Cellular and molecular mechanisms involved in the establishment of HIV-1 latency

Daniel A Donahue, Mark A Wainberg, Daniel A Donahue, Mark A Wainberg

Abstract

Latently infected cells represent the major barrier to either a sterilizing or a functional HIV-1 cure. Multiple approaches to reactivation and depletion of the latent reservoir have been attempted clinically, but full depletion of this compartment remains a long-term goal. Compared to the mechanisms involved in the maintenance of HIV-1 latency and the pathways leading to viral reactivation, less is known about the establishment of latent infection. This review focuses on how HIV-1 latency is established at the cellular and molecular levels. We first discuss how latent infection can be established following infection of an activated CD4 T-cell that undergoes a transition to a resting memory state and also how direct infection of a resting CD4 T-cell can lead to latency. Various animal, primary cell, and cell line models also provide insights into this process and are discussed with respect to the routes of infection that result in latency. A number of molecular mechanisms that are active at both transcriptional and post-transcriptional levels have been associated with HIV-1 latency. Many, but not all of these, help to drive the establishment of latent infection, and we review the evidence in favor of or against each mechanism specifically with regard to the establishment of latency. We also discuss the role of immediate silent integration of viral DNA versus silencing of initially active infections. Finally, we discuss potential approaches aimed at limiting the establishment of latent infection.

Figures

Figure 1
Figure 1
Cellular pathways of the establishment of HIV-1 latency in CD4 T-cells. (A) Generation of memory CD4 T-cells. Transcriptionally active CD4+CD8+ (double positive) thymocytes transition to a resting state upon completion of thymopoiesis to become resting naïve CD4 T-cells. Naïve cells are activated upon encounter with antigen-bearing dendritic cells and undergo rapid clonal expansion. A small fraction of activated CD4 T-cells survive and transition to a resting state, to become resting memory CD4 T-cells. (B) Infection during deactivation. Infection of an activated thymocyte can result in active integration or immediate silent integration. Latency can be established upon the transition to a naïve CD4 T-cell. Infection of an activated CD4 T-cell can result in active integration or immediate silent integration. Latency can be established upon the transition to a resting memory CD4 T-cell. Note that for immediate silent integration into an activated thymocyte or an activated CD4 T-cell, latency has already been established at the virological level. Due to the rapid deaths of activated cells, only cells which transition to a resting state represent clinically relevant latent infections. (C) Direct resting cell infection. Infection of a naïve CD4 T-cell, or of a resting memory CD4 T-cell, results in immediate silent integration, i.e., latency. Note that the relative contributions of the pathways shown here are not known.

References

    1. Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity. 2012;37:377–388. doi: 10.1016/j.immuni.2012.08.010.
    1. Lassen KG, Ramyar KX, Bailey JR, Zhou Y, Siliciano RF. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog. 2006;2:e68. doi: 10.1371/journal.ppat.0020068.
    1. Saleh S, Wightman F, Ramanayake S, Alexander M, Kumar N, Khoury G, Pereira C, Purcell D, Cameron PU, Lewin SR. Expression and reactivation of HIV in a chemokine induced model of HIV latency in primary resting CD4+ T cells. Retrovirology. 2011;8:80. doi: 10.1186/1742-4690-8-80.
    1. Pace MJ, Graf EH, Agosto LM, Mexas AM, Male F, Brady T, Bushman FD, O’Doherty U. Directly infected resting CD4+T cells can produce HIV gag without spreading infection in a model of HIV latency. PLoS Pathog. 2012;8:e1002818. doi: 10.1371/journal.ppat.1002818.
    1. Fischer M, Joos B, Niederöst B, Kaiser P, Hafner R, Wyl von V, Ackermann M, Weber R, Günthard HF. Biphasic decay kinetics suggest progressive slowing in turnover of latently HIV-1 infected cells during antiretroviral therapy. Retrovirology. 2008;5:107. doi: 10.1186/1742-4690-5-107.
    1. Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci USA. 1998;95:8869–8873. doi: 10.1073/pnas.95.15.8869.
    1. 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. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci USA. 2012;109:9523–9528. doi: 10.1073/pnas.1120248109.
    1. Joos B, Fischer M, Kuster H, Pillai SK, Wong JK, Böni J, Hirschel B, Weber R, Trkola A, Günthard HF. HIV Swiss Cohort Study. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc Natl Acad Sci USA. 2008;105:16725–16730. doi: 10.1073/pnas.0804192105.
