Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of nascent viral transcripts. P-TEFb exists in multiple complexes in cells, and its core consists of a kinase, Cdk9, and a regulatory subunit, either Cyclin T1 or Cyclin T2. Tat binds directly to Cyclin T1 and thereby targets the Cyclin T1/P-TEFb complex that phosphorylates the CTD of RNA polymerase II and the negative factors that inhibit elongation, resulting in efficient transcriptional elongation. P-TEFb is tightly regulated in cells infected by HIV-1—CD4 + T lymphocytes and monocytes/macrophages. A number of mechanisms have been identified that inhibit P-TEFb in resting CD4 + T lymphocytes and monocytes, including miRNAs that repress Cyclin T1 protein expression and dephosphorylation of residue Thr186 in the Cdk9 T-loop. These repressive mechanisms are overcome upon T cell activation and macrophage differentiation when the permissivity for HIV-1 replication is greatly increased. This review will summarize what is currently known about mechanisms that regulate P-TEFb and how this regulation impacts HIV-1 replication and latency.
References
[1]
van Driel, R.; Verschure, P.J. Nuclear Organization and Gene Expression: Visualization of Transcription and Higher Order Chromatin Structure; INSERM: Paris, France, 2001.
Core, L.J.; Lis, J.T. Transcription regulation through promoter-proximal pausing of RNA polymerase II. Science 2008, 319, 1791–1792, doi:10.1126/science.1150843.
[4]
Hargreaves, D.C.; Horng, T.; Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 2009, 138, 129–145, doi:10.1016/j.cell.2009.05.047.
[5]
Sikorski, T.W.; Buratowski, S. The basal initiation machinery: Beyond the general transcription factors. Curr. Opin. Cell Biol. 2009, 21, 344–351, doi:10.1016/j.ceb.2009.03.006.
[6]
Boeing, S.; Rigault, C.; Heidemann, M.; Eick, D.; Meisterernst, M. RNA polymerase II C-terminal heptarepeat domain Ser-7 phosphorylation is established in a mediator-dependent fashion. J. Biol. Chem. 2010, 285, 188–196, doi:10.1074/jbc.M109.046565. 19901026
[7]
Hirose, Y.; Ohkuma, Y. Phosphorylation of the C-terminal domain of RNA polymerase II plays central roles in the integrated events of eucaryotic gene expression. J. Biochem. 2007, 141, 601–608, doi:10.1093/jb/mvm090.
[8]
Kim, H.; Erickson, B.; Luo, W.; Seward, D.; Graber, J.H.; Pollock, D.D.; Megee, P.C.; Bentley, D.L. Gene-specific RNA polymerase II phosphorylation and the CTD code. Nat. Struct. Mol. Biol. 2010, 17, 1279–1286, doi:10.1038/nsmb.1913. 20835241
[9]
Guenther, M.G.; Levine, S.S.; Boyer, L.A.; Jaenisch, R.; Young, R.A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 2007, 130, 77–88, doi:10.1016/j.cell.2007.05.042.
[10]
Nechaev, S.; Fargo, D.C.; dos Santos, G.; Liu, L.; Gao, Y.; Adelman, K. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 2010, 327, 335–338, doi:10.1126/science.1181421. 20007866
[11]
Nechaev, S.; Adelman, K. Pol II waiting in the starting gates: Regulating the transition from transcription initiation into productive elongation. Biochim. Biophys. Acta 1809, 34–45.
[12]
Glover-Cutter, K.; Larochelle, S.; Erickson, B.; Zhang, C.; Shokat, K.; Fisher, R.P.; Bentley, D.L. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol. Cell Biol. 2009, 29, 5455–5464, doi:10.1128/MCB.00637-09.
[13]
Chen, H.; Contreras, X.; Yamaguchi, Y.; Handa, H.; Peterlin, B.M.; Guo, S. Repression of RNA polymerase II elongation in vivo is critically dependent on the C-terminus of Spt5. PLoS One 2009, 4, e6918, doi:10.1371/journal.pone.0006918. 19742326
[14]
Fujita, T.; Piuz, I.; Schlegel, W. The transcription elongation factors NELF, DSIF and P-TEFb control constitutive transcription in a gene-specific manner. FEBS Lett. 2009, 583, 2893–2898, doi:10.1016/j.febslet.2009.07.050.
