The introduction of highly active antiretroviral therapy (HAART) has been an important breakthrough in the treatment of HIV-1 infection and has also a powerful tool to upset the equilibrium of viral production and HIV-1 pathogenesis. Despite the advent of potent combinations of this therapy, the long-lived HIV-1 reservoirs like cells from monocyte-macrophage lineage and resting memory CD4+ T cells which are established early during primary infection constitute a major obstacle to virus eradication. Further HAART interruption leads to immediate rebound viremia from latent reservoirs. This paper focuses on the essentials of the molecular mechanisms for the establishment of HIV-1 latency with special concern to present and future possible treatment strategies to completely purge and target viral persistence in the reservoirs. 1. Introduction Infection with HIV-1, which was first isolated in 1983, causes AIDS, a syndrome that was first reported in 1981 [1]. The HIV-1 pandemic represents one of the great plagues in the history of mankind and a major challenge for medicine, public health, and medical research [2]. The majority of people living with HIV-1 belong to low- and middle-income countries. For example, sub-Saharan Africa accounts for two third of all infected people with HIV-1, where in few countries more than one in five adults are infected with HIV. South and south East Asia have second highest number of people living with HIV-1. Furthermore the epidemic is spreading most rapidly in Eastern Europe and central Asia, where the number of people living with HIV increased by 54.2% between 2001 and 2009. UNAIDS estimated that 33.3 million people were infected with HIV at the end 2009 compared to 26.2 million in 1999, a 27% increase in HIV infection. Each year 2.6 million people are infected with HIV-1 and 1.8 million die of AIDS (UNAIDS 2010). Much has been learned about the science of AIDS and continuous research has allowed the development of 25 different active compounds belonging to six different drug families shifting the HIV-1 infection from a fatal illness into a chronic disease [3, 4]. HIV-1 life cycle can be categorized into two phases. The early stage occurs between entry into host cells and integration into its genome (Figure 1). The late phase occurs from the state of integrated provirus to full viral replication [5]. Similarly two types of viral latency can be differentiated: preintegration latency results in generation of different forms of viral DNA before integration, whereas postintegration latency refers to the lack of viral replication
References
[1]
F. Barre-Sinoussi, J. C. Chermann, F. Rey, et al., “Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS),” Science, vol. 220, no. 4599, pp. 868–871, 1983.
[2]
L. O. Kallings, “The first postmodern pandemic: 25 years of HIV/AIDS,” Journal of Internal Medicine, vol. 263, no. 3, pp. 218–243, 2008.
[3]
R. J. Pomerantz and D. L. Horn, “Twenty years of therapy for HIV-1 infection,” Nature Medicine, vol. 9, no. 7, pp. 867–873, 2003.
[4]
D. D. Richman, D. M. Margolis, M. Delaney, W. C. Greene, D. Hazuda, and R. J. Pomerantz, “The challenge of finding a cure for HIV infection,” Science, vol. 323, no. 5919, pp. 1304–1307, 2009.
[5]
M. Stevenson, “HIV-1 pathogenesis,” Nature Medicine, vol. 9, no. 7, pp. 853–860, 2003.
[6]
K. Lassen, Y. Han, Y. Zhou, J. Siliciano, and R. F. Siliciano, “The multifactorial nature of HIV-1 latency,” Trends in Molecular Medicine, vol. 10, no. 11, pp. 525–531, 2004.
[7]
P. Loetscher, B. Moser, and M. Baggiouni, “Chemokines and their receptors in lymphocyte traffic and HIV infection,” Advances in Immunology, no. 74, pp. 127–180, 2000.
[8]
P. Loetscher, A. Pellegrino, J. H. Gong et al., “The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3,” The Journal of Biological Chemistry, vol. 276, no. 5, pp. 2986–2991, 2001.
[9]
N. J. Arhel, S. Souquere-Besse, S. Munier et al., “HIV-1 DNA flap formation promotes uncoating of the pre-integration complex at the nuclear pore,” The EMBO Journal, vol. 26, no. 12, pp. 3025–3037, 2007.
[10]
S. C. Piller, L. Caly, and D. A. Jans, “Nuclear import of the pre-integration complex (PIC): the Achilles heel of HIV?” Current Drug Targets, vol. 4, no. 5, pp. 409–429, 2003.
[11]
B. Corthesy and P. N. Kao, “Purification by dna affinity chromatography of two polypeptides that contact the NF-AT DNA binding site in the interleukin 2 promoter,” The Journal of Biological Chemistry, vol. 269, no. 32, pp. 20682–20690, 1994.
[12]
K. A. Jones, J. T. Kadonaga, P. A. Luciw, and R. Tjian, “Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1,” Science, vol. 232, no. 4751, pp. 755–759, 1986.
[13]
G. Nabel and D. Baltimore, “An inducible transcription factor activates expression of human immunodeficiency virus in T cells,” Nature, vol. 326, no. 6114, pp. 711–713, 1987.
[14]
M. E. Garber, P. Wei, and K. A. Jones, “HIV-1 Tat interacts with cyclin T1 to direct the P-TEFb CTD kinase complex to TAR RNA,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 63, pp. 371–380, 1998.
[15]
V. W. Pollard and M. H. Malim, “The HIV-1 Rev protein,” Annual Review of Microbiology, vol. 52, pp. 491–532, 1998.
[16]
L. Geeraert, G. Kraus, and R. J. Pomerantz, “Hide-and-seek: the challenge of viral persistence in HIV-1 infection,” Annual Review of Medicine, vol. 59, pp. 487–501, 2008.
