Control of HIV latency by epigenetic and non-epigenetic mechanisms

Current HIV Research

Volumn 9, Issue 8, 2011, Pages 554-567

  Mbonye, Uri ^a   Karn, Jonathan ^a  

^a CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Epigenetics; HIV latency; NF B; P TEFb; Tat

Indexed keywords

HISTONE DEACETYLASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; TRANSACTIVATOR PROTEIN; TRANSCRIPTION ELONGATION FACTOR; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR NFAT; TRANSCRIPTION FACTOR P TEFB; UNCLASSIFIED DRUG; VIRUS RNA;

CD4+ T LYMPHOCYTE; CHROMATIN; DISEASE CONTROL; EPIGENETICS; FEEDBACK SYSTEM; GENE SILENCING; HOST CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; MEMORY T LYMPHOCYTE; NONHUMAN; PROTEIN EXPRESSION; PROVIRUS; REVIEW; TRANSCRIPTION INITIATION; VIRUS LATENCY;

ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; DISEASE RESERVOIRS; EPIGENESIS, GENETIC; HIV; HIV INFECTIONS; HUMANS; T-LYMPHOCYTES; TAT GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; TRANSCRIPTION, GENETIC; VIRUS LATENCY;

EID: 84856484784     PISSN: 1570162X     EISSN: 18734251     Source Type: Journal    
DOI: 10.2174/157016211798998736     Document Type: Review

References (206)

1. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997; 387: 183-8.
2. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5(5): 512-7.
3. Pierson T, McArthur J, Siliciano RF. Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol 2000; 18: 665-708.
4. Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009; 106(23): 9403-8.
5. Sedaghat AR, Siliciano JD, Brennan TP, Wilke CO, Siliciano RF. Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART. PLoS Pathog 2007; 3(8): e122.
6. Monie D, Simmons RP, Nettles RE, et al. A novel assay allows genotyping of the latent reservoir for human immunodeficiency virus type 1 in the resting CD4+ T cells of viremic patients. J Virol 2005; 79(8): 5185-202.
7. Shen A, Zink MC, Mankowski JL, et al. Resting CD4+ T lymphocytes but not thymocytes provide a latent viral reservoir in a simian immunodeficiency virus-Macaca nemestrina model of human immunodeficiency virus type 1-infected patients on highly active antiretroviral therapy. J Virol 2003; 77: 4938-49.
8. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003; 9: 727-8.
9. Chun T-W, Engel D, Berrey MM, et al. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A 1998; 95: 8869-73.
10. Chun TW, Davey RT, Jr., Engel D, Lane HC, Fauci AS. Reemergence of HIV after stopping therapy. Nature 1999; 401: 874-5.
11. Chun TW, Justement JS, Pandya P, et al. Relationship between the size of the human immunodeficiency virus type 1 (HIV-1) reservoir in peripheral blood CD4+ T cells and CD4+:CD8+ T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy. J Infect Dis 2002; 185: 1672-6.
12. Chun TW, Nickle DC, Justement JS, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis 2008; 197(5): 714-20.
13. Chomont N, El-Far M, Ancuta P, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 2009; 15(8): 893-900.
14. Schacker T, Little S, Connick E, et al. Productive infection of T cells in lymphoid tissues during primary and early human immunodeficiency virus infection. J Infect Dis 2001; 183(4): 555-62.
15. Strain MC, Gunthard HF, Havlir DV, et al. Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence. Proc Natl Acad Sci U S A 2003; 100(8): 4819-24.
16. Strain MC, Little SJ, Daar ES, et al. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis 2005; 191(9): 1410-8.
17. Brennan TP, Woods JO, Sedaghat AR, et al. Analysis of HIV-1 Viremia and Provirus in Resting CD4+ T Cells Reveals a Novel Source of Residual Viremia in Patients on Antiretroviral Therapy. J Virol 2009; 83(17): 8470-81.
18. Joos B, Fischer M, Kuster H, et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc Natl Acad Sci U S A 2008; 105(43): 16725-30.
19. Chun TW, Nickle DC, Justement JS, et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest 2005; 115(11): 3250-5.
20. Richman DD, Margolis DM, Delaney M, et al. The challenge of finding a cure for HIV infection. Science 2009; 323(5919): 1304-7.
21. Trono D, Van Lint C, Rouzioux C, et al. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 2010; 329(5988): 174-80.
22. Jones K, Kadonaga J, Luciw P, Tjian R. Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1. Science 1986; 232: 755-9.
