Skip to main content
SpringerLink
Log in

HIV Persistence on Antiretroviral Therapy and Barriers to a Cure

  • Chapter
  • First Online:
HIV Vaccines and Cure

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1075))

Abstract

HIV persists within the body despite successful suppression of virus replication with antiretroviral therapy (ART). HIV lurks in latent and active reservoirs, leading to rebound of virus spread if ART is interrupted. The latent HIV reservoir is a natural consequence of the life cycle of HIV, with integration of HIV into the genomes of cells that are or later enter the resting state, resulting in transcriptionally quiescent provirus. Resting CD4 T cells comprise the majority of the latent reservoir, although new evidence points to additional, smaller cellular reservoirs of latent HIV. An alternate, so-called active reservoir of HIV also exists within cells such as those found the B cell follicle of lymph nodes, where expression of HIV RNA can be found, again despite the full suppression of viremia and viral replication. Multiple factors such as the degree of virus exposure, timing of ART, and host factors can influence the size and characteristics of the HIV reservoir. Constructing effective strategies for HIV eradication and measuring their impact will require a sophisticated knowledge of the HIV reservoir.

The original version of this chapter was revised. A correction to this chapter is available at https://doi.org/10.1007/978-981-13-0484-2_13

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Change history

References

  • Alonso LC, Rosenfield RL (2002) Oestrogens and puberty. Best Pract Res Clin Endocrinol Metab 16(1):13–30. https://doi.org/10.1053/beem.2002.0177

    Article  CAS  PubMed  Google Scholar 

  • Althoff KN, Gebo KA, Gange SJ, Klein MB, Brooks JT, Hogg RS, Bosch RJ, Horberg MA, Saag MS, Kitahata MM, Eron JJ, Napravnik S, Rourke SB, Gill MJ, Rodriguez B, Sterling TR, Deeks SG, Martin JN, Jacobson LP, Kirk GD, Collier AC, Benson CA, Silverberg MJ, Goedert JJ, McKaig RG, Thorne J, Rachlis A, Moore RD, Justice AC, North American ACCoR, Design (2010a) CD4 count at presentation for HIV care in the United States and Canada: are those over 50 years more likely to have a delayed presentation? AIDS Res Ther 7:45. https://doi.org/10.1186/1742-6405-7-45

    Article  PubMed  PubMed Central  Google Scholar 

  • Althoff KN, Justice AC, Gange SJ, Deeks SG, Saag MS, Silverberg MJ, Gill MJ, Lau B, Napravnik S, Tedaldi E, Klein MB, Gebo KA, North American Aids Cohorts Collaboration on Research D (2010b) Virologic and immunologic response to HAART, by age and regimen class. AIDS 24(16):2469–2479. https://doi.org/10.1097/QAD.0b013e32833e6d14

    Article  PubMed  Google Scholar 

  • Ananworanich J, Chomont N, Eller LA, Kroon E, Tovanabutra S, Bose M, Nau M, Fletcher JL, Tipsuk S, Vandergeeten C, O'Connell RJ, Pinyakorn S, Michael N, Phanuphak N, Robb ML, Rv, groups RSs (2016a) HIV DNA set point is rapidly established in acute HIV infection and dramatically reduced by early ART. EBioMedicine 11:68–72. https://doi.org/10.1016/j.ebiom.2016.07.024

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 (2016b) Virological and immunological characteristics of HIV-infected individuals at the earliest stage of infection. J Virus Erad 2:43–48

    Google Scholar 

  • Arainga M, Edagwa B, Mosley RL, Poluektova LY, Gorantla S, Gendelman HE (2017) A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy. Retrovirology 14(1):17. https://doi.org/10.1186/s12977-017-0344-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, Cohen MS, Coffin JM, Bosch RJ, Gay CL, Eron JJ, Margolis DM, Perelson AS (2012) Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A 109(24):9523–9528. https://doi.org/10.1073/pnas.1120248109

    Article  PubMed  PubMed Central  Google Scholar 

  • Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM (2014) Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol 12(11):750–764. https://doi.org/10.1038/nrmicro3352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey JR, Sedaghat AR, Kieffer T, Brennan T, Lee PK, Wind-Rotolo M, Haggerty CM, Kamireddi AR, Liu Y, Lee J, Persaud D, Gallant JE, Cofrancesco J, Jr., Quinn TC, Wilke CO, Ray SC, Siliciano JD, Nettles RE, Siliciano RF (2006) Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol 80 (13):6441–6457. doi:https://doi.org/10.1128/JVI.00591-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banga R, Procopio FA, Noto A, Pollakis G, Cavassini M, Ohmiti K, Corpataux JM, de Leval L, Pantaleo G, Perreau M (2016) PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med 22(7):754–761. https://doi.org/10.1038/nm.4113