[17]
G. Dornadula, H. Zhang, B. VanUitert et al., “Residual HIV-1 RNA rna in blood plasma of patients taking suppressive highly active antiretroviral therapy,” Journal of the American Medical Association, vol. 282, no. 17, pp. 1627–1632, 1999.
[18]
P. R. Harrigan, M. Whaley, and J. S. G. Montaner, “Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy,” AIDS, vol. 13, no. 8, pp. F59–F62, 1999.
[19]
L. Zhang, B. Ramratnam, K. Tenner-Racz et al., “Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy,” The New England Journal of Medicine, vol. 340, no. 21, pp. 1605–1613, 1999.
[20]
J. B. Margolick, D. J. Volkman, T. M. Folks, and A. S. Fauci, “Amplification of HTLV-III/LAV infection by antigen-induced activation of t cells and direct suppression by virus of lymphocyte blastogenic responses,” The Journal of Immunology, vol. 138, no. 6, pp. 1719–1723, 1987.
[21]
J. A. Zack, A. J. Cann, J. P. Lugo, and I. S. Y. Chen, “HIV-1 production from infected peripheral blood T cells after HTLV-I induced mitogenic stimulation,” Science, vol. 240, no. 4855, pp. 1026–1029, 1988.
[22]
D. D. Ho, A. U. Neumann, A. S. Perelson, W. Chen, J. M. Leonard, and M. Markowitz, “Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection,” Nature, vol. 373, no. 6510, pp. 123–126, 1995.
[23]
E. J. Duh, W. J. Maury, T. M. Folks, A. S. Fauci, and A. B. Rabson, “Tumor necrosis factor α activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-κB sites in the long terminal repeat,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 15, pp. 5974–5978, 1989.
[24]
Y. K. Kim, C. F. Bourgeois, R. Pearson et al., “Recruitment of TFIIH to the HIV LTR is a rate-limiting step in the emergence of HIV from latency,” The EMBO Journal, vol. 25, no. 15, pp. 3596–3604, 2006.
[25]
Y. Han, M. Wind-Rotolo, H. C. Yang, J. D. Siliciano, and R. F. Siliciano, “Experimental approaches to the study of HIV-1 latency,” Nature Reviews Microbiology, vol. 5, no. 2, pp. 95–106, 2007.
[26]
T. W. Chun, R. T. Davey Jr., M. Ostrowski et al., “Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy,” Nature Medicine, vol. 6, no. 7, pp. 757–761, 2000.
[27]
D. D. Ho and L. Zhang, “HIV-1 rebound after anti-retroviral therapy,” Nature Medicine, vol. 6, no. 7, pp. 736–737, 2000.
[28]
C. M. Coleman and L. Wu, “HIV interactions with monocytes and dendritic cells: viral latency and reservoirs,” Retrovirology, vol. 6, article 51, 2009.
[29]
D. D. Ho, T. R. Rota, and M. S. Hirsch, “Infection of monocyte/macrophages by human T lymphocyte virus type III,” The Journal of Clinical Investigation, vol. 77, no. 5, pp. 1712–1715, 1986.
[30]
K. C. Williams, S. Corey, S. V. Westmoreland et al., “Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS,” The Journal of Experimental Medicine, vol. 193, no. 8, pp. 905–915, 2001.
[31]
V. Dahl, L. Josefsson, and S. Palmer, “HIV reservoirs, latency, and reactivation: prospects for eradication,” Antiviral Research, vol. 85, no. 1, pp. 286–294, 2010.
[32]
A. S. Perelson, P. Essunger, Y. Cao et al., “Decay characteristics of HIV-1-infected compartments during combination therapy,” Nature, vol. 387, no. 6629, pp. 188–191, 1997.
[33]
S. Palmer, A. P. Wiegand, F. Maldarelli et al., “New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma,” Journal of Clinical Microbiology, vol. 41, no. 10, pp. 4531–4536, 2003.
[34]
G. Barbaro, “Metabolic and cardiovascular complications of highly active antiretroviral therapy for HIV infection,” Current HIV Research, vol. 4, no. 1, pp. 79–85, 2006.
[35]
T. Pierson, J. McArthur, and R. F. Siliciano, “Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy,” Annual Review of Immunology, vol. 18, pp. 665–708, 2000.
[36]
G. Nunnari, D. Leto, J. Sullivan et al., “Seminal reservoirs during an HIV type 1 eradication trial,” AIDS Research and Human Retroviruses, vol. 21, no. 9, pp. 768–775, 2005.
[37]
T. P. Brennan, J. O. Woods, A. R. Sedaghat, J. D. Siliciano, R. F. Siliciano, and C. O. Wilke, “Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy,” Journal of Virology, vol. 83, no. 17, pp. 8470–8481, 2009.
[38]
A. Marcello, “Latency: the hidden HIV-1 challenge,” Retrovirology, vol. 3, article 7, 2006.
[39]
D. Bisgrove, M. Lewinski, F. Bushman, and E. Verdin, “Molecular mechanisms of HIV-1 proviral latency,” Expert Review of Anti-infective Therapy, vol. 3, no. 5, pp. 805–814, 2005.
[40]
K. Strebel, J. Luban, and K. T. Jeang, “Human cellular restriction factors that target HIV-1 replication,” BMC Medicine, vol. 7, article 48, 2009.
[41]
S. A. Williams and W. C. Greene, “Regulation of HIV-1 latency by T-cell activation,” Cytokine, vol. 39, no. 1, pp. 63–74, 2007.