23. Garcia JA, Harrich D, Soultanakis E, et al. Human immunodeficiency virus type 1 LTR TATA and TAR region sequences required for transcriptional regulation. EMBO J 1989; 8: 765-78.
24. Zenzie-Gregory B, Sheridan P, Jones KA, Smale ST. HIV-1 core promoter lacks a simple initiator element but contains bipartite activator at the transcription start site. J Biol Chem 1993; 268: 15823-32.
25. Rittner K, Churcher MJ, Gait MJ, Karn J. The human immunodeficiency virus long terminal repeat includes a specialised initiator element which is required for Tat-responsive transcription. J Mol Biol 1995; 248: 562-80.
26. Nabel G, Baltimore DA. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 1987; 326: 711-3.
27. Liu J, Perkins ND, Schmid RM, Nabel GJ. Specific NF-kB subunits act in concert with tat to stimulate human immunodeficiency virus type 1 transcription. J Virol 1992; 66: 3883-7.
28. Kinoshita S, Chen BK, Kaneshima H, Nolan GP. Host control of HIV-1 parasitism in T cells by the nuclear factor of activated T cells. Cell 1998; 95: 595-604.
29. Chen-Park FE, Huang DB, Noro B, Thanos D, Ghosh G. The kB DNA sequence from the HIV long terminal repeat functions as an allosteric regulator of HIV transcription. J Biol Chem 2002; 277: 24701-8.
30. Giffin MJ, Stroud JC, Bates DL, et al. Structure of NFAT1 bound as a dimer to the HIV-1 LTR kB element. Nature Struct Biol 2003; 10: 800-6.
31. Perkins ND, Edwards NL, Duckett CS, et al. A cooperative interaction between NF-kB and Sp1 is required for HIV-1 enhancer activation. EMBO J 1993; 12: 3551-8.
32. Chen BK, Feinberg MB, Baltimore D. The kB sites in the human immunodeficiency virus type 1 long terminal repeat enhance virus replication yet are not absolutely required for viral growth. J Virol 1997; 71(7): 5495-504.
33. Alcami J, de Lera TL, Folgueira L, et al. Absolute dependence on kB responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes. EMBO J 1995; 14: 1552-60.
34. Bosque A, Planelles V. Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood 2008; 113(1): 58-65.
35. Tyagi M, Pearson RJ, Karn J. Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J Virol 2010; 84(13): 6425-37.
36. Yang HC, Xing S, Shan L, 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(11): 3473-86.
37. Xing S, Bullen CK, Shroff NS, et al. Disulfiram reactivates latent HIV-1 in a Bcl-2 transduced primary CD4+ T cell model without inducing global T cell activation. J Virol 2011.
38. Sodroski J, Patarca R, Rosen C, Wong-Staal F, Haseltine WA. Location of the trans-acting region on the genome of human T-cell lymphotropic virus type III. Science 1985; 229: 74-7.
39. Sodroski JG, Rosen CA, Wong-Staal F, et al. Trans-acting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat. Science 1985; 227: 171-3.
40. Dingwall C, Ernberg I, Gait MJ, et al. HIV-1 Tat protein stimulates transcription by binding to a U-rich bulge in the stem of the TAR RNA structure. EMBO J 1990; 9: 4145-53.
41. Dingwall C, Ernberg I, Gait MJ, et al. Human immunodeficiency virus 1 Tat protein binds trans-activation-responsive region (TAR) RNA in vitro. Proc Natl Acad Sci U S A 1989; 86: 6925-9.
42. Aboul-ela F, Karn J, Varani G. The structure of the human immunodeficiency virus type 1 TAR RNA reveals principles of RNA recognition by Tat protein. J Mol Biol 1995; 253: 313-32.
43. Puglisi JD, Tan R, Calnan BJ, Frankel AD, Williamson JR. Conformation of the TAR RNA-arginine complex by NMR spectroscopy. Science 1992; 257: 76-80.
44. Brodsky AS, Williamson JR. Solution structure of the HIV-2 TARargininamide complex. J Mol Biol 1997; 267: 624-39.
45. Davidson A, Leeper TC, Athanassiou Z, et al. Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein. Proc Natl Acad Sci U S A 2009; 106(29): 11931-6.
46. Kao S-Y, Calman AF, Luciw PA, Peterlin BM. Anti-termination of transcription within the long terminal repeat of HIV-1 by Tat gene product. Nature 1987; 330: 489-93.