    1. Zhang L, Chung C, Hu BS, He T, Guo Y, Kim AJ, Skulsky E, Jin X, Hurley A, Ramratnam B, Markowitz M, Ho DD. Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. J Clin Invest. 2000;106:839–845. doi: 10.1172/JCI10565.
    1. Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, Kovacs JA, Davey RT, Rock-Kress D, Dewar R, Liu S, Metcalf JA, Rehm C, Brun SC, Hanna GJ, Kempf DJ, Coffin JM, Mellors JW. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 2007;3:e46. doi: 10.1371/journal.ppat.0030046.
    1. Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, Kempf DJ, Mellors JW, Coffin JM, King MS. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci USA. 2008;105:3879–3884. doi: 10.1073/pnas.0800050105.
    1. Geeraert L, Kraus G, Pomerantz RJ. Hide-and-seek: the challenge of viral persistence in HIV-1 infection. Annu Rev Med. 2008;59:487–501. doi: 10.1146/annurev.med.59.062806.123001.
    1. Chun T-W, Fauci AS. HIV reservoirs: pathogenesis and obstacles to viral eradication and cure. AIDS. 2012;26:1261–1268. doi: 10.1097/QAD.0b013e328353f3f1.
    1. Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang H-C, Zhang H, Margolick JB, Blankson JN, Siliciano RF. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36:491–501. doi: 10.1016/j.immuni.2012.01.014.
    1. Berger EA. Targeted cytotoxic therapy: adapting a rapidly progressing anticancer paradigm for depletion of persistent HIV-infected cell reservoirs. Curr Opin HIV AIDS. 2011;6:80–85. doi: 10.1097/COH.0b013e3283412515.
    1. Chun T-W, Nickle DC, Justement JS, Large D, Semerjian A, Curlin ME, O’Shea MA, Hallahan CW, Daucher M, Ward DJ, Moir S, Mullins JI, Kovacs C, Fauci AS. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest. 2005;115:3250–3255. doi: 10.1172/JCI26197.
    1. Rong L, Perelson AS. Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy. PLoS Comput Biol. 2009;5:e1000533. doi: 10.1371/journal.pcbi.1000533.
    1. Redel L, Le Douce V, Cherrier T, Marban C, Janossy A, Aunis D, Van Lint C, Rohr O, Schwartz C. HIV-1 regulation of latency in the monocyte-macrophage lineage and in CD4+ T lymphocytes. J Leukoc Biol. 2010;87:575–588. doi: 10.1189/jlb.0409264.
    1. Coleman CM, Wu L. HIV interactions with monocytes and dendritic cells: viral latency and reservoirs. Retrovirology. 2009;6:51. doi: 10.1186/1742-4690-6-51.
    1. Le Douce V, Herbein G, Rohr O, Schwartz C. Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage. Retrovirology. 2010;7:32. doi: 10.1186/1742-4690-7-32.
    1. Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol. 2010;11:674–680.
    1. van Leeuwen EMM, Sprent J, Surh CD. Generation and maintenance of memory CD4(+) T Cells. Curr Opin Immunol. 2009;21:167–172. doi: 10.1016/j.coi.2009.02.005.
    1. Fritsch RD, Shen X, Sims GP, Hathcock KS, Hodes RJ, Lipsky PE. Stepwise differentiation of CD4 memory T cells defined by expression of CCR7 and CD27. J Immunol. 2005;175:6489–6497.
    1. Riou C, Yassine-Diab B, Van grevenynghe J, Somogyi R, Greller LD, Gagnon D, Gimmig S, Wilkinson P, Shi Y, Cameron MJ, Campos-Gonzalez R, Balderas RS, Kelvin D, Sékaly R-P, Haddad EK. Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells. J Exp Med. 2007;204:79–91. doi: 10.1084/jem.20061681.
    1. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–763. doi: 10.1146/annurev.immunol.22.012703.104702.
    1. Rivino L, Messi M, Jarrossay D, Lanzavecchia A, Sallusto F, Geginat J. Chemokine receptor expression identifies Pre-T helper (Th)1, Pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J Exp Med. 2004;200:725–735. doi: 10.1084/jem.20040774.