    Article  CAS  PubMed  Google Scholar 

  • Barton K, Hiener B, Winckelmann A, Rasmussen TA, Shao W, Byth K, Lanfear R, Solomon A, McMahon J, Harrington S, Buzon M, Lichterfeld M, Denton PW, Olesen R, Ostergaard L, Tolstrup M, Lewin SR, Sogaard OS, Palmer S (2016) Broad activation of latent HIV-1 in vivo. Nat Commun 7:12731. https://doi.org/10.1038/ncomms12731

    Article  PubMed  PubMed Central  Google Scholar 

  • Beery AK, Zucker I (2011) Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35(3):565–572. https://doi.org/10.1016/j.neubiorev.2010.07.002

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boulassel MR, Chomont N, Pai NP, Gilmore N, Sekaly RP, Routy JP (2012) CD4 T cell nadir independently predicts the magnitude of the HIV reservoir after prolonged suppressive antiretroviral therapy. J Clin Virol 53(1):29–32. https://doi.org/10.1016/j.jcv.2011.09.018

    Article  CAS  PubMed  Google Scholar 

  • Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB, Capoferri AA, Lai J, Strain MC, Lada SM, Hoh R, Ho YC, Richman DD, Deeks SG, Siliciano JD, Siliciano RF (2016) Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med 22:1043. https://doi.org/10.1038/nm.4156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z, Martin-Gayo E, Leng J, Henrich TJ, Li JZ, Pereyra F, Zurakowski R, Walker BD, Rosenberg ES, Yu XG, Lichterfeld M (2014) HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat Med 20(2):139–142. https://doi.org/10.1038/nm.3445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calvanese V, Chavez L, Laurent T, Ding S, Verdin E (2013) Dual-color HIV reporters trace a population of latently infected cells and enable their purification. Virology 446(1–2):283–292. https://doi.org/10.1016/j.virol.2013.07.037

    Article  CAS  PubMed  Google Scholar 

  • CDC (2012) HIV in the United States: the stages of care. https://www.cdc.gov/hiv/pdf/research_mmp_stagesofcare.pdf. Accessed 29 Mar 2017

  • CDC (2016) HIV in the United States: at a glance. http://www.cdc.gov/hiv/statistics/overview/ataglance.html. Accessed 26 Sept 2016

  • Chavez L, Calvanese V, Verdin E (2015) HIV latency is established directly and early in both resting and activated primary CD4 T cells. PLoS Pathog 11(6):e1004955. https://doi.org/10.1371/journal.ppat.1004955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen HY, Di Mascio M, Perelson AS, Ho DD, Zhang L (2007) Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques. Proc Natl Acad Sci U S A 104 (48):19079–19084. doi:https://doi.org/10.1073/pnas.0707449104

    Article  CAS  Google Scholar 

  • 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(8):893–900. https://doi.org/10.1038/nm.1972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 (1997a) Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387(6629):183–188. https://doi.org/10.1038/387183a0

    Article  CAS  PubMed  Google Scholar 

  • Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, Lloyd AL, Nowak MA, Fauci AS (1997b) Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 94(24):13193–13197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chun TW, Justement JS, Murray D, Hallahan CW, Maenza J, Collier AC, Sheth PM, Kaul R, Ostrowski M, Moir S, Kovacs C, Fauci AS (2010) Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS 24(18):2803–2808. https://doi.org/10.1097/QAD.0b013e328340a239

    Article  PubMed  Google Scholar 

  • Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509(7500):282–283

    Article  PubMed  PubMed Central  Google Scholar 

  • 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. https://doi.org/10.1093/infdis/jiv218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crowell TA, Fletcher JL, Sereti I, Pinyakorn S, Dewar R, Krebs SJ, Chomchey N, Rerknimitr R, Schuetz A, Michael NL, Phanuphak N, Chomont N, Ananworanich J, Group RSS (2016) Initiation of antiretroviral therapy before detection of colonic infiltration by HIV reduces viral reservoirs, inflammation and immune activation. J Int AIDS Soc 19(1):21163. https://doi.org/10.7448/IAS.19.1.21163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curno MJ, Rossi S, Hodges-Mameletzis I, Johnston R, Price MA, Heidari S (2016) A systematic review of the inclusion (or exclusion) of women in HIV research: from clinical studies of antiretrovirals and vaccines to cure strategies. J Acquir Immune Defic Syndr 71(2):181–188. https://doi.org/10.1097/QAI.0000000000000842