47. Krumm A, Hickey LB, Groudine M. Promoter-proximal pausing of RNA polymerase II defines a general rate-limiting step after transcription initiation. Genes Dev 1995; 9: 559-72.
48. Lis JT. Promoter-associated pausing in promoter architecture and postinitiation transcriptional regulation. Cold Spring Harbor Symp Quant Biol 1998; 63: 347-56.
49. Min IM, Waterfall JJ, Core LJ, et al. Regulating RNA polymerase pausing and transcription elongation in embryonic stem cells. Genes Dev 2011; 25(7): 742-54.
50. Price DH. Poised polymerases: on your mark. get set. go! Mol Cell 2008; 30(1): 7-10.
51. Mancebo HSY, Lee G, Flygare J, et al. p-TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro. Genes Dev 1997; 11: 2633-44.
52. Zhu Y, Pe'ery T, Peng J, et al. Transcription elongation factor PTEFb is required for HIV-1 Tat transactivation in vitro. Genes Dev 1997; 11: 2622-32.
53. Marshall NF, Price DH. Purification of p-TEFb, a transcription factor required for the transition into productive elongation. J Biol Chem 1995; 270: 12335-8.
54. Marshall NF, Price DH. Control of formation of two distinct classes of RNA polymerase II elongation complexes. Mol Cell Biol 1992; 12: 2078-90.
55. Marciniak RA, Sharp PA. HIV-1 Tat protein promotes formation of more-processive elongation complexes. EMBO J 1991; 10: 4189-96.
56. Herrmann CH, Rice AP. 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: 1612-20.
57. Marshall NF, Peng J, Xie Z, Price DH. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J Biol Chem 1996; 271(43): 27176-83.
58. Wei P, Garber ME, Fang S-M, Fischer WH, Jones KA. 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: 451-62.
59. Bieniasz PD, Grdina TA, Bogerd HP, Cullen BR. Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat. EMBO J 1998; 17: 7056-65.
60. Fujinaga K, Cujec TP, Peng J, et al. The ability of positive transcription elongation factor b to transactive human immodeficiency virus transcription depends on a functional kinase domain, cyclin T1 and Tat. J Virol 1998; 72: 7154-9.
61. Garber ME, Wei P, KewelRamani VN, et al. 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: 3512-27.
62. Kwak YT, Ivanov D, Guo J, Nee E, Gaynor RB. Role of the human and murine cyclin T proteins in regulating HIV-1 Tat-activation. J Mol Biol 1999; 288: 57-69.
63. Wimmer J, Fujinaga K, Taube R, et al. Interactions between Tat and TAR and human immunodeficiency virus replication are facilitated by human cyclin T1 but not cyclins T2a or T2b. Virology 1999; 255: 182.
64. Tahirov TH, Babayeva ND, Varzavand K, et al. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature 2010; 465(7299): 747-51.
65. Adams M, Sharmeen L, Kimpton J, et al. Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts. Proc Natl Acad Sci U S A 1994; 91: 3862-6.
66. Sheldon M, Ratnasabapathy R, Hernandez N. Characterization of the inducer of short transcripts, a human immunodeficiency virus type 1 transcriptional element that activates the synthesis of short RNAs. Mol Cell Biol 1993; 13(2): 1251-63.
67. Toohey MG, Jones KA. In vitro formation of short RNA polymerase II transcripts that terminate within the HIV-1 and HIV-2 promoter-proximal downstream regions. Genes Dev 1989; 3: 265-83.
68. Isel C, Karn J. Direct evidence that HIV-1 Tat activates the Tatassociated kinase (TAK) during transcriptional elongation. J Mol Biol 1999; 290: 929-41.
69. Tirode F, Busso D, Coin F, Egly J-M. Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7. Mol Cell 1999; 3: 87-95.
70. Yamaguchi Y, Takagi T, Wada T, et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 1999; 97: 41-51.
71. Yamaguchi Y, Wada T, Watanabe D, et al. Structure and function of the human transcription elongation factor DSIF. J Biol Chem 1999; 274(12): 8085-92.
72. Narita T, Yamaguchi Y, Yano K, et al. Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex. Mol Cell Biol 2003; 23(6): 1863-73.
73. Zhang Z, Klatt A, Gilmour DS, Henderson AJ. Negative elongation factor NELF represses human immunodeficiency virus transcription by pausing the RNA polymerase II complex. J Biol Chem 2007; 282(23): 16981-8.