[15]
Yamada, T.; Yamaguchi, Y.; Inukai, N.; Okamoto, S.; Mura, T.; Handa, H. P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation. Mol. Cell 2006, 21, 227–237, doi:10.1016/j.molcel.2005.11.024.
[16]
Fujinaga, K.; Irwin, D.; Huang, Y.; Taube, R.; Kurosu, T.; Peterlin, B.M. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol. Cell Biol. 2004, 24, 787–795, doi:10.1128/MCB.24.2.787-795.2004. 14701750
[17]
Karn, J.; Stoltzfus, C.M. Transcriptional and posttranscriptional regulation of Hiv-1 gene expression. Cold Spring Harb. Perspect. Med. 2012, 2, a006916. 22355797
Lin, C.; Smith, E.R.; Takahashi, H.; Lai, K.C.; Martin-Brown, S.; Florens, L.; Washburn, M.P.; Conaway, J.W.; Conaway, R.C.; Shilatifard, A. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol. Cell 2010, 37, 429–437, doi:10.1016/j.molcel.2010.01.026.
[20]
Bres, V.; Gomes, N.; Pickle, L.; Jones, K.A. A human splicing factor, SKIP, associates with P-TEFb and enhances transcription elongation by HIV-1 Tat. Genes. Dev. 2005, 19, 1211–1226, doi:10.1101/gad.1291705.
[21]
Ardehali, M.B.; Lis, J.T. Tracking rates of transcription and splicing in vivo. Nat. Struct. Mol. Biol. 2009, 16, 1123–1124, doi:10.1038/nsmb1109-1123.
[22]
Maiuri, P.; Knezevich, A.; de Marco, A.; Mazza, D.; Kula, A.; McNally, J.G.; Marcello, A. Fast transcription rates of RNA polymerase II in human cells. EMBO Rep. 2011, 12, 1280–1285, doi:10.1038/embor.2011.196.
Shuman, S. Structure, mechanism, and evolution of the mRNA capping apparatus. Prog. Nucleic Acid. Res. Mol. Biol. 2001, 66, 1–40, doi:10.1016/S0079-6603(00)66025-7.
[25]
Cho, E.J.; Takagi, T.; Moore, C.R.; Buratowski, S. mRNA capping enzyme is recruited to the transcription complex by phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes. Dev. 1997, 11, 3319–3326, doi:10.1101/gad.11.24.3319.
Das, R.; Yu, J.; Zhang, Z.; Gygi, M.P.; Krainer, A.R.; Gygi, S.P.; Reed, R. SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol. Cell 2007, 26, 867–881, doi:10.1016/j.molcel.2007.05.036.
[28]
Mortillaro, M.J.; Blencowe, B.J.; Wei, X.; Nakayasu, H.; Du, L.; Warren, S.L.; Sharp, P.A.; Berezney, R. A hyperphosphorylated form of the large subunit of RNA polymerase II is associated with splicing complexes and the nuclear matrix. Proc. Natl. Acad. Sci. USA 1996, 93, 8253–8257, doi:10.1073/pnas.93.16.8253. 8710856
[29]
Yuryev, A.; Patturajan, M.; Litingtung, Y.; Joshi, R.V.; Gentile, C.; Gebara, M.; Corden, J.L. The C-terminal domain of the largest subunit of RNA polymerase II interacts with a novel set of serine/arginine-rich proteins. Proc. Natl. Acad. Sci. USA 1996, 93, 6975–6980, doi:10.1073/pnas.93.14.6975. 8692929
[30]
Barboric, M.; Lenasi, T.; Chen, H.; Johansen, E.B.; Guo, S.; Peterlin, B.M. 7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development. Proc. Natl. Acad. Sci. USA 2009, 106, 7798–7803, doi:10.1073/pnas.0903188106. 19416841
[31]
Kao, S.Y.; Calman, A.F.; Luciw, P.A.; Peterlin, B.M. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature 1987, 330, 489–493, doi:10.1038/330489a0.
[32]
Herrmann, C.H.; Gold, M.O.; Rice, A.P. Viral transactivators specifically target distinct cellular protein kinases that phosphorylate the RNA polymerase II C-terminal domain. Nucleic Acids Res. 1996, 24, 501–508, doi:10.1093/nar/24.3.501.