[42]
Y. Zhou, H. Zhang, J. D. Siliciano, and R. F. Siliciano, “Kinetics of human immunodeficiency virus type 1 decay following entry into resting CD4+ T cells,” Journal of Virology, vol. 79, no. 4, pp. 2199–2210, 2005.
[43]
R. S. Mitchell, B. F. Beitzel, A. R. W. Schroder et al., “Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences,” PloS Biology, vol. 2, no. 8, article E234, 2004.
[44]
Y. Han, K. Lassen, D. Monie et al., “Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes,” Journal of Virology, vol. 78, no. 12, pp. 6122–6133, 2004.
[45]
M. K. Lewinski, D. Bisgrove, P. Shinn et al., “Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription,” Journal of Virology, vol. 79, no. 11, pp. 6610–6619, 2005.
[46]
Y. Han, Y. B. Lin, W. An et al., “Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough,” Cell Host and Microbe, vol. 4, no. 2, pp. 134–146, 2008.
[47]
I. H. Greger, F. Demarchi, M. Giacca, and N. J. Proudfoot, “Transcriptional interference perturbs the binding of Sp1 to the HIV-1 promoter,” Nucleic Acids Research, vol. 26, no. 5, pp. 1294–1300, 1998.
[48]
B. P. Callen, K. E. Shearwin, and J. B. Egan, “Transcriptional interference between convergent promoters caused by elongation over the promoter,” Molecular Cell, vol. 14, no. 5, pp. 647–656, 2004.
[49]
T. Lenasi, X. Contreras, and B. M. Peterlin, “Transcriptional interference antagonizes proviral gene expression to promote HIV latency,” Cell Host and Microbe, vol. 4, no. 2, pp. 123–133, 2008.
[50]
A. de Marco, C. Biancotto, A. Knezevich, P. Maiuri, C. Vardabasso, and A. Marcello, “Intragenic transcriptional cis-activation of the human immunodeficiency virus 1 does not result in allele-specific inhibition of the endogenous gene,” Retrovirology, vol. 5, article 98, 2008.
[51]
N. Crampton, W. A. Bonass, J. Kirkham, C. Rivetti, and N. H. Thomson, “Collision events between RNA polymerases in convergent transcription studied by atomic force microscopy,” Nucleic Acids Research, vol. 34, no. 19, pp. 5416–5425, 2006.
[52]
K. V. Morris, S. W. L. Chan, S. E. Jacobsen, and D. J. Looney, “Small interfering RNA-induced transcriptional gene silencing in human cells,” Science, vol. 305, no. 5688, pp. 1289–1292, 2004.
[53]
W. Y. Hu, F. D. Bushman, and A. C. Siva, “RNA interference against retroviruses,” Virus Research, vol. 102, no. 1, pp. 59–64, 2004.
[54]
K. J. Perkins and N. J. Proudfoot, “An ungracious host for an unwelcome guest,” Cell Host and Microbe, vol. 4, no. 2, pp. 89–91, 2008.
[55]
A. Mazo, J. W. Hodgson, S. Petruk, Y. Sedkov, and H. W. Brock, “Transcriptional interference: an unexpected layer of complexity in gene regulation,” Journal of Cell Science, vol. 120, part 16, pp. 2755–2761, 2007.
[56]
N. D. Perkins, N. L. Edwards, C. S. Duckett, A. B. Agranoff, R. M. Schmid, and G. J. Nabel, “A cooperative interaction between NF-κB and Sp1 is required for HIV-1 enhancer activation,” The EMBO Journal, vol. 12, no. 9, pp. 3551–3558, 1993.
[57]
C. Sune and M. A. Garcia-Blanco, “Sp1 transcription factor is required for in vitro basal and Tat-activated transcription from the human immunodeficiency virus type 1 long terminal repeat,” Journal of Virology, vol. 69, no. 10, pp. 6572–6576, 1995.
[58]
R. Weil and A. Israel, “T-cell-receptor- and B-cell-receptor-mediated activation of NF-κB in lymphocytes,” Current Opinion in Immunology, vol. 16, no. 3, pp. 374–381, 2004.
[59]
M. Coiras, M. R. Lopez-Huertas, J. Rullas, M. Mittelbrunn, and J. Alcami, “Basal shuttle of NF-κB/I κB alpha in resting T lymphocytes regulates HIV-1 LTR dependent expression,” Retrovirology, vol. 4, article 56, 2007.
[60]
A. J. Henderson and K. L. Calame, “CCAAT/enhancer binding protein (C/EBP) sites are required for HIV-1 replication in primary macrophages but not CD4+ T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 16, pp. 8714–8719, 1997.
[61]
S. A. Williams, L. F. Chen, H. Kwon, C. M. Ruiz-Jarabo, E. Verdin, and W. C. Greene, “NF-κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation,” The EMBO Journal, vol. 25, no. 1, pp. 139–149, 2006.
[62]
M. E. Gerritsen, A. J. Williams, A. S. Neish, S. Moore, Y. Shi, and T. Collins, “CREB-binding protein/p300 are transcriptional coactivators of p65,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 7, pp. 2927–2932, 1997.
[63]
H. Zhong, M. J. May, E. Jimi, and S. Ghosh, “The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1,” Molecular Cell, vol. 9, no. 3, pp. 625–636, 2002.
[64]
V. Quivy and C. van Lint, “Regulation at multiple levels of NF-κB-mediated transactivation by protein acetylation,” Biochemical Pharmacology, vol. 68, no. 6, pp. 1221–1229, 2004.