74. Keen NJ, Churcher MJ, Karn J. Transfer of Tat and release of TAR RNA during the activation of the human immunodeficiency virus type-1 transcription elongation complex. EMBO J 1997; 16: 5260-72.
75. Fujinaga K, Irwin D, Huang Y, et al. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol Cell Biol 2004; 24: 787-95.
76. Yamaguchi Y, Inukai N, Narita T, Wada T, Handa H. Evidence that negative elongation factor represses transcription elongation through binding to a DRB sensitivity-inducing factor/RNA polymerase II complex and RNA. Mol Cell Biol 2002; 22(9): 2918-27.
77. Kim YK, Bourgeois CF, Isel C, Churcher MJ, Karn J. Phosphorylation of the RNA polymerase II carboxyl-terminal domain by CDK9 is directly responsible for human immunodeficiency virus type 1 Tat-activated transcriptional elongation. Mol Cell Biol 2002; 22(13): 4622-37.
78. Ramanathan Y, Rajpara SM, Reza SM, et al. Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences. J Biol Chem 2001; 276(14): 10913-20.
79. Bourgeois CF, Kim YK, Churcher MJ, West MJ, Karn J. Spt5 cooperates with Tat by preventing premature RNA release at terminator sequences. Mol Cell Biol 2002; 22: 1079-93.
80. Ivanov D, Kwak YT, Guo J, Gaynor RB. Domains in the SPT5 protein that modulate its transcriptional regulatory properties. Mol Cell Biol 2000; 20: 2970-83.
81. Aida M, Chen Y, Nakajima K, et al. Transcriptional pausing caused by NELF plays a dual role in regulating immediate-early expression of the junB gene. Mol Cell Biol 2006; 26(16): 6094-104.
82. Yamada T, Yamaguchi Y, Inukai N, et al. P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation. Mol Cell 2006; 21(2): 227-37.
83. Keen NJ, Gait MJ, Karn J. Human immunodeficiency virus type-1 Tat is an integral component of the activated transcriptionelongation complex. Proc Natl Acad Sci U S A 1996; 93: 2505-10.
84. Kim YK, Mbonye U, Hokello J, Karn J. T-Cell Receptor Signaling Enhances Transcriptional Elongation from Latent HIV Proviruses by Activating P-TEFb through an ERK-Dependent Pathway. Journal of molecular biology 2011; 410(5): 896-916.
85. Sobhian B, Laguette N, Yatim A, et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol Cell 2010; 38(3): 439-51.
86. He N, Liu M, Hsu J, et al. 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(3): 428-38.
87. He N, Chan CK, Sobhian B, et al. Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. Proc Natl Acad Sci U S A 2011; 108(36): E636-45.
88. Bres V, Gomes N, Pickle L, Jones KA. A human splicing factor, SKIP, associates with P-TEFb and enhances transcription elongation by HIV-1 Tat. Genes Dev 2005; 19(10): 1211-26.
89. Ahn SH, Kim M, Buratowski S. Phosphorylation of Serine 2 within the RNA polymerase II C-terminal domain couples transcription and 3' end processing. Mol Cell 2004; 13: 67-76.
90. Barboric M, Lenasi T, Chen H, et al. 7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development. Proc Natl Acad Sci U S A 2009; 106(19): 7798-803.
91. Pirngruber J, Shchebet A, Schreiber L, et al. CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing. EMBO Rep 2009; 10(8): 894-900.
92. Lenasi T, Peterlin BM, Barboric M. Cap-binding protein complex links pre-mRNA capping to transcription elongation and alternative splicing through positive transcription elongation factor b (PTEFb). J Biol Chem 2011; 286: 22758-68.
93. Valente ST, Gilmartin GM, Venkatarama K, Arriagada G, Goff SP. HIV-1 mRNA 3' end processing is distinctively regulated by eIF3f, CDK11, and splice factor 9G8. Mol Cell 2009; 36: 279-89.
94. Berro R, Pedati C, Kehn-Hall K, et al. CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing. J Virol 2008; 82(14): 7155-66.
95. Bartkowiak B, Liu P, Phatnani HP, et al. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev 2010; 24: 2303-16.
96. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell 2005; 122(2): 169-82.
97. Weinberger LS, Dar RD, Simpson ML. Transient-mediated fate determination in a transcriptional circuit of HIV. Nat Genet 2008; 40(4): 466-70.