[33]
Herrmann, C.H.; Rice, A.P. Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: Candidate for a Tat cofactor. J. Virol. 1995, 69, 1612–1620. 7853496
[34]
Marshall, N.F.; Price, D.H. Control of formation of two distinct classes of RNA polymerase II elongation complexes. Mol. Cell Biol. 1992, 12, 2078–2090. 1569941
[35]
Marshall, N.F.; Peng, J.; Xie, Z.; Price, D.H. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J. Biol. Chem. 1996, 271, 27176–27183, doi:10.1074/jbc.271.43.27176. 8900211
[36]
Yang, X.; Gold, M.O.; Tang, D.N.; Lewis, D.E.; Aguilar-Cordova, E.; Rice, A.P.; Herrmann, C.H. TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. Proc. Natl. Acad. Sci. USA 1997, 94, 12331–12336, doi:10.1073/pnas.94.23.12331. 9356449
[37]
Zhu, Y.; Pe’ery, T.; Peng, J.; Ramanathan, Y.; Marshall, N.; Marshall, T.; Amendt, B.; Mathews, M.B.; Price, D.H. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev. 1997, 11, 2622–2632, doi:10.1101/gad.11.20.2622.
[38]
Marshall, N.F.; Price, D.H. Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J. Biol. Chem. 1995, 270, 12335–12338, doi:10.1074/jbc.270.21.12335.
[39]
Wei, P.; Garber, M.E.; Fang, S.M.; Fischer, W.H.; Jones, K.A. 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 1998, 92, 451–462, doi:10.1016/S0092-8674(00)80939-3.
[40]
Garber, M.E.; Wei, P.; KewalRamani, V.N.; Mayall, T.P.; Herrmann, C.H.; Rice, A.P.; Littman, D.R.; Jones, K.A. The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein. Genes Dev. 1998, 12, 3512–3527, doi:10.1101/gad.12.22.3512.
[41]
Bieniasz, P.D.; Grdina, T.A.; Bogerd, H.P.; Cullen, B.R. Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat. EMBO J. 1998, 17, 7056–7065, doi:10.1093/emboj/17.23.7056.
[42]
Kwak, Y.T.; Ivanov, D.; Guo, J.; Nee, E.; Gaynor, R.B. Role of the human and murine cyclin T proteins in regulating HIV-1 tat-activation. J. Mol. Biol. 1999, 288, 57–69, doi:10.1006/jmbi.1999.2664.
[43]
Albrecht, T.R.; Lund, L.H.; Garcia-Blanco, M.A. Canine cyclin T1 rescues equine infectious anemia virus tat trans-activation in human cells. Virology 2000, 268, 7–11, doi:10.1006/viro.1999.0141.
[44]
Bieniasz, P.D.; Grdina, T.A.; Bogerd, H.P.; Cullen, B.R. Highly divergent lentiviral Tat proteins activate viral gene expression by a common mechanism. Mol. Cell Biol. 1999, 19, 4592–4599. 10373508
[45]
Korin, Y.D.; Zack, J.A. Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0 lymphocytes. J. Virol. 1999, 73, 6526–6532. 10400748
[46]
Bukrinsky, M.I.; Sharova, N.; Dempsey, M.P.; Stanwick, T.L.; Bukrinskaya, A.G.; Haggerty, S.; Stevenson, M. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc. Natl. Acad. Sci. USA 1992, 89, 6580–6584, doi:10.1073/pnas.89.14.6580. 1631159
[47]
Lassen, K.G.; Bailey, J.R.; Siliciano, R.F. Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J. Virol. 2004, 78, 9105–9114, doi:10.1128/JVI.78.17.9105-9114.2004.
[48]
Nabel, G.; Baltimore, D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 1987, 326, 711–713, doi:10.1038/326711a0.
[49]
Tong-Starksen, S.E.; Luciw, P.A.; Peterlin, B.M. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc. Natl. Acad. Sci. USA 1987, 84, 6845–6849, doi:10.1073/pnas.84.19.6845.
[50]
Lassen, K.G.; Ramyar, K.X.; Bailey, J.R.; Zhou, Y.; Siliciano, R.F. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog. 2006, 2, e68, doi:10.1371/journal.ppat.0020068.
