Long-lived latent HIV-infected cells lead to the rebound of virus replication following antiretroviral treatment interruption and present a major barrier to eliminating HIV infection. These latent reservoirs, which include quiescent memory T cells and tissue-resident macrophages, represent a subset of cells with decreased or inactive proviral transcription. HIV proviral transcription is regulated at multiple levels including transcription initiation, polymerase recruitment, transcription elongation, and chromatin organization. How these biochemical processes are coordinated and their potential role in repressing HIV transcription along with establishing and maintaining latency are reviewed. 1. Introduction A critical step in the HIV life cycle is transcriptional regulation of the integrated provirus. Robust transcription assures that sufficient mRNA and genomic RNA are produced for efficient virus assembly and infectivity. Repression of HIV transcription leads to the establishment of HIV latency, which creates repositories for infectious and drug-resistant viruses that reemerge upon treatment failure or interruption [1–4]. The existence of long-lived stable HIV reservoirs was demonstrated by the rebound of virus replication following highly active antiretroviral therapy (HAART) interruption [5–8]. These latent reservoirs, which include quiescent memory T cells, tissue-resident macrophages [9, 10], and potentially hematopoietic stem cells [11], although this is still controversial [12], represent long-lived subsets of cells with decreased or inactive proviral transcription. In general, studies with chronically and acutely infected cells show that mutations in Tat [13, 14], absence of cellular transcription factors [15–18], miRNA machinery [19, 20], and proviral integration into transcriptionally silent sites contribute to postintegration latency [21, 22]. Although there may not be a common mechanism that promotes HIV latency, it is critical to understand the molecular events that establish and maintain latency if strategies to reduce or purge HIV from latent reservoirs are to be devised [9, 23, 24]. HIV transcription is regulated at multiple levels including transcription initiation, polymerase recruitment, transcriptional elongation, and chromatin organization. How these events are coordinated and their role in HIV latency will be reviewed. In particular, mechanisms that contribute to repressing HIV transcription will be highlighted. 2. LTR and Transcription Factors Although viral accessory proteins, such as Vpr, and putative elements within the HIV
References
[1]
S. G. Deeks, T. Wrin, T. Liegler et al., “Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia,” The New England Journal of Medicine, vol. 344, no. 7, pp. 472–480, 2001.
[2]
A. No？, J. Plum, and C. Verhofstede, “The latent HIV-1 reservoir in patients undergoing HAART: an archive of pre-HAART drug resistance,” Journal of Antimicrobial Chemotherapy, vol. 55, no. 4, pp. 410–412, 2005.
[3]
D. Persaud, T. Pierson, C. Ruff et al., “A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children,” Journal of Clinical Investigation, vol. 105, no. 7, pp. 995–1003, 2000.
[4]
C. T. Ruff, S. C. Ray, P. Kwon et al., “Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure,” Journal of Virology, vol. 76, no. 18, pp. 9481–9492, 2002.
[5]
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.
[6]
T. W. Chun, L. Stuyver, S. B. Mizell et al., “Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 24, pp. 13193–13197, 1997.
[7]
D. Finzi, M. Hermankova, T. Pierson et al., “Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy,” Science, vol. 278, no. 5341, pp. 1295–1300, 1997.
[8]
J. K. Wong, M. Hezareh, H. F. Günthard et al., “Recovery of replication-competent HIV despite prolonged suppression of plasma viremia,” Science, vol. 278, no. 5341, pp. 1291–1295, 1997.
[9]
T. W. Chun and A. S. Fauci, “Latent reservoirs of HIV: obstacles to the eradication of virus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 20, pp. 10958–10961, 1999.
[10]
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.
[11]
C. C. Carter, A. Onafuwa-Nuga, L. A. McNamara et al., “HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs,” Nature Medicine, vol. 16, no. 4, pp. 446–451, 2010.
[12]
C. M. Durand, G. Ghiaur, J. D. Siliciano, et al., “HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy,” The Journal of Infectious Diseases, vol. 205, no. 6, pp. 1014–1018, 2012.
[13]
S. Emiliani, W. Fischle, M. Ott, C. Van Lint, C. A. Amella, and E. Verdin, “Mutations in the tat gene are responsible for human immunodeficiency virus type 1 postintegration latency in the U1 cell line,” Journal of Virology, vol. 72, no. 2, pp. 1666–1670, 1998.