[65]
M. Calao, A. Burny, V. Quivy, A. Dekoninck, and C. van Lint, “A pervasive role of histone acetyltransferases and deacetylases in an NF-κB-signaling code,” Trends in Biochemical Sciences, vol. 33, no. 7, pp. 339–349, 2008.
[66]
H. Okamura, J. Aramburu, C. Garcia-Rodriguez et al., “Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity,” Molecular Cell, vol. 6, no. 3, pp. 539–550, 2000.
[67]
R. Q. Cron, S. R. Bartz, A. Clausell, S. J. Bort, S. J. Klebanoff, and D. B. Lewis, “NFAT1 enhances HIV-1 gene expression in primary human CD4 T cells,” Clinical Immunology, vol. 94, no. 3, pp. 179–191, 2000.
[68]
C. van Lint, C. A. Amella, S. Emiliani, M. John, T. Jie, and E. Verdin, “Transcription factor binding sites downstream of the human immunodeficiency virus type 1 transcription start site are important for virus infectivity,” Journal of Virology, vol. 71, no. 8, pp. 6113–6127, 1997.
[69]
M. Karin, “The regulation of AP-1 activity by mitogen-activated protein kinases,” The Journal of Biological Chemistry, vol. 270, no. 28, pp. 16483–16486, 1995.
[70]
A. M. Hidalgo-Estevez, E. Gonzalez, C. Punzon, and M. Fresno, “Human immunodeficiency virus type 1 Tat increases cooperation between AP-1 and NFAT transcription factors in T cells,” The Journal of General Virology, vol. 87, no. 6, pp. 1603–1612, 2006.
[71]
J. Brady and F. Kashanchi, “Tat gets the “green” light on transcription initiation,” Retrovirology, vol. 2, article 69, 2005.
[72]
M. Barboric and B. M. Peterlin, “A new paradigm in eukaryotic biology: HIV Tat and the control of transcriptional elongation,” PloS Biology, vol. 3, no. 2, article e76, 2005.
[73]
R. E. Kiernan, C. Vanhulle, L. Schiltz et al., “HIV-1 Tat transcriptional activity is regulated by acetylation,” The EMBO Journal, vol. 18, no. 21, pp. 6106–6118, 1999.
[74]
E. Col, C. Caron, D. Seigneurin-Berny, J. Gracia, A. Favier, and S. Khochbin, “The histone acetyltransferase, hGCN5, interacts with and acetylates the HIV transactivator, Tat,” The Journal of Biological Chemistry, vol. 276, no. 30, pp. 28179–28184, 2001.
[75]
A. Dorr, V. Kiermer, A. Pedal et al., “Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain,” The EMBO Journal, vol. 21, no. 11, pp. 2715–2723, 2002.
[76]
M. Ott, A. Dorr, C. Hetzer-Egger et al., “Tat acetylation: a regulatory switch between early and late phases in HIV transcription elongation,” Novartis Foundation Symposium, vol. 259, pp. 182–193, 2004.
[77]
S. Pagans, A. Pedal, B. J. North et al., “SIRT1 regulates HIV transcription via Tat deacetylation,” PloS Biology, vol. 3, no. 2, article e41, 2005.
[78]
A. Sabo, M. Lusic, A. Cereseto, and M. Giacca, “Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription,” Molecular and Cellular Biology, vol. 28, no. 7, pp. 2201–2212, 2008.
[79]
Y. L. Chiu, V. B. Soros, J. F. Kreisberg, K. Stopak, W. Yonemoto, and W. C. Greene, “Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells,” Nature, vol. 435, no. 7038, pp. 108–114, 2005.
[80]
H. Xu, E. Chertova, J. Chen et al., “Stoichiometry of the antiviral protein APOBEC3G in HIV-1 virions,” Virology, vol. 360, no. 2, pp. 247–256, 2007.
[81]
B. Mangeat, P. Turelli, S. Liao, and D. Trono, “A single amino acid determinant governs the species-specific sensitivity of APOBEC3G to Vif action,” The Journal of Biological Chemistry, vol. 279, no. 15, pp. 14481–14483, 2004.
[82]
C. van Lint, S. Emiliani, M. Ott, and E. Verdin, “Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation,” The EMBO Journal, vol. 15, no. 5, pp. 1112–1120, 1996.
[83]
C. van Lint, “Role of chromatin in HIV-1 transcriptional regulation,” Advances in Pharmacology, vol. 48, pp. 121–160, 2000.
[84]
E. Verdin, P. Paras Jr., and C. van Lint, “Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation,” The EMBO Journal, vol. 12, no. 8, pp. 3249–3259, 1993.
[85]
J. L. Workman and R. E. Kingston, “Alteration of nucleosome structure as a mechanism of transcriptional regulation,” Annual Review of Biochemistry, vol. 67, pp. 545–579, 1998.
[86]
V. K. Gangaraju and B. Bartholomew, “Mechanisms of ATP dependent chromatin remodeling,” Mutation Research, vol. 618, no. 1-2, pp. 3–17, 2007.
[87]
X. J. Yang and E. Seto, “HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention,” Oncogene, vol. 26, no. 37, pp. 5310–5318, 2007.
[88]
X. J. Yang and E. Seto, “Lysine acetylation: codified crosstalk with other posttranslational modifications,” Molecular Cell, vol. 31, no. 4, pp. 449–461, 2008.
[89]
G. Legube and D. Trouche, “Regulating histone acetyltransferases and deacetylases,” EMBO Reports, vol. 4, no. 10, pp. 944–947, 2003.