    1. Vatakis DN, Nixon CC, Zack JA. Quiescent T cells and HIV: an unresolved relationship. Immunol Res. 2010;48:110–121. doi: 10.1007/s12026-010-8171-0.
    1. Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci USA. 1997;94:1925–1930. doi: 10.1073/pnas.94.5.1925.
    1. Spear M, Guo J, Wu Y. The trinity of the cortical actin in the initiation of HIV-1 infection. Retrovirology. 2012;9:45. doi: 10.1186/1742-4690-9-45.
    1. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990;61:213–222. doi: 10.1016/0092-8674(90)90802-L.
    1. Meyerhans A, Vartanian JP, Hultgren C, Plikat U, Karlsson A, Wang L, Eriksson S, Wain-Hobson S. Restriction and enhancement of human immunodeficiency virus type 1 replication by modulation of intracellular deoxynucleoside triphosphate pools. J Virol. 1994;68:535–540.
    1. Descours B, Cribier A, Chable-Bessia C, Ayinde D, Rice G, Crow Y, Yatim A, Schawartz O, Laguette N, Benkirane M. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells. Retrovirology. 2012;9:87. doi: 10.1186/1742-4690-9-87.
    1. Baldauf H-M, Pan X, Erikson E, Schmidt S, Daddacha W, Burggraf M, Schenkova K, Ambiel I, Wabnitz G, Gramberg T, Panitz S, Flory E, Landau NR, Sertel S, Rutsch F, Lasitschka F, Kim B, König R, Fackler OT, Keppler OT. SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med. 2012;18(11):1682–1687. doi: 10.1038/nm.2964.
    1. Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990;9:1551–1560.
    1. Schnittman SM, Lane HC, Greenhouse J, Justement JS, Baseler M, Fauci AS. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci USA. 1990;87:6058–6062. doi: 10.1073/pnas.87.16.6058.
    1. Woods TC, Roberts BD, Butera ST, Folks TM. Loss of inducible virus in CD45RA naive cells after human immunodeficiency virus-1 entry accounts for preferential viral replication in CD45RO memory cells. Blood. 1997;89:1635–1641.
    1. Mo H, Monard S, Pollack H, Ip J, Rochford G, Wu L, Hoxie J, Borkowsky W, Ho DD, Moore JP. Expression patterns of the HIV type 1 coreceptors CCR5 and CXCR4 on CD4+ T cells and monocytes from cord and adult blood. AIDS Res Hum Retroviruses. 1998;14:607–617. doi: 10.1089/aid.1998.14.607.
    1. Pierson T, Hoffman TL, Blankson J, Finzi D, Chadwick K, Margolick JB, Buck C, Siliciano JD, Doms RW, Siliciano RF. Characterization of chemokine receptor utilization of viruses in the latent reservoir for human immunodeficiency virus type 1. J Virol. 2000;74:7824–7833. doi: 10.1128/JVI.74.17.7824-7833.2000.
    1. Dai J, Agosto LM, Baytop C, Yu JJ, Pace MJ, Liszewski MK, O’Doherty U. Human immunodeficiency virus integrates directly into naive resting CD4+ T cells but enters naive cells less efficiently than memory cells. J Virol. 2009;83:4528–4537. doi: 10.1128/JVI.01910-08.
    1. Wang W, Guo J, Yu D, Vorster PJ, Chen W, Wu Y. A dichotomy in cortical actin and chemotactic actin activity between human memory and naive T cells contributes to their differential susceptibility to HIV-1 infection. J Biol Chem. 2012;287(42):35455–35469. doi: 10.1074/jbc.M112.362400.
    1. 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. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997;387:183–188. doi: 10.1038/387183a0.
    1. Delobel P, Sandres-Sauné K, Cazabat M, L’Faqihi F-E, Aquilina C, Obadia M, Pasquier C, Marchou B, Massip P, Izopet J. Persistence of distinct HIV-1 populations in blood monocytes and naive and memory CD4 T cells during prolonged suppressive HAART. AIDS. 2005;19:1739–1750. doi: 10.1097/01.aids.0000183125.93958.26.
    1. Ostrowski MA, Chun TW, Justement SJ, Motola I, Spinelli MA, Adelsberger J, Ehler LA, Mizell SB, Hallahan CW, Fauci AS. Both memory and CD45RA+/CD62L+ naive CD4(+) T cells are infected in human immunodeficiency virus type 1-infected individuals. J Virol. 1999;73:6430–6435.