[14]
S. Yukl, S. Pillai, P. Li et al., “Latently-infected CD4+ T cells are enriched for HIV-1 Tat variants with impaired transactivation activity,” Virology, vol. 387, no. 1, pp. 98–108, 2009.
[15]
R. M. van der Sluis, G. Pollakis, M. L. van Gerven, B. Berkhout, and R. E. Jeeninga, “Latency profiles of full length HIV-1 molecular clone variants with a subtype specific promoter,” Retrovirology, vol. 8, p. 73, 2011.
[16]
T. M. Folks, J. Justement, A. Kinter et al., “Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate,” Journal of Immunology, vol. 140, no. 4, pp. 1117–1122, 1988.
[17]
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.
[18]
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.
[19]
A. Narayanan, K. Kehn-Hall, C. Bailey, and F. Kashanchi, “Analysis of the roles of HIV-derived microRNAs,” Expert Opinion on Biological Therapy, vol. 11, no. 1, pp. 17–29, 2011.
[20]
R. Triboulet, B. Mari, Y. L. Lin et al., “Suppression of MicroRNA-silencing pathway by HIV-1 during virus replication,” Science, vol. 315, no. 5818, pp. 1579–1582, 2007.
[21]
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.
[22]
A. Jordan, P. Defechereux, and E. Verdin, “The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation,” The EMBO Journal, vol. 20, no. 7, pp. 1726–1738, 2001.
[23]
R. Pearson, K. K. Young, J. Hokello et al., “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,” Journal of Virology, vol. 82, no. 24, pp. 12291–12303, 2008.
[24]
R. F. Siliciano and W. C. Greene, “HIV latency,” Cold Spring Harbor Perspectives in Medicine, vol. 1, Article ID a007096, 2011.
[25]
M. Kogan and J. Rappaport, “HIV-1 accessory protein Vpr: relevance in the pathogenesis of HIV and potential for therapeutic intervention,” Retrovirology, vol. 8, article 25, 2011.
[26]
M. D. Marsden, B. P. Burke, and J. A. Zack, “HIV latency is influenced by regions of the viral genome outside of the long terminal repeats and regulatory genes,” Virology, vol. 417, pp. 394–399, 2011.
[27]
E. M. Kilareski, S. Shah, M. R. Nonnemacher, and B. Wigdahl, “Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage,” Retrovirology, vol. 6, article 118, 2009.
[28]
L. A. Pereira, K. Bentley, A. Peeters, M. J. Churchill, and N. J. Deacon, “A compilation of cellular transcription factor interactions with the HIV-1 LTR promoter,” Nucleic Acids Research, vol. 28, no. 3, pp. 663–668, 2000.
[29]
O. Rohr, C. Marban, D. Aunis, and E. Schaeffer, “Regulation of HIV-1 gene transcription: from lymphocytes to microglial cells,” Journal of Leukocyte Biology, vol. 74, no. 5, pp. 736–749, 2003.
[30]
Y. Li, G. Mak, and B. R. Franza Jr., “In vitro study of functional involvement of Sp1, NF-κB/Rel, and AP1 in phorbol 12-myristate 13-acetate-mediated HIV-1 long terminal repeat activation,” Journal of Biological Chemistry, vol. 269, no. 48, pp. 30616–30619, 1994.
[31]
B. Majello, P. De Luca, G. Hagen, G. Suske, and L. Lania, “Different members of the Sp1 multigene family exert opposite transcriptional regulation of the long terminal repeat of HIV-1,” Nucleic Acids Research, vol. 22, no. 23, pp. 4914–4921, 1994.
[32]
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.
[33]
F. Canonne-Hergaux, D. Aunis, and E. Schaeffer, “Interactions of the transcription factor AP-1 with the long terminal repeat of different human immunodeficiency virus type 1 strains in Jurkat, glial, and neuronal cells,” Journal of Virology, vol. 69, no. 11, pp. 6634–6642, 1995.
[34]
K. A. Roebuck, S. De Gu, and M. F. Kagnoff, “Activating protein-1 cooperates with phorbol ester activation signals to increase HIV-1 expression,” AIDS, vol. 10, no. 8, pp. 819–826, 1996.
[35]
A. J. Henderson, R. I. Connor, and K. L. Calame, “C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines,” Immunity, vol. 5, no. 1, pp. 91–101, 1996.
[36]
V. M. Tesmer, A. Rajadhyaksha, J. Babin, and M. Bina, “NF-IL6-mediated transcriptional activation of the long terminal repeat of the human immunodeficiency virus type 1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 15, pp. 7298–7302, 1993.