    Article  CAS  PubMed  Google Scholar 

  • Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA, Shan L, Siliciano RF (2015) Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517:381. https://doi.org/10.1038/nature14053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, O'Shea A, Callender M, Spivak A, Brennan T, Kearney MF, Proschan MA, Mican JM, Rehm CA, Coffin JM, Mellors JW, Siliciano RF, Maldarelli F (2009) Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 106(23):9403–9408. https://doi.org/10.1073/pnas.0903107106

    Article  PubMed  PubMed Central  Google Scholar 

  • Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Munoz-Arias I, Greene WC (2014) Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505(7484):509–514. https://doi.org/10.1038/nature12940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D’Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA, Collaboration ARTC (2002) Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 360(9327):119–129

    Article  PubMed  Google Scholar 

  • Feinstein MJ, Bogorodskaya M, Bloomfield GS, Vedanthan R, Siedner MJ, Kwan GF, Longenecker CT (2016) Cardiovascular complications of HIV in endemic countries. Curr Cardiol Rep 18(11):113. https://doi.org/10.1007/s11886-016-0794-x

    Article  PubMed  PubMed Central  Google Scholar 

  • Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, Kallungal B, Palmer S, Medvik K, Lederman MM, Alatrakchi N, Jacobson JM, Wiegand A, Kearney M, Coffin JM, Mellors JW, Eron JJ, team ACTGA (2010) The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med 7(8):e1000321. https://doi.org/10.1371/journal.pmed.1000321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gandhi RT, Coombs RW, Chan ES, Bosch RJ, Zheng L, Margolis DM, Read S, Kallungal B, Chang M, Goecker EA, Wiegand A, Kearney M, Jacobson JM, D'Aquila R, Lederman MM, Mellors JW, Eron JJ, Team ACTGA (2012) 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 59(3):229–235. https://doi.org/10.1097/QAI.0b013e31823fd1f2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gartland AJ, Li S, McNevin J, Tomaras GD, Gottardo R, Janes H, Fong Y, Morris D, Geraghty DE, Kijak GH, Edlefsen PT, Frahm N, Larsen BB, Tovanabutra S, Sanders-Buell E, deCamp AC, Magaret CA, Ahmed H, Goodridge JP, Chen L, Konopa P, Nariya S, Stoddard JN, Wong K, Zhao H, Deng W, Maust BS, Bose M, Howell S, Bates A, Lazzaro M, O'Sullivan A, Lei E, Bradfield A, Ibitamuno G, Assawadarachai V, O'Connell RJ, deSouza MS, Nitayaphan S, Rerks-Ngarm S, Robb ML, Sidney J, Sette A, Zolla-Pazner S, Montefiori D, McElrath MJ, Mullins JI, Kim JH, Gilbert PB, Hertz T (2014) Analysis of HLA A*02 association with vaccine efficacy in the RV144 HIV-1 vaccine trial. J Virol 88(15):8242–8255. https://doi.org/10.1128/JVI.01164-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodkin K, Shapshak P, Asthana D, Zheng W, Concha M, Wilkie FL, Molina R, Lee D, Suarez P, Symes S, Khamis I (2004) Older age and plasma viral load in HIV-1 infection. AIDS 18(Suppl 1):S87–S98

    Article  PubMed  Google Scholar 

  • Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, Ganusov VV, Keele BF, Learn GH, Turnbull EL, Salazar MG, Weinhold KJ, Moore S, CCC B, Letvin N, Haynes BF, Cohen MS, Hraber P, Bhattacharya T, Borrow P, Perelson AS, Hahn BH, Shaw GM, Korber BT, McMichael AJ (2009) The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 206(6):1253–1272. https://doi.org/10.1084/jem.20090365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenblatt RM, Ameli N, Grant RM, Bacchetti P, Taylor RN (2000) Impact of the ovulatory cycle on virologic and immunologic markers in HIV-infected women. J Infect Dis 181(1):82–90. https://doi.org/10.1086/315207

    Article  CAS  PubMed  Google Scholar 

  • Hao S, Zhao J, Zhou J, Zhao S, Hu Y, Hou Y (2007) Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors. Int Immunopharmacol 7(13):1765–1775. https://doi.org/10.1016/j.intimp.2007.09.017