    1. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, Kuruppu J, Yazdani J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol. 2004;78:1160–1168. doi: 10.1128/JVI.78.3.1160-1168.2004.
    1. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel M-R, Ghattas G, Brenchley JM, Schacker TW, Hill BJ, Douek DC, Routy J-P, Haddad EK, Sékaly R-P. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893–900. doi: 10.1038/nm.1972.
    1. Wightman F, Solomon A, Khoury G, Green JA, Gray L, Gorry PR, Ho YS, Saksena NK, Hoy J, Crowe SM, Cameron PU, Lewin SR. Both CD31(+) and CD31− naive CD4(+) T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. J Infect Dis. 2010;202:1738–1748. doi: 10.1086/656721.
    1. Li Q, Duan L, Estes JD, Ma Z-M, Rourke T, Wang Y, Reilly C, Carlis J, Miller CJ, Haase AT. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005;434:1148–1152.
    1. Unutmaz D, KewalRamani VN, Marmon S, Littman DR. Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. J Exp Med. 1999;189:1735–1746. doi: 10.1084/jem.189.11.1735.
    1. Kinter A, Moorthy A, Jackson R, Fauci AS. Productive HIV infection of resting CD4+ T cells: role of lymphoid tissue microenvironment and effect of immunomodulating agents. AIDS Res Hum Retroviruses. 2003;19:847–856. doi: 10.1089/088922203322493012.
    1. Eckstein DA, Penn ML, Korin YD, Scripture-Adams DD, Zack JA, Kreisberg JF, Roederer M, Sherman MP, Chin PS, Goldsmith MA. HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues. Immunity. 2001;15:671–682. doi: 10.1016/S1074-7613(01)00217-5.
    1. Weissman D, Daucher J, Barker T, Adelsberger J, Baseler M, Fauci AS. Cytokine regulation of HIV replication induced by dendritic cell-CD4-positive T cell interactions. AIDS Res Hum Retroviruses. 1996;12:759–767. doi: 10.1089/aid.1996.12.759.
    1. Saleh S, Solomon A, Wightman F, Xhilaga M, Cameron PU, Lewin SR. CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency. Blood. 2007;110:4161–4164. doi: 10.1182/blood-2007-06-097907.
    1. Cameron PU, Saleh S, Sallmann G, Solomon A, Wightman F, Evans VA, Boucher G, Haddad EK, Sékaly R-P, Harman AN, Anderson JL, Jones KL, Mak J, Cunningham AL, Jaworowski A, Lewin SR. Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton. Proc Natl Acad Sci USA. 2010;107:16934–16939. doi: 10.1073/pnas.1002894107.
    1. Deere JD, Schinazi RF, North TW. Simian immunodeficiency virus macaque models of HIV latency. Curr Opin HIV AIDS. 2011;6:57–61. doi: 10.1097/COH.0b013e32834086ce.
    1. Brooks DG, Kitchen SG, Kitchen CM, Scripture-Adams DD, Zack JA. Generation of HIV latency during thymopoiesis. Nat Med. 2001;7:459–464. doi: 10.1038/86531.
    1. Marsden MD, Kovochich M, Suree N, Shimizu S, Mehta R, Cortado R, Bristol G, An DS, Zack JA. HIV latency in the humanized BLT mouse. J Virol. 2012;86:339–347. doi: 10.1128/JVI.06366-11.
    1. Denton PW, Olesen R, Choudhary SK, Archin NM, Wahl A, Swanson MD, Chateau M, Nochi T, Krisko JF, Spagnuolo RA, Margolis DM, Garcia JV. Generation of HIV latency in humanized BLT mice. J Virol. 2012;86:630–634. doi: 10.1128/JVI.06120-11.
    1. Choudhary SK, Archin NM, Cheema M, Dahl NP, Garcia JV, Margolis DM. Latent HIV-1 infection of resting CD4+ T cells in the humanized Rag2−/− γc−/− mouse. J Virol. 2012;86:114–120. doi: 10.1128/JVI.05590-11.
    1. Tyagi M, Romerio F. Models of HIV-1 persistence in the CD4+ T cell compartment: past, present and future. Curr HIV Res. 2011;9:579–587. doi: 10.2174/157016211798998754.