98. Weinberger LS, Shenk T. An HIV Feedback Resistor: Auto-Regulatory Circuit Deactivator and Noise Buffer. PLoS Biol 2006; 5(1): e9.
99. Burnett JC, Miller-Jensen K, Shah PS, Arkin AP, Schaffer DV. Control of stochastic gene expression by host factors at the HIV promoter. PLoS Pathog 2009; 5(1): e1000260.
100. Pearson R, Kim YK, Hokello J, 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. J Virol 2008; 82(24): 12291-303.
101. Yukl S, Pillai S, Li P, et al. Latently-infected CD4+ T cells are enriched for HIV-1 Tat variants with impaired transactivation activity. Virology 2009; 387(1): 98-108.
102. Han Y, Lassen K, Monie D, 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. J Virol 2004; 78(12): 6122-33.
103. Shan L, Yang HC, Rabi SA, et al. Influence of host gene transcription level and orientation on HIV-1 latency in a primary cell model. J Virol 2011.
104. Brady T, Agosto LM, Malani N, et al. HIV integration site distributions in resting and activated CD4+ T cells infected in culture. AIDS 2009; 23(12): 1461-71.
105. Verdin E, Paras PJ, Van Lint C. Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation. EMBO J 1993; 12: 3249-59.
106. Van Lint C, Emiliani S, Ott M, Verdin E. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J 1996; 15(5): 1112-20.
107. Mahmoudi T, Parra M, Vries RG, et al. The SWI/SNF chromatinremodeling complex is a cofactor for tat transactivation of the HIV promoter. J Biol Chem 2006; 281(29): 19960-8.
108. Coull JJ, Romerio F, Sun JM, et al. 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(15): 6790-9.
109. Friedman J, Cho WK, Chu CK, et al. Epigenetic silencing of HIV-1 by the Histone H3 lysine 27 Methyltransferase Enhancer of Zeste 2 (EZH2). J Virol 2011; 85(17): 9078-89.
110. Marban C, Suzanne S, Dequiedt F, et al. Recruitment of chromatinmodifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J 2007; 26(2): 412-23.
111. du Chene I, Basyuk E, Lin YL, et al. Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J 2007; 26(2): 424-35.
112. Blazkova J, Trejbalova K, Gondois-Rey F, et al. CpG methylation controls reactivation of HIV from latency. PLoS Pathog 2009; 5(8): e1000554.
113. Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E. Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog 2009; 5(6): e1000495.
114. Keedy KS, Archin NM, Gates AT, et al. A limited group of class I histone deacetylases act to repress human immunodeficiency virus type-1 expression. J Virol 2009; 83(10): 4749-56.
115. He G, Margolis DM. 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. Mol Cell Biol 2002; 22(9): 2965-73.
116. Margolis DM, Somasundaran M, Green MR. Human transcription factor YY1 represses human immunodeficiency virus type 1 transcription and virion production. J Virol 1994; 68: 905-10.
117. Williams SA, Chen LF, Kwon H, et al. NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J 2006; 25(1): 139-49.
118. Tyagi M, Karn J. CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J 2007; 26(24): 4985-95.
119. Imai K, Togami H, Okamoto T. Involvement of Histone H3 Lysine 9 (H3K9) Methyltransferase G9a in the Maintenance of HIV-1 Latency and Its Reactivation by BIX01294. J Biol Chem 2010; 285(22): 16538-45.
120. Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev 2002; 12(2): 198-209.
121. Vire E, Brenner C, Deplus R, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439(7078): 871-4.
122. Tae S, Karkhanis V, Velasco K, et al. Bromodomain protein 7 interacts with PRMT5 and PRC2, and is involved in transcriptional repression of their target genes. Nucleic Acids Res 2011.
123. Cheng AS, Lau SS, Chen Y, et al. EZH2-Mediated Concordant Repression of Wnt Antagonists Promotes {beta}-Catenin-Dependent Hepatocarcinogenesis. Cancer Res 2011; 71(11): 4028-39.
124. Kanhere A, Viiri K, Araujo CC, et al. Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol Cell 2010; 38(5): 675-88.
125. Enderle D, Beisel C, Stadler MB, et al. Polycomb preferentially targets stalled promoters of coding and noncoding transcripts. Genome Res 2011; 21(2): 216-26.
126. Ku M, Koche RP, Rheinbay E, et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS genetics 2008; 4(10): e1000242.
127. Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006; 125(2): 315-26.