    Article  CAS  PubMed  Google Scholar 

  • Hatano H, Hayes TL, Dahl V, Sinclair E, Lee TH, Hoh R, Lampiris H, Hunt PW, Palmer S, McCune JM, Martin JN, Busch MP, Shacklett BL, Deeks SG (2011) A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis 203(7):960–968. https://doi.org/10.1093/infdis/jiq138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heesters BA, Lindqvist M, Vagefi PA, Scully EP, Schildberg FA, Altfeld M, Walker BD, Kaufmann DE, Carroll MC (2015) Follicular dendritic cells retain infectious HIV in cycling endosomes. PLoS Pathog 11(12):e1005285. https://doi.org/10.1371/journal.ppat.1005285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hellmuth J, Valcour V, Spudich S (2015) CNS reservoirs for HIV: implications for eradication. J Virus Eradic 1(2):67–71

    Google Scholar 

  • High KP, Brennan-Ing M, Clifford DB, Cohen MH, Currier J, Deeks SG, Deren S, Effros RB, Gebo K, Goronzy JJ, Justice AC, Landay A, Levin J, Miotti PG, Munk RJ, Nass H, Rinaldo CR, Jr., Shlipak MG, Tracy R, Valcour V, Vance DE, Walston JD, Volberding P, HIV OARWGo, Aging (2012) HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J Acquir Immune Def Syndr 60:Suppl 1S1–18. doi:https://doi.org/10.1097/QAI.0b013e31825a3668

    Article  CAS  PubMed  Google Scholar 

  • Ho HN, Hultin LE, Mitsuyasu RT, Matud JL, Hausner MA, Bockstoce D, Chou CC, O'Rourke S, Taylor JM, Giorgi JV (1993) Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J Immunol 150(7):3070–3079

    CAS  PubMed  Google Scholar 

  • Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373(6510):123–126. https://doi.org/10.1038/373123a0

    Article  CAS  PubMed  Google Scholar 

  • Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, Lai J, Blankson JN, Siliciano JD, Siliciano RF (2013) Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155(3):540–551. https://doi.org/10.1016/j.cell.2013.09.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hockett RD, Kilby JM, Derdeyn CA, Saag MS, Sillers M, Squires K, Chiz S, Nowak MA, Shaw GM, Bucy RP (1999) Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA. J Exp Med 189(10):1545–1554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Honeycutt JB, Wahl A, Baker C, Spagnuolo RA, Foster J, Zakharova O, Wietgrefe S, Caro-Vegas C, Madden V, Sharpe G, Haase AT, Eron JJ, Garcia JV (2016) Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest 126(4):1353–1366. https://doi.org/10.1172/JCI84456

    Article  PubMed  PubMed Central  Google Scholar 

  • Hosmane NN, Kwon KJ, Bruner KM, Capoferri AA, Beg S, Rosenbloom DI, Keele BF, Ho YC, Siliciano JD, Siliciano RF (2017) Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics. J Exp Med 214:959. https://doi.org/10.1084/jem.20170193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hunt PW, Lee SA, Siedner MJ (2016) Immunologic biomarkers, morbidity, and mortality in treated HIV infection. J Infect Dis 214(Suppl 2):S44–S50. https://doi.org/10.1093/infdis/jiw275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(8):1202–1211. https://doi.org/10.1093/infdis/jit311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston RE, Heitzeg MM (2015) Sex, age, race and intervention type in clinical studies of HIV cure: a systematic review. AIDS Res Hum Retrovir 31(1):85–97. https://doi.org/10.1089/AID.2014.0205

    Article  PubMed  PubMed Central  Google Scholar 

  • Josefsson L, von Stockenstrom S, Faria NR, Sinclair E, Bacchetti P, Killian M, Epling L, Tan A, Ho T, Lemey P, Shao W, Hunt PW, Somsouk M, Wylie W, Douek DC, Loeb L, Custer J, Hoh R, Poole L, Deeks SG, Hecht F, Palmer S (2013) 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 110 (51):E4987–E4996. doi:https://doi.org/10.1073/pnas.1308313110

    Article  CAS  Google Scholar 

  • Kalayjian RC, Spritzler J, Matining RM, Fiscus SA, Gross BH, Francis IR, Pollard RB, Lederman MM, Landay A (2013) Older HIV-infected patients on antiretroviral therapy have B-cell expansion and attenuated CD4 cell increases with immune activation reduction. AIDS 27(10):1563–1571. https://doi.org/10.1097/QAD.0b013e32835fabc2