    1. Planelles V, Wolschendorf F, Kutsch O. Facts and fiction: cellular models for high throughput screening for HIV-1 reactivating drugs. Curr HIV Res. 2011;9:568–578. doi: 10.2174/157016211798998826.
    1. Pace MJ, Agosto L, Graf EH, O’Doherty U. HIV reservoirs and latency models. Virology. 2011;411:344–354. doi: 10.1016/j.virol.2010.12.041.
    1. Yang H-C. Primary cell models of HIV latency. Curr Opin HIV AIDS. 2011;6:62–67. doi: 10.1097/COH.0b013e3283412568.
    1. Hakre S, Chávez L, Shirakawa K, Verdin E. HIV latency: experimental systems and molecular models. FEMS Microbiol Rev. 2012;36:706–716. doi: 10.1111/j.1574-6976.2012.00335.x.
    1. Sahu GK, Lee K, Ji J, Braciale V, Baron S, Cloyd MW. A novel in vitro system to generate and study latently HIV-infected long-lived normal CD4+ T-lymphocytes. Virology. 2006;355:127–137. doi: 10.1016/j.virol.2006.07.020.
    1. Marini A, Harper JM, Romerio F. An in vitro system to model the establishment and reactivation of HIV-1 latency. J Immunol. 2008;181:7713–7720.
    1. Bosque A, Planelles V. Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood. 2009;113:58–65. doi: 10.1182/blood-2008-07-168393.
    1. Yang H-C, Xing S, Shan L, O’Connell K, Dinoso J, Shen A, Zhou Y, Shrum CK, Han Y, Liu JO, Zhang H, Margolick JB, Siliciano RF. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J Clin Invest. 2009;119:3473–3486.
    1. Burnett JC, Lim K-I, Calafi A, Rossi JJ, Schaffer DV, Arkin AP. Combinatorial latency reactivation for HIV-1 subtypes and variants. J Virol. 2010;84:5958–5974. doi: 10.1128/JVI.00161-10.
    1. Tyagi M, Pearson RJ, Karn J. Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J Virol. 2010;84:6425–6437. doi: 10.1128/JVI.01519-09.
    1. Swiggard WJ, Baytop C, Yu JJ, Dai J, Li C, Schretzenmair R, Theodosopoulos T, O’Doherty U. Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. J Virol. 2005;79:14179–14188. doi: 10.1128/JVI.79.22.14179-14188.2005.
    1. Lassen KG, Hebbeler AM, Bhattacharyya D, Lobritz MA, Greene WC. A flexible model of HIV-1 latency permitting evaluation of many primary CD4 T-cell reservoirs. PLoS One. 2012;7:e30176. doi: 10.1371/journal.pone.0030176.
    1. Burke B, Brown HJ, Marsden MD, Bristol G, Vatakis DN, Zack JA. Primary cell model for activation-inducible human immunodeficiency virus. J Virol. 2007;81:7424–7434. doi: 10.1128/JVI.02838-06.
    1. McNamara LA, Ganesh JA, Collins KL. Latent HIV-1 infection occurs in multiple subsets of hematopoietic progenitor cells and is reversed by NF-κB activation. J Virol. 2012;86:9337–9350. doi: 10.1128/JVI.00895-12.
    1. Redd AD, Avalos A, Essex M. Infection of hematopoietic progenitor cells by HIV-1 subtype C, and its association with anemia in southern Africa. Blood. 2007;110:3143–3149. doi: 10.1182/blood-2007-04-086314.
    1. Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J, Bixby D, Savona MR, Collins KL. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010;16:446–451. doi: 10.1038/nm.2109.
    1. Durand CM, Ghiaur G, Siliciano JD, Rabi SA, Eisele EE, Salgado M, Shan L, Lai JF, Zhang H, Margolick J, Jones RJ, Gallant JE, Ambinder RF, Siliciano RF. HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. 2012;205:1014–1018. doi: 10.1093/infdis/jir884.
    1. Josefsson L, Eriksson S, Sinclair E, Ho T, Killian M, Epling L, Shao W, Lewis B, Bacchetti P, Loeb L, Custer J, Poole L, Hecht FM, Palmer S. Hematopoietic precursor cells isolated from patients on long-term suppressive HIV therapy did not contain HIV-1 DNA. J Infect Dis. 2012;206:28–34. doi: 10.1093/infdis/jis301.