[37]
A. Bosque and V. Planelles, “Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells,” Blood, vol. 113, no. 1, pp. 58–65, 2009.
[38]
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.
[39]
J. F. Fortin, B. Barbeau, G. A. Robichaud, M. è. Paré, A. M. Lemieux, and M. J. Tremblay, “Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat-driven transcription and a possible implication of SHP-1,” Blood, vol. 97, no. 8, pp. 2390–2400, 2001.
[40]
T. A. Lodie, M. Reiner, S. Coniglio, G. Viglianti, and M. J. Fenton, “Both PU.1 and nuclear factor-κB mediate lipopolysaccharide-induced HIV-1 long terminal repeat transcription in macrophages,” Journal of Immunology, vol. 161, no. 1, pp. 268–276, 1998.
[41]
C. Van Lint, J. Ghysdael, P. Paras, A. Burny, and E. Verdin, “A transcriptional regulatory element is associated with a nuclease- hypersensitive site in the pol gene of human immunodeficiency virus type 1,” Journal of Virology, vol. 68, no. 4, pp. 2632–2648, 1994.
[42]
D. Carroll-Anzinger, A. Kumar, V. Adarichev, F. Kashanchi, and L. Al-Harthi, “Human immunodeficiency virus-restricted replication in astrocytes and the ability of gamma interferon to modulate this restriction are regulated by a downstream effector of the Wnt signaling pathway,” Journal of Virology, vol. 81, no. 11, pp. 5864–5871, 2007.
[43]
B. Wortman, N. Darbinian, B. E. Sawaya, K. Khalili, and S. Amini, “Evidence for regulation of long terminal repeat transcription by Wnt transcription factor TCF-4 in human astrocytic cells,” Journal of Virology, vol. 76, no. 21, pp. 11159–11165, 2002.
[44]
J. K. Chan and W. C. Greene, “NF-κB/Rel: agonist and antagonist roles in HIV-1 latency,” Current Opinion in HIV and AIDS, vol. 6, no. 1, pp. 12–18, 2011.
[45]
L. Ylisastigui, R. Kaur, H. Johnson et al., “Mitogen-activated protein kinases regulate LSF occupancy at the human immunodeficiency virus type 1 promoter,” Journal of Virology, vol. 79, no. 10, pp. 5952–5962, 2005.
[46]
F. Romerio, M. N. Gabriel, and D. M. Margolis, “Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF,” Journal of Virology, vol. 71, no. 12, pp. 9375–9382, 1997.
[47]
G. Jiang, A. Espeseth, D. J. Hazuda, and D. M. Margolis, “c-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter,” Journal of Virology, vol. 81, no. 20, pp. 10914–10923, 2007.
[48]
V. B. Cismasiu, E. Paskaleva, S. Suman Daya, M. Canki, K. Duus, and D. Avram, “BCL11B is a general transcriptional repressor of the HIV-1 long terminal repeat in T lymphocytes through recruitment of the NuRD complex,” Virology, vol. 380, no. 2, pp. 173–181, 2008.
[49]
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.
[50]
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.
[51]
T. M. Hanley and G. A. Viglianti, “Nuclear receptor signaling inhibits HIV-1 replication in macrophages through multiple trans-repression mechanisms,” Journal of Virology, vol. 85, no. 20, pp. 10834–10850, 2011.
[52]
D. J. Morrison, P. S. Pendergrast, P. Stavropoulos, S. U. Colmenares, R. Kobayashi, and N. Hernandez, “FBI-1, a factor that binds to the HIV-1 inducer of short transcripts (IST), is a POZ domain protein,” Nucleic Acids Research, vol. 27, no. 5, pp. 1251–1262, 1999.
[53]
E. S. Lee, D. Sarma, H. Zhou, and A. J. Henderson, “CCAAT/enhancer binding proteins are not required for HIV-1 entry but regulate proviral transcription by recruiting coactivators to the long-terminal repeat in monocytic cells,” Virology, vol. 299, no. 1, pp. 20–31, 2002.
[54]
D. M. Margolis, “Histone deacetylase inhibitors and HIV latency,” Current Opinion in HIV and AIDS, vol. 6, no. 1, pp. 25–29, 2011.
[55]
U. Mbonye and J. Karn, “Control of HIV latency by epigenetic and non-epigenetic mechanisms,” Current HIV Research, vol. 9, no. 8, pp. 554–567, 2011.
[56]
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.
[57]
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.