    Article  CAS  PubMed  Google Scholar 

  • Karn (2015) Estrogen blocks HIV re-emergence from latency and points to gender-specific differences in HIV reservoirs. In: IAS towards an HIV cure symposium, Vancouver

    Google Scholar 

  • Kearney MF, Spindler J, Shao W, Yu S, Anderson EM, O'Shea A, Rehm C, Poethke C, Kovacs N, Mellors JW, Coffin JM, Maldarelli F (2014) Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLoS Pathog 10(3):e1004010. https://doi.org/10.1371/journal.ppat.1004010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kieffer TL, Finucane MM, Nettles RE, Quinn TC, Broman KW, Ray SC, Persaud D, Siliciano RF (2004) Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without evolution in treated adults with undetectable HIV loads. J Infect Dis 189(8):1452–1465. https://doi.org/10.1086/382488

    Article  CAS  PubMed  Google Scholar 

  • Kolte L, Strandberg C, Dreves AM, Ersboll AK, Jeppesen DL, Ryder LP, Nielsen SD (2002) Thymic involvement in immune recovery during antiretroviral treatment of HIV infection in adults; comparison of CT and sonographic findings. Scand J Infect Dis 34(9):668–672

    Article  PubMed  Google Scholar 

  • Kvaratskhelia M, Sharma A, Larue RC, Serrao E, Engelman A (2014) Molecular mechanisms of retroviral integration site selection. Nucleic Acids Res 42(16):10209–10225. https://doi.org/10.1093/nar/gku769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu MK, Hawkins N, Ritchie AJ, Ganusov VV, Whale V, Brackenridge S, Li H, Pavlicek JW, Cai F, Rose-Abrahams M, Treurnicht F, Hraber P, Riou C, Gray C, Ferrari G, Tanner R, Ping LH, Anderson JA, Swanstrom R, CC B, Cohen M, Karim SS, Haynes B, Borrow P, Perelson AS, Shaw GM, Hahn BH, Williamson C, Korber BT, Gao F, Self S, McMichael A, Goonetilleke N (2013) Vertical T cell immunodominance and epitope entropy determine HIV-1 escape. J Clin Invest 123(1):380–393. https://doi.org/10.1172/JCI65330

    Article  CAS  PubMed  Google Scholar 

  • Luther VP, Wilkin AM (2007) HIV infection in older adults. Clin Geriatr Med 23(3):567–583., vii. https://doi.org/10.1016/j.cger.2007.02.004

    Article  PubMed  Google Scholar 

  • 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(8):786–788. https://doi.org/10.1056/NEJMc1413931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, Hill S, Spindler J, Ferris AL, Mellors JW, Kearney MF, Coffin JM, Hughes SH (2014) HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345(6193):179–183. https://doi.org/10.1126/science.1254194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manfredi R (2002) HIV disease and advanced age: an increasing therapeutic challenge. Drugs Aging 19(9):647–669

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Bonet M, Clemente MI, Serramia MJ, Moreno S, Munoz E, Munoz-Fernandez MA (2015a) Immunological and pharmacological strategies to reactivate HIV-1 from latently infected cells: a possibility for HIV-1 paediatric patients? J Virus Rradic 1(3):148–152

    CAS  Google Scholar 

  • Martinez-Bonet M, Puertas MC, Fortuny C, Ouchi D, Mellado MJ, Rojo P, Noguera-Julian A, Munoz-Fernandez MA, Martinez-Picado J (2015b) Establishment and replenishment of the viral reservoir in perinatally HIV-1-infected children initiating very early antiretroviral therapy. Clin Inf Dis 61(7):1169–1178. https://doi.org/10.1093/cid/civ456

    Article  CAS  Google Scholar 

  • Mo R, Chen J, Grolleau-Julius A, Murphy HS, Richardson BC, Yung RL (2005) Estrogen regulates CCR gene expression and function in T lymphocytes. J Immunol 174(10):6023–6029

    Article  CAS  PubMed  Google Scholar 

  • Mofenson LM, Korelitz J, Meyer WA 3rd, Bethel J, Rich K, Pahwa S, Moye J Jr, Nugent R, Read J (1997) The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. J Infect Dis 175(5):1029–1038