128. Zhou M, Deng L, Lacoste V, et al. Coordination of Transcription Factor Phosphorylation and Histone Methylation by the P-TEFb Kinase during Human Immunodeficiency Virus Type 1 Transcription. J Virol 2004; 78(24): 13522-33.
129. Lenasi T, Contreras X, Peterlin BM. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe 2008; 4(2): 123-33.
130. Han Y, Lin YB, An W, et al. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe 2008; 4(2): 134-46.
131. Duverger A, Jones J, May J, et al. Determinants of the establishment of human immunodeficiency virus type 1 latency. J Virol 2009; 83(7): 3078-93.
132. Gallastegui E, Millan-Zambrano G, Terme JM, Chavez S, Jordan A. Chromatin reassembly factors are involved in transcriptional interference promoting HIV latency. Journal of virology 2011; 85(7): 3187-202.
133. Lusic M, Marcello A, Cereseto A, Giacca M. Regulation of HIV-1 gene expression by histone acetylation and factor recruitment at the LTR promoter. EMBO J 2003; 22: 6550-61.
134. Benkirane M, Chun RF, Xiao H, et al. Activation of integrated provirus requires histone acetyltransferase: p300 and p/CAF are coactivators for HIV-1 Tat. J Biol Chem 1998; 273: 24898-905.
135. Hottiger MO, Nabel GJ. Interaction of human immunodeficiency virus type 1 Tat with the transcriptional coactivators p300 and CREB binding protein. J Virol 1998; 72: 8252-6.
136. Marzio G, Tyagi M, Gutierrez MI, Giacca M. HIV-1 Tat transactivator recruits p300 and CREB-binding protein histone acetyltransferases to the viral promoter. Proc Natl Acad Sci U S A 1998; 95: 13519-24.
137. Easley R, Van Duyne R, Coley W, et al. Chromatin dynamics associated with HIV-1 Tat-activated transcription. Biochim Biophys Acta 2009; 1799(3-4): 275-85.
138. Agbottah E, Deng L, Dannenberg LO, Pumfery A, Kashanchi F. Effect of SWI/SNF chromatin remodeling complex on HIV-1 Tat activated transcription. Retrovirology 2006; 3: 48.
139. Pumfery A, Deng L, Maddukuri A, et al. Chromatin remodeling and modification during HIV-1 Tat-activated transcription. Curr HIV Res 2003; 1(3): 343-62.
140. Chen LF, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kB action regulated by reversible acetylation. Science 2001; 293: 1653-7.
141. Furia B, Deng L, Wu K, et al. Enhancement of nuclear factor-k B acetylation by coactivator p300 and HIV-1 Tat proteins. J Biol Chem 2002; 277(7): 4973-80.
142. Lu T, Jackson MW, Wang B, et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A 2010; 107(1): 46-51.
143. Garcia-Rodriguez C, Rao A. Nuclear factor of activated T cells (NFAT)-dependent transactivation regulated by the coactivators p300/CREB-binding protein (CBP). J Exp Med 1998; 187(12): 2031-6.
144. Robichaud GA, Barbeau B, Fortin J-F, Rothstein DM, Tremblay MJ. Nuclear factor of activated T cells is a driving force for preferential productive HIV-1 infection of CD45RO-expressing CD4+ T cells. J Biol Chem 2002; 277: 23733-41.
145. Brooks DG, Arlen PA, Gao L, Kitchen CM, Zack JA. Identification of T cell-signaling pathways that stimulate latent HIV in primary cells. Proc Natl Acad Sci U S A 2003; 100: 12955-60.
146. Williams SA, Chen LF, Kwon H, et al. Prostratin antagonizes HIV latency by activating NF-kappaB. J Biol Chem 2004; 279(40): 42008-17.
147. Thibault S, Imbeault M, Tardif MR, Tremblay MJ. TLR5 stimulation is sufficient to trigger reactivation of latent HIV-1 provirus in T lymphoid cells and activate virus gene expression in central memory CD4+ T cells. Virology 2009; 3889(1-2): 20-5.
148. Wolschendorf F, Duverger A, Jones J, et al. Hit-and-Run Stimulation: A Novel Concept to Reactivate Latent HIV-1 Infection Without Cytokine Gene Induction. J Virol 2010; 84(17): 8712-20.
149. Biancotto A, Grivel JC, Gondois-Rey F, et al. Dual role of prostratin in inhibition of infection and reactivation of human immunodeficiency virus from latency in primary blood lymphocytes and lymphoid tissue. J Virol 2004; 78(19): 10507-15.