[90]
A. El Kharroubi, G. Piras, R. Zensen, and M. A. Martin, “Transcriptional activation of the integrated chromatin-associated human immunodeficiency virus type 1 promoter,” Molecular and Cellular Biology, vol. 18, no. 5, pp. 2535–2544, 1998.
[91]
A. Jordan, D. Bisgrove, and E. Verdin, “HIV reproducibly establishes a latent infection after acute infection of T cells in vitro,” The EMBO Journal, vol. 22, no. 8, pp. 1868–1877, 2003.
[92]
G. He and D. M. Margolis, “Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat,” Molecular and Cellular Biology, vol. 22, no. 9, pp. 2965–2973, 2002.
[93]
S. Gordon, G. Akopyan, H. Garban, and B. Bonavida, “Transcription factor YY1: structure, function, and therapeutic implications in cancer biology,” Oncogene, vol. 25, no. 8, pp. 1125–1142, 2006.
[94]
L. Ylisastigui, J. J. Coull, V. C. Rucker et al., “Polyamides reveal a role for repression in latency within resting T cells of HIV-infected donors,” The Journal of Infectious Diseases, vol. 190, no. 8, pp. 1429–1437, 2004.
[95]
M. Tyagi and J. Karn, “CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency,” The EMBO Journal, vol. 26, no. 24, pp. 4985–4995, 2007.
[96]
I. D. Chene, E. Basyuk, Y. L. Lin et al., “Suv39H1 and HP1γ are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency,” The EMBO Journal, vol. 26, no. 2, pp. 424–435, 2007.
[97]
L. F. Chen, W. Fischle, E. Verdin, and W. C. Greene, “Duration of nuclear NF-κB action regulated by reversible acetylation,” Science, vol. 293, no. 5535, pp. 1653–1657, 2001.
[98]
A. Doetzlhofer, H. Rotheneder, G. Lagger et al., “Histone deacetylase 1 can repress transcription by binding to Sp1,” Molecular and Cellular Biology, vol. 19, no. 8, pp. 5504–5511, 1999.
[99]
K. I. Ansari, B. P. Mishra, and S. S. Mandal, “MLL histone methylases in gene expression, hormone signaling and cell cycle,” Frontiers in Bioscience, vol. 14, no. 9, pp. 3483–3495, 2009.
[100]
D. Avram, A. Fields, K. Pretty On Top, D. J. Nevrivy, J. E. Ishmael, and M. Leid, “Isolation of a novel family of C2H2 zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors,” The Journal of Biological Chemistry, vol. 275, no. 14, pp. 10315–10322, 2000.
[101]
C. Marban, S. Suzanne, F. Dequiedt et al., “Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing,” The EMBO Journal, vol. 26, no. 2, pp. 412–423, 2007.
[102]
S. I. S. Grewal and D. Moazed, “Heterochromatin and epigenetic control of gene expression,” Science, vol. 301, no. 5634, pp. 798–802, 2003.
[103]
P. Brodersen and O. Voinnet, “Revisiting the principles of microRNA target recognition and mode of action,” Nature Reviews Molecular Cell Biology, vol. 10, no. 2, pp. 141–148, 2009.
[104]
D. H. Kim and J. J. Rossi, “Strategies for silencing human disease using RNA interference,” Nature Reviews Genetics, vol. 8, no. 3, pp. 173–184, 2007.
[105]
D. J. Obbard, K. H. J. Gordon, A. H. Buck, and F. M. Jiggins, “The evolution of RNAi as a defence against viruses and transposable elements,” Philosophical Transactions of the Royal Society B, vol. 364, no. 1513, pp. 99–115, 2009.
[106]
J. Huang, F. Wang, E. Argyris et al., “Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes,” Nature Medicine, vol. 13, no. 10, pp. 1241–1247, 2007.
[107]
Y. Han and R. F. Siliciano, “Keeping quiet: microRNAs in HIV-1 latency,” Nature Medicine, vol. 13, no. 10, pp. 1138–1140, 2007.
[108]
S. Omoto, M. Ito, Y. Tsutsumi et al., “HIV-1 Nef suppression by virally encoded microRNA,” Retrovirology, vol. 1, article 44, 2004.
[109]
Y. Bennasser, S. Y. Le, M. L. Yeung, and K. T. Jeang, “MicroRNAs in human immunodeficiency virus-1 infection,” Methods in Molecular Biology, vol. 342, pp. 241–253, 2006.
[110]
J. Lin and B. R. Cullen, “Analysis of the interaction of primate retroviruses with the human RNA interference machinery,” Journal of Virology, vol. 81, no. 22, pp. 12218–12226, 2007.
[111]
Y. Bennasser, S. Y. Le, M. Benkirane, and K. T. Jeang, “Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing,” Immunity, vol. 22, no. 5, pp. 607–619, 2005.
[112]
Y. Bennasser and K. T. Jeang, “HIV-1 Tat interaction with Dicer: requirement for RNA,” Retrovirology, vol. 3, article 95, 2006.
[113]
H. S. Christensen, A. Daher, K. J. Soye et al., “Small interfering RNAs against the TAR RNA binding protein, TRBP, a Dicer cofactor, inhibit human immunodeficiency virus type 1 long terminal repeat expression and viral production,” Journal of Virology, vol. 81, no. 10, pp. 5121–5131, 2007.
[114]
A. Gatignol, S. Laine, and G. Clerzius, “Dual role of TRBP in HIV replication and RNA interference: viral diversion of a cellular pathway or evasion from antiviral immunity?” Retrovirology, vol. 2, article 65, 2005.