    Article  CAS  PubMed  Google Scholar 

  • Muyanja D, Muzoora C, Muyingo A, Muyindike W, Siedner MJ (2016) High prevalence of metabolic syndrome and cardiovascular disease risk among people with HIV on stable ART in southwestern Uganda. AIDS Patient Care STDs 30(1):4–10. https://doi.org/10.1089/apc.2015.0213

    Article  PubMed  PubMed Central  Google Scholar 

  • Ndhlovu ZM, Kamya P, Mewalal N, Kloverpris HN, Nkosi T, Pretorius K, Laher F, Ogunshola F, Chopera D, Shekhar K, Ghebremichael M, Ismail N, Moodley A, Malik A, Leslie A, Goulder PJ, Buus S, Chakraborty A, Dong K, Ndung'u T, Walker BD (2015) Magnitude and kinetics of CD8+ T cell activation during Hyperacute HIV infection impact viral set point. Immunity 43(3):591–604. https://doi.org/10.1016/j.immuni.2015.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neely MN, Benning L, Xu J, Strickler HD, Greenblatt RM, Minkoff H, Young M, Bremer J, Levine AM, Kovacs A (2007) Cervical shedding of HIV-1 RNA among women with low levels of viremia while receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 44(1):38–42. https://doi.org/10.1097/01.qai.0000248352.18007.1f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ostrowski MA, Chun TW, Justement SJ, Motola I, Spinelli MA, Adelsberger J, Ehler LA, Mizell SB, Hallahan CW, Fauci AS (1999) Both memory and CD45RA+/CD62L+ naive CD4(+) T cells are infected in human immunodeficiency virus type 1-infected individuals. J Virol 73(8):6430–6435

    CAS  PubMed  PubMed Central  Google Scholar 

  • Paiardini M, Lichterfeld M (2016) Follicular T helper cells: hotspots for HIV-1 persistence. Nat Med 22(7):711–712. https://doi.org/10.1038/nm.4138

    Article  CAS  PubMed  Google Scholar 

  • Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, Kempf DJ, Mellors JW, Coffin JM, King MS (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 105(10):3879–3884. https://doi.org/10.1073/pnas.0800050105

    Article  PubMed  PubMed Central  Google Scholar 

  • Papuchon J, Pinson P, Lazaro E, Reigadas S, Guidicelli G, Taupin JL, Neau D, Fleury H, Provir/Latitude p (2013) Resistance mutations and CTL epitopes in archived HIV-1 DNA of patients on antiviral treatment: toward a new concept of vaccine. PLoS One 8(7):e69029. https://doi.org/10.1371/journal.pone.0069029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Persaud D, Palumbo PE, Ziemniak C, Hughes MD, Alvero CG, Luzuriaga K, Yogev R, Capparelli EV, Chadwick EG (2012) Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age. AIDS 26(12):1483–1490. https://doi.org/10.1097/QAD.0b013e3283553638

    Article  CAS  PubMed  Google Scholar 

  • Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M Jr, Chun TW, Strain M, Richman D, Luzuriaga K (2013) Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 369(19):1828–1835. https://doi.org/10.1056/NEJMoa1302976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Psomas C, Younas M, Reynes C, Cezar R, Portales P, Tuaillon E, Guigues A, Merle C, Atoui N, Fernandez C, Le Moing V, Barbuat C, Marin G, Nagot N, Sotto A, Eliaou JF, Sabatier R, Reynes J, Corbeau P (2016) One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: the ACTIVIH study. EBioMedicine 8:265–276. https://doi.org/10.1016/j.ebiom.2016.05.008

    Article  PubMed  PubMed Central  Google Scholar 

  • Rainwater-Lovett K, Uprety P, Persaud D (2016) Advances and hope for perinatal HIV remission and cure in children and adolescents. Curr Opin Pediatr 28(1):86–92. https://doi.org/10.1097/MOP.0000000000000304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rainwater-Lovett K, Ziemniak C, Watson D, Luzuriaga K, Siberry G, Petru A, Chen Y, Uprety P, McManus M, Ho YC, Lamers SL, Persaud D (2017) Paucity of intact non-induced provirus with early, long-term antiretroviral therapy of perinatal HIV infection. PLoS One 12(2):e0170548. https://doi.org/10.1371/journal.pone.0170548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raz L, Miller VM (2012) Considerations of sex and gender differences in preclinical and clinical trials. Handb Exp Pharmacol 214:127–147. https://doi.org/10.1007/978-3-642-30726-3_7