[58]
M. Benkirane, R. F. Chun, H. Xiao et al., “Activation of integrated provirus requires histone acetyltransferase: p300 and P/CAF are coactivators for HIV-1 Tat,” Journal of Biological Chemistry, vol. 273, no. 38, pp. 24898–24905, 1998.
[59]
A. Pumfery, L. Deng, A. Maddukuri et al., “Chromatin remodeling and modification during HIV-1 Tat-activated transcription,” Current HIV Research, vol. 1, no. 3, pp. 343–362, 2003.
[60]
D. J. Steger, A. Eberharter, S. John, P. A. Grant, and J. L. Workman, “Purified histone acetyltransferase complexes stimulate HIV-1 transcription from preassembled nucleosomal arrays,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 22, pp. 12924–12929, 1998.
[61]
E. Agbottah, L. Deng, L. O. Dannenberg, A. Pumfery, and F. Kashanchi, “Effect of SWI/SNF chromatin remodeling complex on HIV-1 Tat activated transcription,” Retrovirology, vol. 3, article 48, 2006.
[62]
R. Easley, L. Carpio, L. Dannenberg et al., “Transcription through the HIV-1 nucleosomes: effects of the PBAF complex in Tat activated transcription,” Virology, vol. 405, no. 2, pp. 322–333, 2010.
[63]
T. Mahmoudi, M. Parra, R. G. J. Vries et al., “The SWI/SNF chromatin-remodeling complex is a cofactor for Tat transactivation of the HIV promoter,” Journal of Biological Chemistry, vol. 281, no. 29, pp. 19960–19968, 2006.
[64]
C. Tréand, I. du Chéné, V. Brès et al., “Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediated activation of the HIV-1 promoter,” The EMBO Journal, vol. 25, no. 8, pp. 1690–1699, 2006.
[65]
P. L. Sheridan, T. P. Mayall, E. Verdin, and K. A. Jones, “Histone acetyltransferases regulate HIV-1 enhancer activity in vitro,” Genes and Development, vol. 11, no. 24, pp. 3327–3340, 1997.
[66]
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.
[67]
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.
[68]
M. G. Izban and D. S. Luse, “Transcription on nucleosomal templates by RNA polymerase II in vitro: inhibition of elongation with enhancement of sequence-specific pausing,” Genes and Development, vol. 5, no. 4, pp. 683–696, 1991.
[69]
J. L. Workman and R. G. Roeder, “Binding of transcription factor TFIID to the major late promoter during in vitro nucleosome assembly potentiates subsequent initiation by RNA polymerase II,” Cell, vol. 51, no. 4, pp. 613–622, 1987.
[70]
K. S. Keedy, N. M. Archin, A. T. Gates, A. Espeseth, D. J. Hazuda, and D. M. Margolis, “A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression,” Journal of Virology, vol. 83, no. 10, pp. 4749–4756, 2009.
[71]
I. D. Chéné, 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.
[72]
J. Friedman, W. K. Cho, C. K. Chu, et al., “Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2,” Journal of Virology, vol. 85, no. 17, pp. 9078–9089, 2011.
[73]
S. E. Kauder, A. Bosque, A. Lindqvist, V. Planelles, and E. Verdin, “Epigenetic regulation of HIV-1 latency by cytosine methylation,” Plos Pathogens, vol. 5, no. 6, Article ID e1000495, 2009.
[74]
F. Bushman, M. Lewinski, A. Ciuffi et al., “Genome-wide analysis of retroviral DNA integration,” Nature Reviews Microbiology, vol. 3, no. 11, pp. 848–858, 2005.
[75]
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.
[76]
M. K. Lewinski, M. Yamashita, M. Emerman et al., “Retroviral DNA integration: viral and cellular determinants of target-site selection,” Plos Pathogens, vol. 2, no. 6, p. e60, 2006.
[77]
A. R. W. Schr？der, P. Shinn, H. Chen, C. Berry, J. R. Ecker, and F. Bushman, “HIV-1 integration in the human genome favors active genes and local hotspots,” Cell, vol. 110, no. 4, pp. 521–529, 2002.
[78]
A. Duverger, J. Jones, J. May et al., “Determinants of the establishment of human immunodeficiency virus type 1 latency,” Journal of Virology, vol. 83, no. 7, pp. 3078–3093, 2009.
[79]
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.
[80]
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.