[115]
G. Herbein and A. Varin, “The macrophage in HIV-1 infection: from activation to deactivation?” Retrovirology, vol. 7, article 33, 2010.
[116]
P. J. Ellery, E. Tippett, Y. L. Chiu et al., “The CD16+ monocyte subset is more permissive to infection and preferentially harbors HIV-1 in vivo,” The Journal of Immunology, vol. 178, no. 10, pp. 6581–6589, 2007.
[117]
C. F. Perno, V. Svicher, D. Schols, M. Pollicita, J. Balzarini, and S. Aquaro, “Therapeutic strategies towards HIV-1 infection in macrophages,” Antiviral Research, vol. 71, no. 2-3, pp. 293–300, 2006.
[118]
G. A. Garden, “Microglia in human immunodeficiency virus-associated neurodegeneration,” Glia, vol. 40, no. 2, pp. 240–251, 2002.
[119]
H. Lassmann, M. Schmied, K. Vass, and W. F. Hickey, “Bone marrow derived elements and resident microglia in brain inflammation,” Glia, vol. 7, no. 1, pp. 19–24, 1993.
[120]
L. Gillim-Ross, A. Cara, and M. E. Klotman, “HIV-1 extrachromosomal 2-LTR circular DNA is long-lived in human macrophages,” Viral Immunology, vol. 18, no. 1, pp. 190–196, 2005.
[121]
S. Pang, Y. Koyanagi, S. Miles, C. Wiley, H. V. Vinsters, and I. S. Y. Chen, “High levels of unintegrated HIV-1 DNA in brain tissue of AIDS dementia patients,” Nature, vol. 343, no. 6253, pp. 85–89, 1990.
[122]
D. A. Eckstein, M. P. Sherman, M. L. Penn et al., “HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells,” The Journal of Experimental Medicine, vol. 194, no. 10, pp. 1407–1419, 2001.
[123]
B. Poon and I. S. Y. Chen, “Human immunodeficiency virus type 1 (HIV-1) vpr enhances expression from unintegrated HIV-1 DNA,” Journal of Virology, vol. 77, no. 7, pp. 3962–3972, 2003.
[124]
A. Cara and M. E. Klotman, “Retroviral E-DNA: persistence and gene expression in nondividing immune cells,” Journal of Leukocyte Biology, vol. 80, no. 5, pp. 1013–1017, 2006.
[125]
J. Kelly, M. H. Beddall, D. Yu, S. R. Iyer, J. W. Marsh, and Y. Wu, “Human macrophages support persistent transcription from unintegrated HIV-1 DNA,” Virology, vol. 372, no. 2, pp. 300–312, 2008.
[126]
V. le Douce, G. Herbein, O. Rohr, and C. Schwartz, “Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage,” Retrovirology, vol. 7, article 32, 2010.
[127]
S. Asin, J. A. Taylor, S. Trushin, G. Bren, and C. V. Paya, “Iκκ mediates NF-κB activation in human immunodeficiency virus-infected cells,” Journal of Virology, vol. 73, no. 5, pp. 3893–3903, 1999.
[128]
W. Choe, D. J. Volsky, and M. J. Potash, “Activation of NF-κB by R5 and X4 human immunodeficiency virus type 1 induces macrophage inflammatory protein 1α and tumor necrosis factor alpha in macrophages,” Journal of Virology, vol. 76, no. 10, pp. 5274–5277, 2002.
[129]
G. Herbein and K. A. Khan, “Is HIV infection a TNF receptor signalling-driven disease?” Trends in Immunology, vol. 29, no. 2, pp. 61–67, 2008.
[130]
E. Guillemard, C. Jacquemot, F. Aillet, N. Schmitt, F. Barre-Sinoussi, and N. Israel, “Human immunodeficiency virus 1 favors the persistence of infection by activating macrophages through TNF,” Virology, vol. 329, no. 2, pp. 371–380, 2004.
[131]
B. Lee, M. Sharron, L. J. Montaner, D. Weissman, and R. W. Doms, “Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 9, pp. 5215–5220, 1999.
[132]
J. Lama, A. Mangasarian, and D. Trono, “Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner,” Current Biology, vol. 9, no. 12, pp. 622–631, 1999.
[133]
M. Collin, P. Illei, W. James, and S. Gordon, “Definition of the range and distribution of human immunodeficiency virus macrophage tropism using PCR-based infectivity measurements,” The Journal of General Virology, vol. 75, part 7, pp. 1597–1603, 1994.
[134]
W. A. O'Brien, A. Namazi, H. Kalhor, S. H. Mao, J. A. Zack, and I. S. Y. Chen, “Kinetics of human immunodeficiency virus type 1 reverse transcription in blood mononuclear phagocytes are slowed by limitations of nucleotide precursors,” Journal of Virology, vol. 68, no. 2, pp. 1258–1263, 1994.
[135]
A. I. Spira, P. A. Marx, B. K. Patterson et al., “Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques,” The Journal of Experimental Medicine, vol. 183, no. 1, pp. 215–225, 1996.
[136]
A. Smed-Sorensen, K. Lore, J. Vasudevan et al., “Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells,” Journal of Virology, vol. 79, no. 14, pp. 8861–8869, 2005.
[137]
K. Lore, A. Smed-Sorensen, J. Vasudevan, J. R. Mascola, and R. A. Koup, “Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells,” The Journal of Experimental Medicine, vol. 201, no. 12, pp. 2023–2033, 2005.