150. Stroud JC, Chen L. Structure of NFAT bound to DNA as a monomer. J Mol Biol 2003; 334(5): 1009-22.
151. Stroud JC, Oltman A, Han A, Bates DL, Chen L. Structural basis of HIV-1 activation by NF-kappaB--a higher-order complex of p50:RelA bound to the HIV-1 LTR. J Mol Biol 2009; 393(1): 98-112.
152. Dow EC, Liu H, Rice AP. T-loop phosphorylated Cdk9 localizes to nuclear speckle domains which may serve as sites of active P-TEFb function and exchange between the Brd4 and 7SK/HEXIM1 regulatory complexes. J Cell Physiol 2010; 224(1): 84-93.
153. Ramakrishnan R, Dow EC, Rice AP. Characterization of Cdk9 Tloop phosphorylation in resting and activated CD4(+) T lymphocytes. J Leukoc Biol 2009; 86(6): 1345-50.
154. Ramakrishnan R, Rice AP. Cdk9 T-loop phosphorylation is regulated by the calcium signaling pathway. J Cell Physiol 2011.
155. Ghose R, Liou LY, Herrmann CH, Rice AP. Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. J Virol 2001; 75(23): 11336-43.
156. Sung TL, Rice AP. Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4+ T cells. Retrovirology 2006; 3: 66.
157. Hoque M, Shamanna RA, Guan D, Pe'ery T, Mathews MB. HIV-1 Replication and Latency Are Regulated by Translational Control of Cyclin T1. Journal of molecular biology 2011; 410(5): 917-32.
158. Sung TL, Rice AP. 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(1): e1000263.
159. Yu W, Ramakrishnan R, Wang Y, et al. Cyclin T1-dependent genes in activated CD4 T and macrophage cell lines appear enriched in HIV-1 co-factors. PLoS One 2008; 3(9): e3146.
160. Shore SM, Byers SA, Maury W, Price DH. Identification of a novel isoform of CDK9. Gene 2003; 307: 175-82.
161. Liu H, Herrmann CH. Differential localization and expression of the CDK9 42K and 55K isoforms. J Cell Physiol 2005; 203(1): 251-60.
162. Baumli S, Lolli G, Lowe ED, et al. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J 2008; 27(13): 1907-18.
163. 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(6): 4153-60.
164. Yang Z, Yik JH, Chen R, et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 2005; 19(4): 535-45.
165. Chen R, Liu M, Li H, et al. PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling. Genes Dev 2008; 22(10): 1356-68.
166. Yang Z, Zhu Q, Luo K, Zhou Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 2001; 414: 317-22.
167. Nguyen VT, Kiss T, Michels AA, Bensaude O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 2001; 414: 322-5.
168. Yik JH, Chen R, Nishimura R, et al. 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: 971-82.
169. Michels AA, Fraldi A, Li Q, et al. Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor. EMBO J 2004; 23(13): 2608-19.
170. Barboric M, Kohoutek J, Price JP, et al. Interplay between 7SK snRNA and oppositely charged regions in HEXIM1 direct the inhibition of P-TEFb. EMBO J 2005; 24(24): 4291-303.
171. Blazek D, Barboric M, Kohoutek J, Oven I, Peterlin BM. Oligomerization of HEXIM1 via 7SK snRNA and coiled-coil region directs the inhibition of P-TEFb. Nucleic Acids Res 2005; 33(22): 7000-10.
172. Schulte A, Czudnochowski N, Barboric M, et al. Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat. J Biol Chem 2005; 280(26): 24968-77.
173. Kohoutek J, Blazek D, Peterlin BM. Hexim1 sequesters positive transcription elongation factor b from the class II transactivator on MHC class II promoters. Proc Natl Acad Sci U S A 2006; 103(46): 17349-54.
174. Barboric M, Yik JH, Czudnochowski N, et al. Tat competes with HEXIM1 to increase the active pool of P-TEFb for HIV-1 transcription. Nucleic Acids Res 2007; 35(6): 2003-12.
175. Li Q, Cooper JJ, Altwerger GH, et al. 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(8): 2503-12.
176. Krueger BJ, Varzavand K, Cooper JJ, Price DH. 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(8): e12335.
177. Michels AA, Nguyen M, Fraldi A, et al. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcriptiondependent manner. Mol Cell Biol 2003; 23(14): 4859-69.