[81]
H. Liu, E. C. Dow, R. Arora et al., “Integration of human immunodeficiency virus type 1 in untreated infection occurs preferentially within genes,” Journal of Virology, vol. 80, no. 15, pp. 7765–7768, 2006.
[82]
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.
[83]
K. E. Shearwin, B. P. Callen, and J. B. Egan, “Transcriptional interference—a crash course,” Trends in Genetics, vol. 21, no. 6, pp. 339–345, 2005.
[84]
S. Adhya and M. Gottesman, “Promoter occlusion: transcription through a promoter may inhibit its activity,” Cell, vol. 29, no. 3, pp. 939–944, 1982.
[85]
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.
[86]
S. K. Eszterhas, E. E. Bouhassira, D. I. K. Martin, and S. Fiering, “Transcriptional interference by independently regulated genes occurs in any relative arrangement of the genes and is influenced by chromosomal integration position,” Molecular and Cellular Biology, vol. 22, no. 2, pp. 469–479, 2002.
[87]
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.
[88]
S. Petruk, Y. Sedkov, K. M. Riley et al., “Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference,” Cell, vol. 127, no. 6, pp. 1209–1221, 2006.
[89]
E. Gallastegui, B. Marshall, D. Vidal, et al., “Combination of biological screening in a cellular model of viral latency and virtual screening identifies novel compounds that reactivate HIV-1,” Journal of Virology, vol. 86, no. 7, pp. 3795–3808, 2012.
[90]
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.
[91]
J. A. D'Alessio, K. J. Wright, and R. Tjian, “Shifting players and paradigms in cell-specific transcription,” Molecular Cell, vol. 36, no. 6, pp. 924–931, 2009.
[92]
J. M. Espinosa, “Get back TFIIF, don't let me Gdown1,” Molecular Cell, vol. 45, pp. 3–5, 2012.
[93]
M. Jishage, S. Malik, U. Wagner, et al., “Transcriptional regulation by Pol II(G) involving mediator and competitive interactions of Gdown1 and TFIIF with Pol II,” Molecular Cell, vol. 45, pp. 51–63, 2012.
[94]
T. Raha, S. W. Cheng, and M. R. Green, “HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs,” Plos Biology, vol. 3, no. 2, article e44, 2005.
[95]
M. Aida, Y. Chen, K. Nakajima, Y. Yamaguchi, T. Wada, and H. Handa, “Transcriptional pausing caused by NELF plays a dual role in regulating immediate-early expression of the junB gene,” Molecular and Cellular Biology, vol. 26, no. 16, pp. 6094–6104, 2006.
[96]
M. B. Feinberg, D. Baltimore, and A. D. Frankel, “The role of Tat in the human immunodeficiency virus life cycle indicates a primary effect on transcriptional elongation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 9, pp. 4045–4049, 1991.
[97]
S. Y. Kao, A. F. Calman, P. A. Luciw, and B. M. Peterlin, “Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product,” Nature, vol. 330, no. 6147, pp. 489–493, 1987.
[98]
M. F. Laspia, A. P. Rice, and M. B. Mathews, “HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation,” Cell, vol. 59, no. 2, pp. 283–292, 1989.
[99]
J. Lis, “Promoter-associated pausing in promoter architecture and postinitiation transcriptional regulation,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 63, pp. 347–356, 1998.
[100]
R. Landick, “The regulatory roles and mechanism of transcriptional pausing,” Biochemical Society Transactions, vol. 34, no. 6, pp. 1062–1066, 2006.
[101]
M. G. Guenther, S. S. Levine, L. A. Boyer, R. Jaenisch, and R. A. Young, “A chromatin landmark and transcription initiation at most promoters in human cells,” Cell, vol. 130, no. 1, pp. 77–88, 2007.
[102]
T. H. Kim, L. O. Barrera, M. Zheng et al., “A high-resolution map of active promoters in the human genome,” Nature, vol. 436, no. 7052, pp. 876–880, 2005.
[103]
G. W. Muse, D. A. Gilchrist, S. Nechaev et al., “RNA polymerase is poised for activation across the genome,” Nature Genetics, vol. 39, no. 12, pp. 1507–1511, 2007.
[104]
J. Zeitlinger, A. Stark, M. Kellis et al., “RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo,” Nature Genetics, vol. 39, no. 12, pp. 1512–1516, 2007.
[105]
L. J. Core and J. T. Lis, “Transcription regulation through promoter-proximal pausing of RNA polymerase II,” Science, vol. 319, no. 5871, pp. 1791–1792, 2008.