[138]
A. T. Haase, K. Henry, M. Zupancic et al., “Quantitative image analysis of HIV-1 infection in lymphoid tissue,” Science, vol. 274, no. 5289, pp. 985–989, 1996.
[139]
M. Otero, G. Nunnari, D. Leto et al., “Peripheral blood dendritic cells are not a major reservoir for HIV type 1 in infected individuals on virally suppressive HAART,” AIDS Research and Human Retroviruses, vol. 19, no. 12, pp. 1097–1103, 2003.
[140]
J. M. Carr, H. S. Ramshaw, P. Li, and C. J. Burrell, “Cd34+ cells and their derivatives contain mRNA for CD4 and human immunodeficiency virus (HIV) co-receptors and are susceptible to infection with M- and T-tropic HIV,” The Journal of General Virology, vol. 79, no. 1, pp. 71–75, 1998.
[141]
A. Aiuti, L. Turchetto, M. Cota et al., “Human CD34+ cells express CXCR4 and its ligand stromal cell-derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus,” Blood, vol. 94, no. 1, pp. 62–73, 1999.
[142]
G. J. Randolph, K. Inaba, D. F. Robbiani, R. M. Steinman, and W. A. Muller, “Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo,” Immunity, vol. 11, no. 6, pp. 753–761, 1999.
[143]
G. J. Randolph, S. Beaulieu, S. Lebecque, R. M. Steinman, and W. A. Muller, “Differentiation of monocytes into dendritic cells in a model of transendothelial trafficking,” Science, vol. 282, no. 5388, pp. 480–483, 1998.
[144]
J. Sprent and C. D. Surh, “Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells,” Nature Immunology, vol. 12, no. 6, pp. 478–484, 2011.
[145]
R. D. Michalek and J. C. Rathmell, “The metabolic life and times of a T-cell,” Immunological Reviews, vol. 236, no. 1, pp. 190–202, 2010.
[146]
M. I. Bukrinsky, N. Sharova, M. P. Dempsey et al., “Active nuclear import of human immunodeficiency virus type 1 preintegration complexes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 14, pp. 6580–6584, 1992.
[147]
S. Swingler, B. Brichacek, J. M. Jacque, C. Ulich, J. Zhou, and M. Stevenson, “HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection,” Nature, vol. 424, no. 6945, pp. 213–219, 2003.
[148]
Y. Wu and J. W. Marsh, “Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA,” Science, vol. 293, no. 5534, pp. 1503–1506, 2001.
[149]
D. Persaud, T. Pierson, C. Ruff et al., “A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children,” The Journal of Clinical Investigation, vol. 105, no. 7, pp. 995–1003, 2000.
[150]
Y. Wu, “Chemokine control of HIV-1 infection: beyond a binding competition,” Retrovirology, vol. 7, article 86, 2010.
[151]
J. A. Zack, S. J. Arrigo, S. R. Weitsman, A. S. Go, A. Haislip, and I. S. Y. Chen, “HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure,” Cell, vol. 61, no. 2, pp. 213–222, 1990.
[152]
T. W. Chun, D. Finzi, J. Margolick, K. Chadwick, D. Schwartz, and R. F. Siliciano, “In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency,” Nature Medicine, vol. 1, no. 12, pp. 1284–1290, 1995.
[153]
T. W. Chun, L. Carruth, D. Finzi et al., “Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection,” Nature, vol. 387, no. 6629, pp. 183–188, 1997.
[154]
J. D. Siliciano, J. Kajdas, D. Finzi et al., “Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells,” Nature Medicine, vol. 9, no. 6, pp. 727–728, 2003.
[155]
D. D. Richman, “Antiviral drug resistance,” Antiviral Research, vol. 71, no. 2-3, pp. 117–121, 2006.
[156]
D. Finzi, J. Blankson, J. D. Siliciano et al., “Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy,” Nature Medicine, vol. 5, no. 5, pp. 512–517, 1999.
[157]
O. Lambotte, K. Deiva, and M. Tardieu, “HIV-1 persistence, viral reservoir, and the central nervous system in the HAART era,” Brain Pathology, vol. 13, no. 1, pp. 95–103, 2003.
[158]
M. Coiras, M. R. Lopez-Huertas, M. Perez-Olmeda, and J. Alcami, “Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs,” Nature Reviews, vol. 7, no. 11, pp. 798–812, 2009.
[159]
L. M. Frenkel, Y. Wang, G. H. Learn et al., “Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy,” Journal of Virology, vol. 77, no. 10, pp. 5721–5730, 2003.
[160]
T. W. Chun, J. S. Justement, S. Moir et al., “Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus,” The Journal of Infectious Diseases, vol. 195, no. 12, pp. 1762–1764, 2007.
[161]
J. B. Dinoso, S. Y. Kim, A. M. Wiegand et al., “Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 23, pp. 9403–9408, 2009.
[162]
R. M. Gulick, J. Lalezari, J. Goodrich et al., “Maraviroc for previously treated patients with R 5 HIV-1 infection,” The New England Journal of Medicine, vol. 359, no. 14, pp. 1429–1441, 2008.
[163]
R. T. Steigbigel, D. A. Cooper, P. N. Kumar et al., “Raltegravir with optimized background therapy for resistant HIV-1 infection,” The New England Journal of Medicine, vol. 359, no. 4, pp. 339–354, 2008.
[164]
D. A. Cooper, R. T. Steigbigel, J. M. Gatell et al., “Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection,” The New England Journal of Medicine, vol. 359, no. 4, pp. 355–365, 2008.