    1. McNamara LA, Collins KL. Hematopoietic stem/precursor cells as HIV reservoirs. Curr Opin HIV AIDS. 2011;6:43–48. doi: 10.1097/COH.0b013e32834086b3.
    1. Jordan A, Bisgrove D, Verdin E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 2003;22:1868–1877. doi: 10.1093/emboj/cdg188.
    1. Kim YK, Bourgeois CF, Pearson R, Tyagi M, West MJ, Wong J, Wu S-Y, Chiang C-M, Karn J. Recruitment of TFIIH to the HIV LTR is a rate-limiting step in the emergence of HIV from latency. EMBO J. 2006;25:3596–3604. doi: 10.1038/sj.emboj.7601248.
    1. Duverger A, Jones J, May J, Bibollet-Ruche F, Wagner FA, Cron RQ, Kutsch O. Determinants of the establishment of human immunodeficiency virus type 1 latency. J Virol. 2009;83:3078–3093. doi: 10.1128/JVI.02058-08.
    1. Donahue DA, Kuhl BD, Sloan RD, Wainberg MA. The viral protein Tat can inhibit the establishment of HIV-1 latency. J Virol. 2012;86:3253–3263. doi: 10.1128/JVI.06648-11.
    1. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell. 2005;122:169–182. doi: 10.1016/j.cell.2005.06.006.
    1. Burnett JC, Miller-Jensen K, Shah PS, Arkin AP, Schaffer DV. Control of stochastic gene expression by host factors at the HIV promoter. PLoS Pathog. 2009;5:e1000260. doi: 10.1371/journal.ppat.1000260.
    1. Micheva-Viteva S, Pacchia AL, Ron Y, Peltz SW, Dougherty JP. Human immunodeficiency virus type 1 latency model for high-throughput screening. Antimicrob Agents Chemother. 2005;49:5185–5188. doi: 10.1128/AAC.49.12.5185-5188.2005.
    1. Jeeninga RE, Westerhout EM, van Gerven ML, Berkhout B. HIV-1 latency in actively dividing human T cell lines. Retrovirology. 2008;5:37. doi: 10.1186/1742-4690-5-37.
    1. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996;271:1582–1586. doi: 10.1126/science.271.5255.1582.
    1. Coiras M, López-Huertas MR, Pérez-Olmeda M, Alcamí J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nat Rev Microbiol. 2009;7:798–812. doi: 10.1038/nrmicro2223.
    1. Siliciano RF, Greene WC. HIV Latency. Cold Spring Harb Perspect Med. 2011;1:a007096.
    1. Mbonye U, Karn J. Control of HIV latency by epigenetic and non-epigenetic mechanisms. Curr HIV Res. 2011;9:554–567. doi: 10.2174/157016211798998736.
    1. Margolis DM. Mechanisms of HIV latency: an emerging picture of complexity. Curr HIV/AIDS Rep. 2010;7:37–43. doi: 10.1007/s11904-009-0033-9.
    1. Chomont N, DaFonseca S, Vandergeeten C, Ancuta P, Sékaly R-P. Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr Opin HIV AIDS. 2011;6:30–36. doi: 10.1097/COH.0b013e3283413775.
    1. Schröder ARW, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell. 2002;110:521–529. doi: 10.1016/S0092-8674(02)00864-4.
    1. Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD. HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 2007;17:1186–1194. doi: 10.1101/gr.6286907.
    1. Vatakis DN, Kim S, Kim N, Chow SA, Zack JA. Human immunodeficiency virus integration efficiency and site selection in quiescent CD4+ T cells. J Virol. 2009;83:6222–6233. doi: 10.1128/JVI.00356-09.
    1. Brady T, Agosto LM, Malani N, Berry CC, O’Doherty U, Bushman F. HIV integration site distributions in resting and activated CD4+ T cells infected in culture. AIDS. 2009;23:1461–1471. doi: 10.1097/QAD.0b013e32832caf28.
    1. Shan L, Yang H-C, Rabi SA, Bravo HC, Shroff NS, Irizarry RA, Zhang H, Margolick JB, Siliciano JD, Siliciano RF. Influence of host gene transcription level and orientation on HIV-1 latency in a primary-cell model. J Virol. 2011;85:5384–5393. doi: 10.1128/JVI.02536-10.
