Avettand-Fenoel V, Croughs T, Beq S, Thiebaut R, Chene G, Morre M, Delfraissy JF. 2009. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 119:997–1007. http://dx.doi.org/10.1172/JCI38052
231. Levy Y, Sereti I, Tambussi G, Routy JP, Lelievre JD, Delfraissy JF, Molina JM, Fischl M, Goujard C, Rodriguez B, Rouzioux C, Avettand-Fenoel V, Croughs T, Beq S, Morre M, Poulin JF, Sekaly RP, Thiebaut R, Lederman MM. 2012. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebocontrolled, multicenter study. Clin Infect Dis 55:291–300. http://dx.doi.org/10.1093/cid/cis383
232. Vandergeeten C, Fromentin R, DaFonseca S, Lawani MB, Sereti I, Lederman MM, Ramgopal M, Routy JP, Sekaly RP, Chomont N. 2013. Interleukin-7 promotes HIV persistence during antiretroviral therapy. Blood 121:4321–4329. http://dx.doi.org/10.1182/blood-2012-11-465625
233. Sagot-Lerolle N, Lamine A, Chaix ML, Boufassa F, Aboulker JP, Costagliola D, Goujard C, Pallier C, Delfraissy JF, Lambotte O. 2008. Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir. AIDS 22:1125–1129. http://dx.doi.org/10.1097/QAD.0b013e3282fd6ddc
234. Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, Brown G, Roney J, Watson J, Prince MH, Hoy JF, Chomont N, Fromentin R, Procopio FA, Zeidan J, Palmer S, Odevall L, Johnstone RW, Martin BP, Sinclair E, Deeks SG, Hazuda DJ, Cameron PU, Sekaly RP, Lewin SR. 2014. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog 10:e1004473. http://dx.doi.org/10.1371/journal.ppat.1004473
235. Scott-Algara D, Rouzioux C, Blanche S, Burgard M, Didier C, Riviere Y, Buseyne F. 2010. In untreated HIV-1-infected children, PBMCassociated HIVDNAlevels and cell-free HIVRNAlevels are correlated to distinct T-lymphocyte populations. J Acquir Immune Defic Syndr 53: 553–563. http://dx.doi.org/10.1097/QAI.0b013e3181cf060r
236. De Rossi A, Walker AS, De Forni D, Klein N, Gibb DM. 2005. Relationship between changes in thymic emigrants and cell-associated HIV-1 DNA in HIV-1-infected children initiating antiretroviral therapy. Antivir Ther 10:63–71
237. Sheth PM, Chege D, Shin LY, Huibner S, Yue FY, Loutfy M, Halpenny R, Persad D, Kovacs C, Chun TW, Kandel G, Ostrowski M, Kaul R. 2008. Immune reconstitution in the sigmoid colon after long-term HIV therapy. Mucosal Immunol 1:382–388. http://dx.doi.org/10.1038/mi.2008.23
238. Gianella S, Anderson CM, Vargas MV, Richman DD, Little SJ, Morris SR, Smith DM. 2013. Cytomegalovirus DNA in semen and blood is associated with higher levels of proviral HIV DNA. J Infect Dis 207:898–902. http://dx.doi.org/10.1093/infdis/jis777
239. 4+ T cell activation during antiretroviral treatment. J Virol 88:7818–7827. http://dx.doi.org/10.1128/JVI.00831-14
240. 4+ cell subsets within one month post-infection. PLoS One 8:e64219. http://dx.doi.org/10.1371/journal.pone.0064219
241. Ganesan A, Chattopadhyay PK, Brodie TM, Qin J, Gu W, Mascola JR, Michael NL, Follmann DA, Roederer M. 2010. Immunologic and virologic events in early HIV infection predict subsequent rate of progression. J Infect Dis 201:272–284. http://dx.doi.org/10.1086/649430
242. 4+ T cells and can induce remission. J Antimicrob Chemother 70:2108–2120. http://dx.doi.org/10.1093/jac/dkv084
243. Descours B, Avettand-Fenoel V, Blanc C, Samri A, Melard A, Supervie V, Theodorou I, Carcelain G, Rouzioux C, Autran B. 2012. Immune responses driven by protective human leukocyte antigen alleles from long-term nonprogressors are associated with low HIV reservoir in central memory CD4 T cells. Clin Infect Dis 54:1495–1503. http://dx.doi.org/10.1093/cid/cis188
244. von Stockenstrom S, Odevall L, Lee E, Sinclair E, Bacchetti P, Killian M, Epling L, Shao W, Hoh R, Ho T, Faria NR, Lemey P, Albert J, Hunt P, Loeb L, Pilcher C, Poole L, Hatano H, Somsouk M, Douek D, Boritz E, Deeks SG, Hecht FM, Palmer S. 2015. Longitudinal genetic characterization reveals that cell proliferation maintains a persistent HIV type 1 DNA pool during effective HIV therapy. J Infect Dis 212:596–607. http://dx.doi.org/10.1093/infdis/jiv092
245. Ananworanich J, Dube K, Chomont N. 2015. How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs? Curr Opin HIV AIDS 10:18–28. http://dx.doi.org/10.1097/COH.0000000000000122
246. Ghosn J, Delaugerre C. 2015. Can we avoid treatment interruption studies in the search for an HIV cure? AIDS 29:1575–1577. http://dx.doi.org/10.1097/QAD.0000000000000763
247. Stevenson M, Haggerty S, Lamonica CA, Meier CM, Welch SK, Wasiak AJ. 1990. Integration is not necessary for expression of human immunodeficiency virus type 1 protein products. J Virol 64:2421–2425