[106]
T. Yamada, Y. Yamaguchi, N. Inukai, S. Okamoto, T. Mura, and H. Handa, “P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation,” Molecular Cell, vol. 21, no. 2, pp. 227–237, 2006.
[107]
Y. Yamaguchi, N. Inukai, T. Narita, T. Wada, and H. Handa, “Evidence that negative elongation factor represses transcription elongation through binding to a DRB sensitivity-inducing factor/RNA polymerase II complex and RNA,” Molecular and Cellular Biology, vol. 22, no. 9, pp. 2918–2927, 2002.
[108]
B. M. Peterlin and D. H. Price, “Controlling the elongation phase of transcription with P-TEFb,” Molecular Cell, vol. 23, no. 3, pp. 297–305, 2006.
[109]
Y. H. Ping, C. Y. Chu, H. Cao, J. M. Jacque, M. Stevenson, and T. M. Rana, “Modulating HIV-1 replication by RNA interference directed against human transcription elongation factor SPT5,” Retrovirology, vol. 1, article 46, 2004.
[110]
Y. H. Ping and T. M. Rana, “DSIF and NELF interact with RNA polymerase II elongation complex and HIV-1 Tat stimulates P-TEFb-mediated phosphorylation of RNA polymerase II and DSIF during transcription elongation,” Journal of Biological Chemistry, vol. 276, no. 16, pp. 12951–12958, 2001.
[111]
T. Wada, T. Takagi, Y. Yamaguchi et al., “DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs,” Genes and Development, vol. 12, no. 3, pp. 343–356, 1998.
[112]
Y. Yamaguchi, T. Takagi, T. Wada et al., “NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation,” Cell, vol. 97, no. 1, pp. 41–51, 1999.
[113]
K. Fujinaga, D. Irwin, Y. Huang, R. Taube, T. Kurosu, and B. M. Peterlin, “Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element,” Molecular and Cellular Biology, vol. 24, no. 2, pp. 787–795, 2004.
[114]
C. H. Wu, Y. Yamaguchi, L. R. Benjamin et al., “NELF and DSIF cause promoter proximal pausing on the hsp70 promoter in Drosophila,” Genes and Development, vol. 17, no. 11, pp. 1402–1414, 2003.
[115]
V. Bres, S. M. Yoh, K. A. Jones, et al., “The multi-tasking P-TEFb complex,” Current Opinion in Cell Biology, vol. 20, pp. 334–340, 2008.
[116]
N. He and Q. Zhou, “New insights into the control of HIV-1 transcription: When tat meets the 7SK snRNP and super elongation complex (SEC),” Journal of Neuroimmune Pharmacology, vol. 6, no. 2, pp. 260–268, 2011.
[117]
Q. Zhou and J. H. N. Yik, “The Yin and Yang of P-TEFb regulation: implications for human immunodeficiency virus gene expression and global control of cell growth and differentiation,” Microbiology and Molecular Biology Reviews, vol. 70, no. 3, pp. 646–659, 2006.
[118]
D. A. Bisgrove, T. Mahmoudi, P. Henklein, and E. Verdin, “Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 34, pp. 13690–13695, 2007.
[119]
K. J. Moon, K. Mochizuki, M. Zhou, H. S. Jeong, J. N. Brady, and K. Ozato, “The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription,” Molecular Cell, vol. 19, no. 4, pp. 523–534, 2005.
[120]
Z. Yang, J. H. N. Yik, R. Chen et al., “Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4,” Molecular Cell, vol. 19, no. 4, pp. 535–545, 2005.
[121]
V. Brès, N. Gomes, L. Pickle, and K. A. Jones, “A human splicing factor, SKIP, associates with P-TEFb and enhances transcription elongation by HIV-1 Tat,” Genes and Development, vol. 19, no. 10, pp. 1211–1226, 2005.
[122]
V. Brès, T. Yoshida, L. Pickle, and K. A. Jones, “SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation,” Molecular Cell, vol. 36, no. 1, pp. 75–87, 2009.
[123]
N. He, C. K. Chan, B. Sobhian, et al., “Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin,” Proceedings of the National Academy of Sciences of the United State, vol. 108, pp. E636–E645, 2011.
[124]
B. Sobhian, N. Laguette, A. Yatim et al., “HIV-1 Tat assembles a multifunctional transcription eongation complex and stably associates with the 7SK snRNP,” Molecular Cell, vol. 38, no. 3, pp. 439–451, 2010.