[51]
Tamaru, H. Confining euchromatin/heterochromatin territory: Jumonji crosses the line. Genes. Dev. 2010, 24, 1465–1478, doi:10.1101/gad.1941010.
[52]
Herrmann, C.H.; Carroll, R.G.; Wei, P.; Jones, K.A.; Rice, A.P. Tat-associated kinase, TAK, activity is regulated by distinct mechanisms in peripheral blood lymphocytes and promonocytic cell lines. J. Virol. 1998, 72, 9881–9888. 9811724
[53]
Liu, H.; Rice, A.P. Genomic organization and characterization of promoter function of the human CDK9 gene. Gene 2000, 252, 51–59, doi:10.1016/S0378-1119(00)00215-8.
[54]
Shore, S.M.; Byers, S.A.; Maury, W.; Price, D.H. Identification of a novel isoform of Cdk9. Gene 2003, 307, 175–182, doi:10.1016/S0378-1119(03)00466-9.
[55]
Herrmann, C.H.; Mancini, M.A. The Cdk9 and cyclin T subunits of TAK/P-TEFb localize to splicing factor-rich nuclear speckle regions. J. Cell Sci. 2001, 114, 1491–1503. 11282025
[56]
Pendergrast, P.S.; Wang, C.; Hernandez, N.; Huang, S. FBI-1 can stimulate HIV-1 Tat activity and is targeted to a novel subnuclear domain that includes the Tat-P-TEFb-containing nuclear speckles. Mol. Biol. Cell 2002, 13, 915–929, doi:10.1091/mbc.01-08-0383.
[57]
Liu, H.; Herrmann, C.H. Differential localization and expression of the Cdk9 42k and 55k isoforms. J. Cell Physiol. 2005, 203, 251–260, doi:10.1002/jcp.20224.
[58]
Ghose, R.; Liou, L.Y.; Herrmann, C.H.; Rice, A.P. Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. J. Virol. 2001, 75, 11336–11343, doi:10.1128/JVI.75.23.11336-11343.2001.
[59]
Chen, R.; Yang, Z.; Zhou, Q. Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA. J. Biol. Chem. 2004, 279, 4153–4160. 14627702
[60]
Baumli, S.; Lolli, G.; Lowe, E.D.; Troiani, S.; Rusconi, L.; Bullock, A.N.; Debreczeni, J.E.; Knapp, S.; Johnson, L.N. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J. 2008, 27, 1907–1918, doi:10.1038/emboj.2008.121.
[61]
Barboric, M.; Zhang, F.; Besenicar, M.; Plemenitas, A.; Peterlin, B.M. Ubiquitylation of Cdk9 by Skp2 facilitates optimal Tat transactivation. J. Virol. 2005, 79, 11135–11141, doi:10.1128/JVI.79.17.11135-11141.2005.
[62]
Sabo, A.; Lusic, M.; Cereseto, A.; Giacca, M. Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription. Mol. Cell Biol. 2008, 28, 2201–2212, doi:10.1128/MCB.01557-07.
Pavletich, N.P. Mechanisms of cyclin-dependent kinase regulation: Structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol. 1999, 287, 821–828, doi:10.1006/jmbi.1999.2640.
[65]
Li, Q.; Price, J.P.; Byers, S.A.; Cheng, D.; Peng, J.; Price, D.H. Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. J. Biol. Chem. 2005, 280, 28819–28826, doi:10.1074/jbc.M502712200. 15965233
[66]
Wang, Y.; Dow, E.C.; Liang, Y.Y.; Ramakrishnan, R.; Liu, H.; Sung, T.L.; Lin, X.; Rice, A.P. Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop. J. Biol. Chem. 2008, 283, 33578–33584, doi:10.1074/jbc.M807495200. 18829461
[67]
Ramakrishnan, R.; Dow, E.C.; Rice, A.P. Characterization of Cdk9 T-loop phosphorylation in resting and activated CD4(+) T lymphocytes. J. Leukoc. Biol. 2009, 86, 1345–1350, doi:10.1189/jlb.0509309.