248. Appay V, Sauce D. 2008. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 214:231–241. http://dx.doi.org/10.1002/path.2276
249. Shimura K, Miyazato P, Oishi S, Fujii N, Matsuoka M. 2015. Impact of HIV-1 infection pathways on susceptibility to antiviral drugs and on virus spread. Virology 484:364–376. http://dx.doi.org/10.1016/j.virol.2015.06.029
250. Thierry S, Thierry E, Subra F, Deprez E, Leh H, Bury-Mone S, Delelis O. 2016. Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-+B pathway. Sci Rep 6:25678. http://dx.doi.org/10.1038/srep25678
251. Ho Y-C, Pollack R, Yong P, Siliciano RF. 2015. Defective HIV-1 proviruses can be transcribed upon activation, abstr 392. Conf Retroviruses Opportunistic Infect 2015, Seattle, WA
252. 4+T cells can produce HIV Gag without spreading infection in a model of HIV latency. PLoS Pathog 8:e1002818. http://dx.doi.org/10.1371/journal.ppat.1002818
253. DeMaster LK, Liu X, VanBelzen DJ, Trinite B, Zheng L, Agosto LM, Migueles SA, Connors M, Sambucetti L, Levy DN, Pasternak AO, O’Doherty U. 2016. A subset of CD4/CD8 double-negative T cells expresses HIV proteins in patients on antiretroviral therapy. J Virol 90: 2165–2179. http://dx.doi.org/10.1128/JVI.01913-15
254. 4+ T cells. PLoS One 9:e110731. http://dx.doi.org/10.1371/journal.pone.0110731
255. Soares RS, Tendeiro R, Foxall RB, Baptista AP, Cavaleiro R, Gomes P, Camacho R, Valadas E, Doroana M, Lucas M, Antunes F, Victorino RM, Sousa AE. 2011. Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients. J Virol 85:2429–2438. http://dx.doi.org/10.1128/JVI.01921-10
256. 4+ T cells may contribute to viral persistence in HIV controllers. Clin Infect Dis 52:681–687. http://dx.doi.org/10.1093/cid/ciq202
257. Ishizaka A, Sato H, Nakamura H, Koga M, Kikuchi T, Hosoya N, Koibuchi T, Nomoto A, Kawana-Tachikawa A, Mizutani T. 2016. Short intracellular HIV-1 transcripts as biomarkers of residual immune activation in patients on antiretroviral therapy. J Virol 90:5665–5674. http://dx.doi.org/10.1128/JVI.03158-415
258. Patterson BK, McCallister S, Schutz M, Siegel JN, Shults K, Flener Z, Landay A. 2001. Persistence of intracellular HIV-1 mRNA correlates with HIV-1-specific immune responses in infected subjects on stable HAART. AIDS 15:1635–1641. http://dx.doi.org/10.1097/00002030 -200109070-00005
259. Beignon AS, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh DG, Larsson M, Gorelick RJ, Lifson JD, Bhardwaj N. 2005. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 115:3265–3275. http://dx.doi.org/10.1172/JCI26032
260. Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, Hebbeler AM, Greene WC. 2010. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 143: 789–801. http://dx.doi.org/10.1016/j.cell.2010.11.001
261. Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC. 2014. IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343:428–432. http://dx.doi.org/10.1126/science.1243640
262. Jakobsen MR, Bak RO, Andersen A, Berg RK, Jensen SB, Tengchuan J, Laustsen A, Hansen K, Ostergaard L, Fitzgerald KA, Xiao TS, Mikkelsen JG, Mogensen TH, Paludan SR. 2013. IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication. Proc Natl Acad Sci U S A 110:E4571–E4580. http://dx.doi.org/10.1073/pnas.1311669110
263. Nissen SK, Hojen JF, Andersen KL, Kofod-Olsen E, Berg RK, Paludan SR, Ostergaard L, Jakobsen MR, Tolstrup M, Mogensen TH. 2014. Innate DNA sensing is impaired in HIV patients and IFI16 expression correlates with chronic immune activation. Clin Exp Immunol 177:295–309. http://dx.doi.org/10.1111/cei.12317
264. Gao D, Wu J, Wu YT, Du F, Aroh C, Yan N, Sun L, Chen ZJ. 2013. CyclicGMP-AMPsynthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–906. http://dx.doi.org/10.1126/science.1240933
265. Landau NR. 2014. The innate immune response to HIV-1: to sense or not to sense. DNA Cell Biol 33:271–274. http://dx.doi.org/10.1089/dna.2014.2378
266. Wagner TA, McLaughlin S, Garg K, Cheung CY, Larsen BB, Styrchak S, Huang HC, Edlefsen PT, Mullins JI, Frenkel LM. 2014. HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345:570–573. http://dx.doi.org/10.1126/science.1256304
267. Manel N, Hogstad B, Wang Y, Levy DE, Unutmaz D, Littman DR. 2010. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467:214–217. http://dx.doi.org/10.1038/nature09337
268. Henrick BM, Yao XD, Rosenthal KL. 2015. HIV-1 structural proteins serve as PAMPs for TLR2 heterodimers significantly increasing infection and innate immune activation. Front Immunol 6:426. http://dx.doi.org/10.3389/fimmu.2015.00426.