    Article  CAS  Google Scholar 

  • Rickabaugh TM, Kilpatrick RD, Hultin LE, Hultin PM, Hausner MA, Sugar CA, Althoff KN, Margolick JB, Rinaldo CR, Detels R, Phair J, Effros RB, Jamieson BD (2011) The dual impact of HIV-1 infection and aging on naive CD4 T-cells: additive and distinct patterns of impairment. PLoS One 6(1):e16459. https://doi.org/10.1371/journal.pone.0016459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robb ML, Ananworanich J (2016) Lessons from acute HIV infection. Curr Opin HIV AIDS 11:555. https://doi.org/10.1097/COH.0000000000000316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, Stancil B, Mosteller M, Brothers C, Wannamaker P, Hughes A, Sutherland-Phillips D, Mallal S, Shaefer M, Study of Hypersensitivity to A, Pharmacogenetic Evaluation Study T (2008) High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis 46(7):1111–1118. doi:https://doi.org/10.1086/529382

    Article  CAS  PubMed  Google Scholar 

  • Sabin CA, Smith CJ, Delpech V, Anderson J, Bansi L, Gilson R, Schwenk A, Leen C, Gazzard B, Porter K, Mackie N, Fisher M, Orkin C, Johnson M, Easterbrook P, Hill T, Phillips AN, Study UKCHC (2009) The associations between age and the development of laboratory abnormalities and treatment discontinuation for reasons other than virological failure in the first year of highly active antiretroviral therapy. HIV Med 10(1):35–43. https://doi.org/10.1111/j.1468-1293.2008.00654.x

    Article  CAS  PubMed  Google Scholar 

  • Schackman BR, Gebo KA, Walensky RP, Losina E, Muccio T, Sax PE, Weinstein MC, Seage GR, 3rd, Moore RD, Freedberg KA (2006) The lifetime cost of current human immunodeficiency virus care in the United States. Med Care 44 (11):990–997. doi:https://doi.org/10.1097/01.mlr.0000228021.89490.2a

    Article  PubMed  Google Scholar 

  • Schackman BR, Fleishman JA, Su AE, Berkowitz BK, Moore RD, Walensky RP, Becker JE, Voss C, Paltiel AD, Weinstein MC, Freedberg KA, Gebo KA, Losina E (2015) The lifetime medical cost savings from preventing HIV in the United States. Med Care 53(4):293–301. https://doi.org/10.1097/MLR.0000000000000308

    Article  PubMed  PubMed Central  Google Scholar 

  • Shah SK, Persaud D, Wendler DS, Taylor HA, Gay H, Kruger M, Grady C (2014) Research into a functional cure for HIV in neonates: the need for ethical foresight. Lancet Infect Dis 14(9):893–898. https://doi.org/10.1016/S1473-3099(14)70766-2

    Article  PubMed  PubMed Central  Google Scholar 

  • Siedner MJ, Kim JH, Nakku RS, Bibangambah P, Hemphill L, Triant VA, Haberer JE, Martin JN, Mocello AR, Boum Y 2nd, Kwon DS, Tracy RP, Burdo T, Huang Y, Cao H, Okello S, Bangsberg DR, Hunt PW (2016a) Persistent immune activation and carotid atherosclerosis in HIV-infected Ugandans receiving antiretroviral therapy. J Infect Dis 213(3):370–378. https://doi.org/10.1093/infdis/jiv450

    Article  CAS  PubMed  Google Scholar 

  • Siedner MJ, Kim JH, Nakku RS, Hemphill L, Triant VA, Haberer JE, Martin JN, Boum Y, 2nd, Kwon DS, Tsai AC, Hunt PW, Okello S, Bangsberg DR (2016b) HIV infection and arterial stiffness among older-adults taking antiretroviral therapy in rural Uganda. AIDS 30 (4):667–670. doi:https://doi.org/10.1097/QAD.0000000000000992

    Article  CAS  PubMed  Google Scholar 

  • Sieweke MH, Allen JE (2013) Beyond stem cells: self-renewal of differentiated macrophages. Science 342(6161):1242974. https://doi.org/10.1126/science.1242974

    Article  CAS  PubMed  Google Scholar 

  • Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF (2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 9(6):727–728. https://doi.org/10.1038/nm880