[68]
Dong, C.; Kwas, C.; Wu, L. Transcriptional restriction of human immunodeficiency virus type 1 gene expression in undifferentiated primary monocytes. J. Virol. 2009, 83, 3518–3527, doi:10.1128/JVI.02665-08.
[69]
Ramakrishnan, R.; Rice, A.P. Cdk9 T-loop phosphorylation is regulated by the calcium signaling pathway. J. Cell Physiol. 2012, 227, 609–617, doi:10.1002/jcp.22760.
[70]
Ammosova, T.; Obukhov, Y.; Kotelkin, A.; Breuer, D.; Beullens, M.; Gordeuk, V.R.; Bollen, M.; Nekhai, S. Protein phosphatase-1 activates CDK9 by dephosphorylating Ser175. PLoS One 2011, 6, e18985, doi:10.1371/journal.pone.0018985. 21533037
[71]
Chen, R.; Liu, M.; Li, H.; Xue, Y.; Ramey, W.N.; He, N.; Ai, N.; Luo, H.; Zhu, Y.; Zhou, N.; Zhou, Q. PP2B and PP1{alpha} cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling. Genes Dev. 2008, 22, 1356–1368, doi:10.1101/gad.1636008.
[72]
Ammosova, T.; Yedavalli, V.R.; Niu, X.; Jerebtsova, M.; van Eynde, A.; Beullens, M.; Bollen, M.; Jeang, K.T.; Nekhai, S. Expression of a protein phosphatase 1 inhibitor, cdNIPP1, increases CDK9 threonine 186 phosphorylation and inhibits HIV-1 transcription. J. Biol. Chem. 2011, 286, 3798–3804, doi:10.1074/jbc.M110.196493. 21098020
[73]
Li, Q.; Cooper, J.J.; Altwerger, G.H.; Feldkamp, M.D.; Shea, M.A.; Price, D.H. HEXIM1 is a promiscuous double-stranded RNA-binding protein and interacts with RNAs in addition to 7SK in cultured cells. Nucleic Acids Res. 2007, 35, 2503–2512, doi:10.1093/nar/gkm150. 17395637
[74]
Chen, H.; Li, C.; Huang, J.; Cung, T.; Seiss, K.; Beamon, J.; Carrington, M.F.; Porter, L.C.; Burke, P.S.; Yang, Y.; et al. CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21. J. Clin. Invest. 2011, 121, 1549–1560, doi:10.1172/JCI44539. 21403397
[75]
Ammosova, T.; Berro, R.; Jerebtsova, M.; Jackson, A.; Charles, S.; Klase, Z.; Southerland, W.; Gordeuk, V.R.; Kashanchi, F.; Nekhai, S. Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription. Retrovirology 2006, 3, 78, doi:10.1186/1742-4690-3-78.
[76]
Debebe, Z.; Ammosova, T.; Breuer, D.; Lovejoy, D.B.; Kalinowski, D.S.; Kumar, K.; Jerebtsova, M.; Ray, P.; Kashanchi, F.; Gordeuk, V.R.; et al. Iron chelators of the di-2-pyridylketone thiosemicarbazone and 2-benzoylpyridine thiosemicarbazone series inhibit HIV-1 transcription: Identification of novel cellular targets--iron, cyclin-dependent kinase (CDK) 2, and CDK9. Mol. Pharmacol. 2011, 79, 185–196, doi:10.1124/mol.110.069062.
[77]
Stewart, Z.A.; Leach, S.D.; Pietenpol, J.A. p21(Waf1/Cip1) inhibition of cyclin E/Cdk2 activity prevents endoreduplication after mitotic spindle disruption. Mol. Cell Biol. 1999, 19, 205–215. 9858545
[78]
Liou, L.Y.; Herrmann, C.H.; Rice, A.P. Transient induction of cyclin T1 during human macrophage differentiation regulates human immunodeficiency virus type 1 Tat transactivation function. J. Virol. 2002, 76, 10579–10587, doi:10.1128/JVI.76.21.10579-10587.2002.
[79]
Liou, L.Y.; Herrmann, C.H.; Rice, A.P. HIV-1 infection and regulation of Tat function in macrophages. Int. J. Biochem. Cell Biol. 2004, 36, 1767–1775, doi:10.1016/j.biocel.2004.02.018.