[125]
T. Ammosova, K. Washington, Z. Debebe, J. Brady, and S. Nekhai, “Dephosphorylation of CDK9 by protein phosphatase 2A and protein phosphatase-I in Tat-activated HIV-I transcription,” Retrovirology, vol. 2, article 47, 2005.
[126]
R. Chen, M. Liu, H. Li et al., “PP2B and PP1α cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling,” Genes and Development, vol. 22, no. 10, pp. 1356–1368, 2008.
[127]
N. Epie, T. Ammosova, W. Turner, and S. Nekhai, “Inhibition of PP2A by LIS1 increases HIV-1 gene expression,” Retrovirology, vol. 3, article 65, 2006.
[128]
S. Nekhai, M. Jerebtsova, A. Jackson, and W. Southerland, “Regulation of HIV-1 transcription by protein phosphatase 1,” Current HIV Research, vol. 5, no. 1, pp. 3–9, 2007.
[129]
Y. Wang, E. C. Dow, Y. Y. Liang et al., “Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop,” Journal of Biological Chemistry, vol. 283, no. 48, pp. 33578–33584, 2008.
[130]
T. L. Sung and A. P. Rice, “miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1,” Plos Pathogens, vol. 5, no. 1, Article ID e1000263, 2009.
[131]
Z. Zhang, A. Klatt, D. S. Gilmour, and A. J. Henderson, “Negative elongation factor NELF represses human immunodeficiency virus transcription by pausing the RNA polymerase II complex,” Journal of Biological Chemistry, vol. 282, no. 23, pp. 16981–16988, 2007.
[132]
J. N. Rao, L. Neumann, S. Wenzel, K. Schweimer, P. R？sch, and B. M. W？hrl, “Structural studies on the RNA-recognition motif of NELF E, a cellular negative transcription elongation factor involved in the regulation of HIV transcription,” Biochemical Journal, vol. 400, no. 3, pp. 449–456, 2006.
[133]
R. A. Marciniak and P. A. Sharp, “HIV-1 Tat protein promotes formation of more-processive elongation complexes,” The EMBO Journal, vol. 10, no. 13, pp. 4189–4196, 1991.
[134]
Y. Jiang, M. Liu, C. A. Spencer, and D. H. Price, “Involvement of transcription termination factor 2 in mitotic repression of transcription elongation,” Molecular Cell, vol. 14, no. 3, pp. 375–385, 2004.
[135]
S. Buratowski, “Connections between mRNA 3′ end processing and transcription termination,” Current Opinion in Cell Biology, vol. 17, no. 3, pp. 257–261, 2005.
[136]
E. Rosonina, S. Kaneko, and J. L. Manley, “Terminating the transcript: breaking up is hard to do,” Genes and Development, vol. 20, no. 9, pp. 1050–1056, 2006.
[137]
S. West and N. J. Proudfoot, “Human Pcf11 enhances degradation of RNA polymerase II-associated nascent RNA and transcriptional termination,” Nucleic Acids Research, vol. 36, no. 3, pp. 905–914, 2008.
[138]
C. Zhang, K. L. Zobeck, and Z. F. Burton, “Human RNA polymerase II elongation in slow motion: role of the TFIIF RAP74 α1 helix in nucleoside triphosphate-driven translocation,” Molecular and Cellular Biology, vol. 25, no. 9, pp. 3583–3595, 2005.
[139]
Z. Zhang and D. S. Gilmour, “Pcf11 is a termination factor in Drosophila that dismantles the elongation complex by bridging the CTD of RNA polymerase II to the nascent transcript,” Molecular Cell, vol. 21, no. 1, pp. 65–74, 2006.
[140]
Z. Zhang, A. Klatt, A. J. Henderson, and D. S. Gilmour, “Transcription termination factor Pcf11 limits the processivity of Pol II on an HIV provirus to repress gene expression,” Genes and Development, vol. 21, no. 13, pp. 1609–1614, 2007.
[141]
P. Wei, M. E. Garber, S. M. Fang, W. H. Fischer, and K. A. Jones, “A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA,” Cell, vol. 92, no. 4, pp. 451–462, 1998.
[142]
A. Henderson, A. Holloway, R. Reeves, and D. J. Tremethick, “Recruitment of SWI/SNF to the human immunodeficiency virus type 1 promoter,” Molecular and Cellular Biology, vol. 24, no. 1, pp. 389–397, 2004.