    Article  CAS  PubMed  Google Scholar 

  • Simonetti FR, Sobolewski MD, Fyne E, Shao W, Spindler J, Hattori J, Anderson EM, Watters SA, Hill S, Wu X, Wells D, Su L, Luke BT, Halvas EK, Besson G, Penrose KJ, Yang Z, Kwan RW, Van Waes C, Uldrick T, Citrin DE, Kovacs J, Polis MA, Rehm CA, Gorelick R, Piatak M, Keele BF, Kearney MF, Coffin JM, Hughes SH, Mellors JW, Maldarelli F (2016) Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc Natl Acad Sci U S A 113 (7):1883–1888. doi:https://doi.org/10.1073/pnas.1522675113

    Article  CAS  Google Scholar 

  • Sinha A, Ma Y, Scherzer R, Hur S, Li D, Ganz P, Deeks SG, Hsue PY (2016) Role of T-cell dysfunction, inflammation, and coagulation in microvascular disease in HIV. J Am Heart Assoc 5(12):e004243. https://doi.org/10.1161/JAHA.116.004243

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith PR, Sarner L, Murphy M, James B, Thomas JM, Skinner CJ, Aitken C (2003) Ethnicity and discordance in plasma HIV-1 RNA viral load and CD4+ lymphocyte count in a cohort of HIV-1-infected individuals. J Clin Virol 26(1):101–107

    Article  CAS  PubMed  Google Scholar 

  • Soriano-Sarabia N, Bateson RE, Dahl NP, Crooks AM, Kuruc JD, Margolis DM, Archin NM (2014) Quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells. J Virol 88(24):14070–14077. https://doi.org/10.1128/JVI.01900-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soriano-Sarabia N, Archin NM, Bateson R, Dahl NP, Crooks AM, Kuruc JD, Garrido C, Margolis DM (2015) Peripheral Vgamma9Vdelta2 T cells are a novel reservoir of latent HIV infection. PLoS Pathog 11(10):e1005201. https://doi.org/10.1371/journal.ppat.1005201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szotek EL, Narasipura SD, Al-Harthi L (2013) 17beta-estradiol inhibits HIV-1 by inducing a complex formation between beta-catenin and estrogen receptor alpha on the HIV promoter to suppress HIV transcription. Virology 443(2):375–383. https://doi.org/10.1016/j.virol.2013.05.027

    Article  CAS  PubMed  Google Scholar 

  • Tiraboschi J, Ray S, Patel K, Pace M, Phalora P, Robinson N, Hopkins E, Meyerowitz J, Wang Y, Davies O, Mant C, Cason J, Kaye S, Sanderson J, Fidler S, Klenerman P, Frater J, Fox J (2017) Short communication: lack of effect of Maraviroc intensification on blood and gut reservoir. AIDS Res Hum Retrovir 33(2):143–146. https://doi.org/10.1089/AID.2016.0198

    Article  PubMed  Google Scholar 

  • Tobin NH, Learn GH, Holte SE, Wang Y, Melvin AJ, McKernan JL, Pawluk DM, Mohan KM, Lewis PF, Mullins JI, Frenkel LM (2005) Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus. J Virol 79(15):9625–9634. https://doi.org/10.1128/JVI.79.15.9625-9634.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uprety P, Patel K, Karalius B, Ziemniak C, Chen YH, Brummel SS, Siminski S, Van Dyke RB, Seage GR, 3rd, Persaud D, Pediatric HIVACS (2017) HIV-1 DNA decay dynamics with early, long-term virologic control of perinatal infection. Clin Inf Dis doi:https://doi.org/10.1093/cid/cix192, 64, 1471

    Article  PubMed  PubMed Central  Google Scholar 

  • 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(6196):570–573. https://doi.org/10.1126/science.1256304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zakiniaeiz Y, Cosgrove KP, Potenza MN, Mazure CM (2016) Balance of the sexes: addressing sex differences in preclinical research. Yale J Biol Med 89(2):255–259

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Julia Marsh Sung & David M. Margolis

  2. Department of Microbiology & Immunology, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    David M. Margolis

Authors
  1. Julia Marsh Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Margolis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Margolis .

Editor information

Editors and Affiliations

  1. Comprehensive AIDS Research Center, School of Medicine, Tsinghua University, Beijing, China

    Linqi Zhang

  2. The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, VIC, Australia

    Sharon R. Lewin

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sung, J.M., Margolis, D.M. (2018). HIV Persistence on Antiretroviral Therapy and Barriers to a Cure. In: Zhang, L., Lewin, S. (eds) HIV Vaccines and Cure . Advances in Experimental Medicine and Biology, vol 1075. Springer, Singapore. https://doi.org/10.1007/978-981-13-0484-2_7

Download citation

Publish with us

Policies and ethics

Search

Navigation