[80]
Rechsteiner, M.; Rogers, S.W. PEST sequences and regulation by proteolysis. Trends Biochem. Sci. 1996, 21, 267–271. 8755249
[81]
Kurosu, T.; Peterlin, B.M. VP16 and ubiquitin; binding of P-TEFb via its activation domain and ubiquitin facilitates elongation of transcription of target genes. Curr. Biol. 2004, 14, 1112–1116, doi:10.1016/j.cub.2004.06.020.
[82]
Chiang, K.; Sung, T.L.; Rice, A.P. Regulation of cyclin T1 and HIV-1 Replication by microRNAs in resting CD4+ T lymphocytes. J. Virol. 2012, 86, 3244–3252, doi:10.1128/JVI.05065-11.
[83]
Sung, T.L.; Rice, A.P. miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1. PLoS Pathog. 2009, 5, e1000263, doi:10.1371/journal.ppat.1000263.
[84]
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.
Hoque, M.; Shamanna, R.A.; Guan, D.; Pe’ery, T.; Mathews, M.B. HIV-1 replication and latency are regulated by translational control of cyclin T1. J. Mol. Biol. 2011, 410, 917–932, doi:10.1016/j.jmb.2011.03.060.
[87]
Agbottah, E.T.; Traviss, C.; McArdle, J.; Karki, S.; St Laurent, G.C., 3rd; Kumar, A. Nuclear Factor 90(NF90) targeted to TAR RNA inhibits transcriptional activation of HIV-1. Retrovirology 2007, 4, 41, doi:10.1186/1742-4690-4-41.
[88]
Sung, T.L.; Rice, A.P. Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4+ T cells. Retrovirology 2006, 3, 66, doi:10.1186/1742-4690-3-66.
[89]
Ramakrishnan, R.; Yu, W.; Rice, A.P. Limited redundancy in genes regulated by Cyclin T2 and Cyclin T1. BMC Res. Notes 2011, 4, 260, doi:10.1186/1756-0500-4-260.
[90]
Yu, W.; Ramakrishnan, R.; Wang, Y.; Chiang, K.; Sung, T.L.; Rice, A.P. Cyclin T1-dependent genes in activated CD4 T and macrophage cell lines appear enriched in HIV-1 co-factors. PLoS One 2008, 3, e3146, doi:10.1371/journal.pone.0003146. 18773076
[91]
Yu, W.; Wang, Y.; Shaw, C.A.; Qin, X.F.; Rice, A.P. Induction of the HIV-1 Tat co-factor cyclin T1 during monocyte differentiation is required for the regulated expression of a large portion of cellular mRNAs. Retrovirology 2006, 3, 32, doi:10.1186/1742-4690-3-32.
de Luca, A.; Tosolini, A.; Russo, P.; Severino, A.; Baldi, A.; de Luca, L.; Cavallotti, I.; Baldi, F.; Giordano, A.; Testa, J.R.; Paggi, M.G. Cyclin T2a gene maps on human chromosome 2q21. J. Histochem. Cytochem. 2001, 49, 693–698, doi:10.1177/002215540104900603.
[94]
de Luca, A.; de Falco, M.; Baldi, A.; Paggi, M.G. Cyclin T: Three forms for different roles in physiological and pathological functions. J. Cell Physiol. 2003, 194, 101–107, doi:10.1002/jcp.10196.
[95]
Choo, S.; Schroeder, S.; Ott, M. CYCLINg through transcription: Posttranslational modifications of P-TEFb regulate transcription elongation. Cell Cycle 2010, 9, 1697–1705, doi:10.4161/cc.9.9.11346.
[96]
Michels, A.A.; Nguyen, V.T.; Fraldi, A.; Labas, V.; Edwards, M.; Bonnet, F.; Lania, L.; Bensaude, O. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol. Cell Biol. 2003, 23, 4859–4869, doi:10.1128/MCB.23.14.4859-4869.2003.
[97]
Nguyen, V.T.; Kiss, T.; Michels, A.A.; Bensaude, O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 2001, 414, 322–325, doi:10.1038/35104581.
[98]
Yik, J.H.; Chen, R.; Nishimura, R.; Jennings, J.L.; Link, A.J.; Zhou, Q. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Mol. Cell 2003, 12, 971–982, doi:10.1016/S1097-2765(03)00388-5.