[143]
M. Ott, M. Geyer, and Q. Zhou, “The control of HIV transcription: keeping RNA polymerase II on track,” Cell Host & Microbe, vol. 10, pp. 426–435, 2011.
[144]
L. S. Weinberger, J. C. Burnett, J. E. Toettcher, A. P. Arkin, and D. V. Schaffer, “Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity,” Cell, vol. 122, no. 2, pp. 169–182, 2005.
[145]
C. Hetzer, W. Dormeyer, M. Schn？lzer, and M. Ott, “Decoding Tat: the biology of HIV Tat posttranslational modifications,” Microbes and Infection, vol. 7, no. 13, pp. 1364–1369, 2005.
[146]
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,” Journal of Biological Chemistry, vol. 276, no. 30, pp. 28179–28184, 2001.
[147]
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.
[148]
M. Ott, M. Schn？lzer, J. Garnica et al., “Acetylation of the HIV-1 tat protein by p300 is important for its transcriptional activity,” Current Biology, vol. 9, no. 24, pp. 1489–1492, 1999.
[149]
S. Pagans, A. Pedal, B. J. North et al., “SIRT1 regulates HIV transcription via Tat deacetylation,” Plos Biology, vol. 3, no. 2, article 41, 2005.
[150]
N. Sakane, H. S. Kwon, S. Pagans, et al., “Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1),” PLoS Pathogens, vol. 7, no. 8, Article ID e1002184, 2011.
[151]
K. A. Clouse, D. Powell, I. Washington et al., “Monokine regulation of human immunodeficiency virus-1 expression in a chronically infected human T cell clone,” Journal of Immunology, vol. 142, no. 2, pp. 431–438, 1989.
[152]
D. G. Brooks, P. A. Arlen, L. Gao, C. M. R. Kitchen, and J. A. Zack, “Identification of T cell-signaling pathways that stimulate latent HIV in primary cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 22, pp. 12955–12960, 2003.
[153]
H. C. Yang, S. Xing, L. Shan et al., “Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation,” Journal of Clinical Investigation, vol. 119, no. 11, pp. 3473–3486, 2009.
[154]
V. Planelles, F. Wolschendorf, and O. Kutsch, “Facts and fiction: cellular models for high throughput screening for HIV-1 reactivating drugs,” Current HIV Research, vol. 9, no. 8, pp. 568–578, 2011.
[155]
D. Demonté, V. Quivy, Y. Colette, and C. Van Lint, “Administration of HDAC inhibitors to reactivate HIV-1 expression in latent cellular reservoirs: Implications for the development of therapeutic strategies,” Biochemical Pharmacology, vol. 68, no. 6, pp. 1231–1238, 2004.
[156]
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.
[157]
J. P. Routy, “Valproic acid: a potential role in treating latent HIV infection,” The Lancet, vol. 366, no. 9485, pp. 523–524, 2005.
[158]
L. Ylisastigui, N. M. Archin, G. Lehrman, R. J. Bosch, and D. M. Margolis, “Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression,” AIDS, vol. 18, no. 8, pp. 1101–1108, 2004.
[159]
N. M. Archin, M. Cheema, D. Parker et al., “Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection,” Plos ONE, vol. 5, no. 2, Article ID e9390, 2010.
[160]
N. M. Archin, J. J. Eron, S. Palmer et al., “Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells,” AIDS, vol. 22, no. 10, pp. 1131–1135, 2008.
[161]
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.
[162]
J. D. Siliciano, J. Lai, M. Callender et al., “Stability of the latent reservoir for HIV-1 in patients receiving valproic acid,” Journal of Infectious Diseases, vol. 195, no. 6, pp. 833–836, 2007.
[163]
A. Steel, S. Clark, I. Teo et al., “No change to HIV-1 latency with valproate therapy,” AIDS, vol. 20, no. 12, pp. 1681–1682, 2006.
[164]
N. M. Archin, K. S. Keedy, A. Espeseth, H. Dang, D. J. Hazuda, and D. M. Margolis, “Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors,” AIDS, vol. 23, no. 14, pp. 1799–1806, 2009.
[165]
X. Contreras, M. Schweneker, C. S. Chen et al., “Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells,” Journal of Biological Chemistry, vol. 284, no. 11, pp. 6782–6789, 2009.
[166]
W. Bernhard, K. Barreto, A. Saunders, M. S. Dahabieh, P. Johnson, and I. Sadowski, “The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response,” FEBS Letters, vol. 585, no. 22, pp. 3549–3554, 2011.