[165]
M. Baba, “Recent status of HIV-1 gene expression inhibitors,” Antiviral Research, vol. 71, no. 2-3, pp. 301–306, 2006.
[166]
A. Gatignol and K. T. Jeang, “Tat as a transcriptional activator and a potential therapeutic target for HIV-1,” Advances in Pharmacology, vol. 48, pp. 209–227, 2000.
[167]
A. Crotti, M. Lusic, R. Lupo et al., “Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression,” Blood, vol. 109, no. 12, pp. 5380–5389, 2007.
[168]
A. Mosoian, A. Teixeira, A. A. High et al., “Novel function of prothymosin alpha as a potent inhibitor of human immunodeficiency virus type 1 gene expression in primary macrophages,” Journal of Virology, vol. 80, no. 18, pp. 9200–9206, 2006.
[169]
S. Ranjbar, A. V. Tsytsykova, S. K. Lee et al., “NFAT5 regulates HIV-1 in primary monocytes via a highly conserved long terminal repeat site.,” PLoS pathogens, vol. 2, no. 12, article e130, 2006.
[170]
R. Jochmann, M. Thurau, S. Jung et al., “O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter,” Journal of Virology, vol. 83, no. 8, pp. 3704–3718, 2009.
[171]
S. R. Eberhardy, J. Goncalves, S. Coelho, D. J. Segal, B. Berkhout, and C. F. Barbas III, “Inhibition of human immunodeficiency virus type 1 replication with artificial transcription factors targeting the highly conserved primer-binding site,” Journal of Virology, vol. 80, no. 6, pp. 2873–2883, 2006.
[172]
P. J. Verschure, A. E. Visser, and M. G. Rots, “Step out of the groove: epigenetic gene control systems and engineered transcription factors,” Advances in Genetics, vol. 56, pp. 163–204, 2006.
[173]
M. Horiba, L. B. Martinez, J. L. Buescher et al., “OTK18, a zinc-finger protein, regulates human immunodeficiency virus type 1 long terminal repeat through two distinct regulatory regions,” The Journal of General Virology, vol. 88, no. 1, pp. 236–241, 2007.
[174]
J. L. Buescher, F. Duan, J. Sun, R. W. Price, and T. Ikezu, “OTK18 levels in plasma and cerebrospinal fluid correlate with viral load and CD8 T-cells in normal and AIDS patients,” Journal of Neuroimmune Pharmacology, vol. 3, no. 4, pp. 230–235, 2008.
[175]
D. R. Kuritzkes, “HIV-1 entry inhibitors: an overview,” Current Opinion in HIV and AIDS, vol. 4, no. 2, pp. 82–87, 2009.
[176]
M. Saag, J. Goodrich, G. Fatkenheuer et al., “A double-blind, placebo-controlled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1,” The Journal of Infectious Diseases, vol. 199, no. 11, pp. 1638–1647, 2009.
[177]
S. Swingler, A. M. Mann, J. Zhou, C. Swingler, and M. Stevenson, “Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein,” PloS Pathogens, vol. 3, no. 9, pp. 1281–1290, 2007.
[178]
P. Chugh, B. Bradel-Tretheway, C. M. R. Monteiro-Filho et al., “Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy,” Retrovirology, vol. 5, article 11, 2008.
[179]
A. Savarino, A. Mai, S. Norelli et al., “‘Shock and kill’ effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence,” Retrovirology, vol. 6, article 52, 2009.
[180]
J. M. Prins, S. Jurriaans, R. M. van Praag, et al., “Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy,” AIDS, vol. 13, no. 17, pp. 2405–2410, 1999.
[181]
H. J. Stellbrink, J. van Lunzen, M. Westby, et al., “Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial),” AIDS, vol. 16, no. 11, pp. 1479–1487, 2002.
[182]
F. X. Wang, Y. Xu, J. Sullivan et al., “IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART,” The Journal of Clinical Investigation, vol. 115, no. 1, pp. 128–137, 2005.
[183]
D. G. Brooks, D. H. Hamer, P. A. Arlen et al., “Molecular characterization, reactivation, and depletion of latent HIV,” Immunity, vol. 19, no. 3, pp. 413–423, 2003.
[184]
H. C. Yang, L. Shen, R. F. Siliciano, and J. L. Pomerantz, “Isolation of a cellular factor that can reactivate latent HIV-1 without T cell activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 15, pp. 6321–6326, 2009.
[185]
G. Lehrman, I. B. Hogue, S. Palmer et al., “Depletion of latent HIV-1 infection in vivo: a proof-of-concept study,” The Lancet, vol. 366, no. 9485, pp. 549–555, 2005.
[186]
N. Sagot-Lerolle, A. Lamine, M. L. Chaix, et al., “Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir,” AIDS, vol. 22, no. 10, pp. 1125–1129, 2008.
[187]
J. D. Siliciano, J. Lai, M. Callender et al., “Stability of the latent reservoir for HIV-1 in patients receiving valproic acid,” The Journal of Infectious Diseases, vol. 195, no. 6, pp. 833–836, 2007.
[188]
J. Rullas, M. Bermejo, J. Garcia-Perez, et al., “Prostratin induces HIV activation and downregulates HIV receptors in peripheral blood lymphocytes,” Antiviral Therapy, vol. 9, no. 4, pp. 545–554, 2004.
[189]
P. A. Wender, J. M. Kee, and J. M. Warrington, “Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV,” Science, vol. 320, no. 5876, pp. 649–652, 2008.