[99]
Jang, M.K.; Mochizuki, K.; Zhou, M.; Jeong, H.S.; Brady, J.N.; Ozato, K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 2005, 19, 523–534, doi:10.1016/j.molcel.2005.06.027.
[100]
Yang, Z.; Yik, J.H.; Chen, R.; He, N.; Jang, M.K.; Ozato, K.; Zhou, Q. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 2005, 19, 535–545, doi:10.1016/j.molcel.2005.06.029.
[101]
He, N.; Liu, M.; Hsu, J.; Xue, Y.; Chou, S.; Burlingame, A.; Krogan, N.J.; 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.
[102]
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.
[103]
Krueger, B.J.; Varzavand, K.; Cooper, J.J.; Price, D.H. The mechanism of release of P-TEFb and HEXIM1 from the 7SK snRNP by viral and cellular activators includes a conformational change in 7SK. PLoS One 2010, 5, e12335, doi:10.1371/journal.pone.0012335. 20808803
[104]
Muniz, L.; Egloff, S.; Ughy, B.; Jady, B.E.; Kiss, T. Controlling cellular P-TEFb activity by the HIV-1 transcriptional transactivator Tat. PLoS Pathog. 2010, 6, e1001152, doi:10.1371/journal.ppat.1001152.
[105]
Markert, A.; Grimm, M.; Martinez, J.; Wiesner, J.; Meyerhans, A.; Meyuhas, O.; Sickmann, A.; Fischer, U. The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes. EMBO Rep. 2008, 9, 569–575, doi:10.1038/embor.2008.72.
[106]
He, N.; Jahchan, N.S.; Hong, E.; Li, Q.; Bayfield, M.A.; Maraia, R.J.; Luo, K.; Zhou, Q. A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis. Mol. Cell 2008, 29, 588–599, doi:10.1016/j.molcel.2008.01.003.
[107]
Xue, Y.; Yang, Z.; Chen, R.; Zhou, Q. A capping-independent function of MePCE in stabilizing 7SK snRNA and facilitating the assembly of 7SK snRNP. Nucleic Acids Res. 2010, 38, 360–369, doi:10.1093/nar/gkp977.
[108]
Diribarne, G.; Bensaude, O. 7SK RNA, a non-coding RNA regulating P-TEFb, a general transcription factor. RNA Biol. 2009, 6, 122–128, doi:10.4161/rna.6.2.8115.
[109]
Blazek, D.; Barboric, M.; Kohoutek, J.; Oven, I.; Peterlin, B.M. Oligomerization of HEXIM1 via 7SK snRNA and coiled-coil region directs the inhibition of P-TEFb. Nucleic Acids Res. 2005, 33, 7000–7010, doi:10.1093/nar/gki997.
[110]
Zhou, M.; Huang, K.; Jung, K.J.; Cho, W.K.; Klase, Z.; Kashanchi, F.; Pise-Masison, C.A.; Brady, J.N. Bromodomain protein Brd4 regulates human immunodeficiency virus transcription through phosphorylation of CDK9 at threonine 29. J. Virol. 2009, 83, 1036–1044, doi:10.1128/JVI.01316-08.
[111]
Ramirez-Carrozzi, V.R.; Nazarian, A.A.; Li, C.C.; Gore, S.L.; Sridharan, R.; Imbalzano, A.N.; Smale, S.T. Selective and antagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response. Genes. Dev. 2006, 20, 282–296, doi:10.1101/gad.1383206.
Malovannaya, A.; Lanz, R.B.; Jung, S.Y.; Bulynko, Y.; Le, N.T.; Chan, D.W.; Ding, C.; Shi, Y.; Yucer, N.; Krenciute, G.; et al. Analysis of the human endogenous coregulator complexome. Cell 2011, 145, 787–799, doi:10.1016/j.cell.2011.05.006.
[114]
Ho, D.D.; Neumann, A.U.; Perelson, A.S.; Chen, W.; Leonard, J.M.; Markowitz, M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373, 123–126, doi:10.1038/373123a0.