178. Krueger BJ, Jeronimo C, Roy BB, et al. LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated. Nucleic Acids Res 2008; 36(7): 2219-29.
179. Jeronimo C, Forget D, Bouchard A, et al. Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Mol Cell 2007; 27(2): 262-74.
180. He N, Jahchan NS, Hong E, et al. A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis. Mol Cell 2008; 29(5): 588-99.
181. Jang MK, Mochizuki K, Zhou M, et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 2005; 19(4): 523-34.
182. Bisgrove DA, Mahmoudi T, Henklein P, Verdin E. Conserved PTEFb-interacting domain of BRD4 inhibits HIV transcription. Proc Natl Acad Sci U S A 2007; 104(34): 13690-5.
183. Natarajan M, August A, Henderson AJ. Combinatorial signals from CD28 differentially regulate human immunodeficiency virus transcription in T cells. J Biol Chem 2010; 285(23): 17338-47.
184. Cho S, Schroeder S, Kaehlcke K, et al. Acetylation of cyclin T1 regulates the equilibrium between active and inactive P-TEFb in cells. EMBO J 2009; 28(10): 1407-17.
185. Lassen KG, Ramyar KX, Bailey JR, Zhou Y, Siliciano RF. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog 2006; 2(7): e68.
186. Lassen KG, Bailey JR, Siliciano RF. Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J Virol 2004; 78(17): 9105-14.
187. Savarino A, Mai A, Norelli S, 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 2009; 6: 52.
188. Choudhary SK, Margolis DM. Curing HIV: Pharmacologic approaches to target HIV-1 latency. Annu Rev Pharmacol Toxicol 2011; 51: 397-418.
189. Siliciano RF. What do we need to do to cure HIV infection. Top HIV Med 2010; 18(3): 104-8.
190. Lewin SR, Evans VA, Elliott JH, Spire B, Chomont N. Finding a cure for HIV: will it ever be achievable? J Int AIDS Soc 2011; 14: 4.
191. Sanchez-Duffhues G, Vo MQ, Perez M, et al. Activation of Latent HIV-1 Expression by Protein Kinase C Agonists. A Novel Therapeutic Approach to Eradicate HIV-1 Reservoirs. Curr Drug Targets 2011; 12: 348-56.
192. Korin YD, Brooks DG, Brown S, Korotzer A, Zack JA. Effects of prostratin on T-cell activation and human immunodeficiency virus latency. J Virol 2002; 76(16): 8118-23.
193. Kovochich M, Marsden MD, Zack JA. Activation of Latent HIV Using Drug-Loaded Nanoparticles. PLoS ONE 2011; 6: e18270.
194. Mehla R, Bivalkar-Mehla S, Zhang R, et al. Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner. PLoS ONE 2010; 5: e11160.
195. Pérez M, de Vinuesa AG, Sanchez-Duffhues G, et al. Bryostatin-1 synergizes with histone deacetylase inhibitors to reactivate HIV-1 from latency. Curr HIV Res 2010; 8: 418-29.
196. Bedoya LM, Marquez N, Marti{dotless}nez N, et al. SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro. Biochem Pharm 2009; 77: 965-78.
197. Archin NM, Espeseth A, Parker D, et al. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses 2009; 25(2): 207-12.
198. Matalon S, Rasmussen TA, Dinarello CA. HDAC Inhibitors for Purging HIV-1 from the Latent Reservoir. Mol Med 2011.
199. Archin NM, Cheema M, Parker D, et al. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One 2010; 5(2): e9390.
200. Archin NM, Keedy KS, Espeseth A, et al. Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. AIDS 2009; 23(14): 1799-806.
201. Hu F, Chou CJ, Gottesfeld JM. Design and synthesis of novel hybrid benzamide-peptide histone deacetylase inhibitors. Bioorg Med Chem Lett 2009; 19: 3928-31.
202. Contreras X, Schweneker M, Chen CS, et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem 2009; 284(11): 6782-9.
203. Margolis DM. Mechanisms of HIV latency: an emerging picture of complexity. Curr HIV/AIDS Rep 2010; 7(1): 37-43.
204. Sanchez-Duffhues G, Vo MQ, Perez M, et al. Activation of latent HIV-1 expression by protein kinase C agonists: A novel therapeutic approach to eradicate HIV-1 reservoirs. Current Drug Targets 2011; 12(3): 348-56.
205. Reuse S, Calao M, Kabeya K, et al. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One 2009; 4(6): e6093.
206. Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. Aids 2004; 18(8): 1101-8.