    1. Lewinski MK, Bisgrove D, Shinn P, Chen H, Hoffmann C, Hannenhalli S, Verdin E, Berry CC, Ecker JR, Bushman FD. Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription. J Virol. 2005;79:6610–6619. doi: 10.1128/JVI.79.11.6610-6619.2005.
    1. Han Y, Lassen K, Monie D, Sedaghat AR, Shimoji S, Liu X, Pierson TC, Margolick JB, Siliciano RF, Siliciano JD. Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J Virol. 2004;78:6122–6133. doi: 10.1128/JVI.78.12.6122-6133.2004.
    1. Shearwin KE, Callen BP, Egan JB. Transcriptional interference–a crash course. Trends Genet. 2005;21:339–345. doi: 10.1016/j.tig.2005.04.009.
    1. Mazo A, Hodgson JW, Petruk S, Sedkov Y, Brock HW. Transcriptional interference: an unexpected layer of complexity in gene regulation. J Cell Sci. 2007;120:2755–2761. doi: 10.1242/jcs.007633.
    1. Han Y, Lin YB, An W, Xu J, Yang H-C, O’Connell K, Dordai D, Boeke JD, Siliciano JD, Siliciano RF. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe. 2008;4:134–146. doi: 10.1016/j.chom.2008.06.008.
    1. Lenasi T, Contreras X, Peterlin BM. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe. 2008;4:123–133. doi: 10.1016/j.chom.2008.05.016.
    1. Gallastegui E, Millán-Zambrano G, Terme J-M, Chávez S, Jordan A. Chromatin reassembly factors are involved in transcriptional interference promoting HIV latency. J Virol. 2011;85:3187–3202. doi: 10.1128/JVI.01920-10.
    1. Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR, Klomp LWJ, Wijmenga C, Duckett CS, Nabel GJ. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature. 2003;426:853–857. doi: 10.1038/nature02171.
    1. Duverger A, Wolschendorf F, Zhang M, Wagner F, Hatcher B, Jones J, Cron RQ, van der Sluis RM, Jeeninga RE, Berkhout B, Kutsch O. An AP-1 binding site in the enhancer/core element of the HIV-1 promoter controls the ability of HIV-1 to establish latent infection. J Virol. 2012. [Epub ahead of print]
    1. Vandergeeten C, Fromentin R, Chomont N. The role of cytokines in the establishment, persistence and eradication of the HIV reservoir. Cytokine Growth Factor Rev. 2012;23:143–149. doi: 10.1016/j.cytogfr.2012.05.001.
    1. Zhou Q, Yik JHN. The Yin and Yang of P-TEFb regulation: implications for human immunodeficiency virus gene expression and global control of cell growth and differentiation. Microbiol Mol Biol Rev. 2006;70:646–659. doi: 10.1128/MMBR.00011-06.
    1. Budhiraja S, Famiglietti M, Bosque A, Planelles V, Rice AP. Cyclin T1 and CDK9 T-loop phosphorylation are downregulated during establishment of HIV-1 latency in primary resting memory CD4+ T cells. J Virol. 2012;87(2):1211–1220.
    1. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–1080. doi: 10.1126/science.1063127.
    1. du Chéné I, Basyuk E, Lin Y-L, Triboulet R, Knezevich A, Chable-Bessia C, Mettling C, Baillat V, Reynes J, Corbeau P, Bertrand E, Marcello A, Emiliani S, Kiernan R, Benkirane M. Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J. 2007;26:424–435. doi: 10.1038/sj.emboj.7601517.
    1. Marban C, Suzanne S, Dequiedt F, de Walque S, Redel L, Van Lint C, Aunis D, Rohr O. Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J. 2007;26:412–423. doi: 10.1038/sj.emboj.7601516.
    1. Tyagi M, Karn J. CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J. 2007;26:4985–4995. doi: 10.1038/sj.emboj.7601928.
    1. Pearson R, Kim YK, Hokello J, Lassen K, Friedman J, Tyagi M, Karn J. Epigenetic silencing of human immunodeficiency virus (HIV) transcription by formation of restrictive chromatin structures at the viral long terminal repeat drives the progressive entry of HIV into latency. J Virol. 2008;82:12291–12303. doi: 10.1128/JVI.01383-08.
    1. Friedman J, Cho W-K, Chu CK, Keedy KS, Archin NM, Margolis DM, Karn J. Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol. 2011;85:9078–9089. doi: 10.1128/JVI.00836-11.