[115]
Strain, M.C.; Little, S.J.; Daar, E.S.; Havlir, D.V.; Gunthard, H.F.; Lam, R.Y.; Daly, O.A.; Nguyen, J.; Ignacio, C.C.; Spina, C.A.; et al. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J. Infect. Dis. 2005, 191, 1410–1418, doi:10.1086/428777.
[116]
Han, Y.; Lassen, K.; Monie, D.; Sedaghat, A.R.; Shimoji, S.; Liu, X.; Pierson, T.C.; Margolick, J.B.; Siliciano, R.F.; Siliciano, J.D. 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. 15163705
[117]
Lewinski, M.K.; Bisgrove, D.; Shinn, P.; Chen, H.; Hoffmann, C.; Hannenhalli, S.; Verdin, E.; Berry, C.C.; Ecker, J.R.; Bushman, F.D. 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. 15890899
[118]
Vatakis, D.N.; Kim, S.; Kim, N.; Chow, S.A.; Zack, J.A. 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.
[119]
Pearson, R.; Kim, Y.K.; 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.
[120]
Weinberger, L.S.; Burnett, J.C.; Toettcher, J.E.; Arkin, A.P.; Schaffer, D.V. 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.
[121]
Weinberger, L.S.; Dar, R.D.; Simpson, M.L. Transient-mediated fate determination in a transcriptional circuit of HIV. Nat. Genet. 2008, 40, 466–470, doi:10.1038/ng.116.
[122]
Yukl, S.; Pillai, S.; Li, P.; Chang, K.; Pasutti, W.; Ahlgren, C.; Havlir, D.; Strain, M.; Gunthard, H.; Richman, D.; et al. 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.
[123]
Choudhary, S.K.; Archin, N.M.; Margolis, D.M. Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells. J. Infect. Dis. 2008, 197, 1162–1170, doi:10.1086/529525.
[124]
Chen, R.; Liu, M.; Li, H.; Xue, Y.; Ramey, W.N.; He, N.; Ai, N.; Luo, H.; Zhu, Y.; Zhou, N.; et al. PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling. Genes Dev. 2008, 22, 1356–1368, doi:10.1101/gad.1636008.
[125]
Contreras, X.; Barboric, M.; Lenasi, T.; Peterlin, B.M. HMBA releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and activates HIV transcription. PLoS Pathog. 2007, 3, 1459–1469. 17937499
[126]
Tyagi, M.; Pearson, R.J.; 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.
[127]
Friedman, J.; Cho, W.K.; Chu, C.K.; Keedy, K.S.; Archin, N.M.; Margolis, D.M.; 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. 21715480
[128]
Kauder, S.E.; 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.
[129]
Coull, J.J.; Romerio, F.; Sun, J.M.; Volker, J.L.; Galvin, K.M.; Davie, J.R.; Shi, Y.; Hansen, U.; Margolis, D.M. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J. Virol. 2000, 74, 6790–6799, doi:10.1128/JVI.74.15.6790-6799.2000. 10888618
[130]
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.
[131]
Sahu, G.K.; Lee, K.; Ji, J.; Braciale, V.; Baron, S.; Cloyd, M.W. 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.
[132]
Lassen, K.G.; Hebbeler, A.M.; Bhattacharyya, D.; Lobritz, M.A.; Greene, W.C. 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. 22291913
[133]
Saleh, S.; Solomon, A.; Wightman, F.; Xhilaga, M.; Cameron, P.U.; Lewin, S.R. 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. 17881634
[134]
Yang, H.C.; Xing, S.; Shan, L.; O’Connell, K.; Dinoso, J.; Shen, A.; Zhou, Y.; Shrum, C.K.; Han, Y.; Liu, J.O.; et al. 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. 19805909
[135]
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.
[136]
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.
[137]
McNamara, L.A.; Collins, K.L. Hematopoietic stem/precursor cells as HIV reservoirs. Curr. Opin. HIV AIDS 2011, 6, 43–48, doi:10.1097/COH.0b013e32834086b3. 21242893
[138]
Durand, C.M.; Ghiaur, G.; Siliciano, J.D.; Rabi, S.A.; Eisele, E.E.; Salgado, M.; Shan, L.; Lai, J.F.; Zhang, H.; Margolick, J.; 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. J. Infect. Dis. 2012, 205, 1014–1018, doi:10.1093/infdis/jir884.