    1. Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E. Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog. 2009;5:e1000495. doi: 10.1371/journal.ppat.1000495.
    1. Rafati H, Parra M, Hakre S, Moshkin Y, Verdin E, Mahmoudi T. Repressive LTR nucleosome positioning by the BAF complex is required for HIV latency. PLoS Biol. 2011;9:e1001206. doi: 10.1371/journal.pbio.1001206.
    1. Sobhian B, Laguette N, Yatim A, Nakamura M, Levy Y, Kiernan R, Benkirane M. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol Cell. 2010;38:439–451. doi: 10.1016/j.molcel.2010.04.012.
    1. He N, Liu M, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010;38:428–438. doi: 10.1016/j.molcel.2010.04.013.
    1. Yukl S, Pillai S, Li P, Chang K, Pasutti W, Ahlgren C, Havlir D, Strain M, Günthard H, Richman D, Rice AP, Daar E, Little S, Wong JK. Latently-infected CD4+ T cells are enriched for HIV-1 Tat variants with impaired transactivation activity. Virology. 2009;387:98–108. doi: 10.1016/j.virol.2009.01.013.
    1. Weinberger LS, Dar RD, Simpson ML. Transient-mediated fate determination in a transcriptional circuit of HIV. Nat Genet. 2008;40:466–470. doi: 10.1038/ng.116.
    1. Huang J, Wang F, Argyris E, Chen K, Liang Z, Tian H, Huang W, Squires K, Verlinghieri G, Zhang H. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med. 2007;13:1241–1247. doi: 10.1038/nm1639.
    1. Chable-Bessia C, Meziane O, Latreille D, Triboulet R, Zamborlini A, Wagschal A, Jacquet J-M, Reynes J, Levy Y, Saib A, Bennasser Y, Benkirane M. Suppression of HIV-1 replication by microRNA effectors. Retrovirology. 2009;6:26. doi: 10.1186/1742-4690-6-26.
    1. Chiang K, Rice AP. MicroRNA-Mediated Restriction of HIV-1 in Resting CD4(+) T Cells and Monocytes. Viruses. 2012;4:1390–1409. doi: 10.3390/v4091390.
    1. Li XD, Moore B, Cloyd MW. Gradual shutdown of virus production resulting in latency is the norm during the chronic phase of human immunodeficiency virus replication and differential rates and mechanisms of shutdown are determined by viral sequences. Virology. 1996;225:196–212. doi: 10.1006/viro.1996.0588.
    1. van der Sluis RM, Pollakis G, van Gerven ML, Berkhout B, Jeeninga RE. Latency profiles of full length HIV-1 molecular clone variants with a subtype specific promoter. Retrovirology. 2011;8:73. doi: 10.1186/1742-4690-8-73.
    1. Trono D, Van Lint C, Rouzioux C, Verdin E, Barré-Sinoussi F, Chun T-W, Chomont N. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science. 2010;329:174–180. doi: 10.1126/science.1191047.
    1. Evans VA, Khoury G, Saleh S, Cameron PU, Lewin SR. HIV persistence: Chemokines and their signalling pathways. Cytokine Growth Factor Rev. 2012;23:151–157. doi: 10.1016/j.cytogfr.2012.05.002.
    1. Strain MC, Little SJ, Daar ES, Havlir DV, Günthard HF, Lam RY, Daly OA, Nguyen J, Ignacio CC, Spina CA, Richman DD, Wong JK. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. In J Infect Dis. 2005;191:1410–1418. doi: 10.1086/428777.
    1. 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. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One. 2012;7:e33948. doi: 10.1371/journal.pone.0033948.
    1. Chun T-W, Justement JS, Moir S, Hallahan CW, Maenza J, Mullins JI, Collier AC, Corey L, Fauci AS. Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis. 2007;195:1762–1764. doi: 10.1086/518250.
    1. Gianella S, Wyl von V, Fischer M, Niederoest B, Battegay M, Bernasconi E, Cavassini M, Rauch A, Hirschel B, Vernazza P, Weber R, Joos B, Günthard HF. Swiss HIV Cohort Study. Effect of early antiretroviral therapy during primary HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA. Antivir Ther (Lond) 2011;16:535–545. doi: 10.3851/IMP1776.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit