Molecular mechanisms of HIV latency

Journal of Clinical Investigation

Volumn 126, Issue 2, 2016, Pages 448-454

  Cary, Daniele C ^a   Fujinaga, Koh ^a   Peterlin, B Matija ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BROMODOMAIN INHIBITOR; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE 11; CYCLIN DEPENDENT KINASE 13; HISTONE DEACETYLASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; POSITIVE TRANSCRIPTION ELONGATION FACTOR B; SMALL NUCLEAR RIBONUCLEOPROTEIN; TRANSACTIVATOR PROTEIN; UNCLASSIFIED DRUG; CDK13 PROTEIN, HUMAN; CDK19 PROTEIN, HUMAN; CYCLIN DEPENDENT KINASE 1;

EPIGENETICS; GENE EXPRESSION; HETEROCHROMATIN; HUMAN IMMUNODEFICIENCY VIRUS; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE ACTIVATION; VIRUS GENE; VIRUS LATENCY; VIRUS TRANSCRIPTION; ANIMAL; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; HIV INFECTIONS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; METABOLISM; PHYSIOLOGY;

ANIMALS; CDC2 PROTEIN KINASE; CYCLIN-DEPENDENT KINASES; GENE EXPRESSION REGULATION, VIRAL; HIV INFECTIONS; HIV-1; HUMANS; NF-KAPPA B; POSITIVE TRANSCRIPTIONAL ELONGATION FACTOR B; RIBONUCLEOPROTEINS, SMALL NUCLEAR; TAT GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; VIRUS LATENCY;

EID: 84956885301     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI80565     Document Type: Review

References (95)

1. Centers for Disease Control (CDC). Pneumocystis pneumonia - Los Angeles. MMWR Morb Mortal Wkly Rep. 1981;30(21):250-252.
2. Barre-Sinoussi F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983;220(4599):868-871.
3. Alizon M, et al. Molecular cloning of lymphadenopathy-associated virus. Nature. 1984;312(5996):757-760.
4. Sanchez-Pescador R, et al. Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science. 1985;227(4686):484-492.
5. Arya SK, Guo C, Josephs SF, Wong-Staal F. Transactivator gene of human T-lymphotropic virus type III (HTLV-III). Science. 1985;229(4708):69-73.
6. Sodroski J, et al. Trans-acting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat. Science. 1985;227(4683):171-173.
7. Ocwieja KE, et al. Dynamic regulation of HIV-1 mRNA populations analyzed by single-molecule enrichment and long-read sequencing. Nucleic Acids Res. 2012;40(20):10345-10355.
8. Nabel G, Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987;326(6114):711-713.
9. Tong-Starksen SE, Luciw PA, Peterlin BM. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc Natl Acad Sci U S A. 1987;84(19):6845-6849.
10. Kinoshita S, Su L, Amano M, Timmerman LA, Kaneshima H, Nolan GP. The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells. Immunity. 1997;6(3):235-244.
11. Kao SY, 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(6147):489-493.
12. Adams M, 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(9):3862-3866.
13. Chun TW, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997;94(24):13193-13197.
14. Finzi D, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295-1300.
15. Wong JK, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997;278(5341):1291-1295.
16. Altfeld M, et al. HLA alleles associated with delayed progression to AIDS contribute strongly to the initial CD8(+) T cell response against HIV-1. PLoS Med. 2006;3(10):e403.
17. Hutter G, et al. Long-term control of HIV by CCR5 Δ32/Δ32 stem-cell transplantation. N Engl J Med. 2009;360(7):692-698.
18. Eriksson S, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 2013;9(2):e1003174.
19. Ho YC, et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013;155(3):540-551.
20. Archin NM, et al. HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. J Infect Dis. 2014;210(5):728-735.
21. Han Y, 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):6122-6133.
22. Jung A, et al. Recombination: Multiply infected spleen cells in HIV patients. Nature. 2002;418(6894):144.
23. Emiliani S, Fischle W, Ott M, Van Lint C, Amella CA, Verdin E. Mutations in the tat gene are responsible for human immunodeficiency virus type 1 postintegration latency in the U1 cell line. J Virol. 1998;72(2):1666-1670.
24. Emiliani S, et al. A point mutation in the HIV-1 Tat responsive element is associated with postintegration latency. Proc Natl Acad Sci U S A. 1996;93(13):6377-6381.
25. Lenasi T, Contreras X, Peterlin BM. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe. 2008;4(2):123-133.
26. Greger IH, Demarchi F, Giacca M, Proudfoot NJ. Transcriptional interference perturbs the binding of Sp1 to the HIV-1 promoter. Nucleic Acids Res. 1998;26(5):1294-1301.
27. Ashe MP, Griffin P, James W, Proudfoot NJ. Poly(A) site selection in the HIV-1 provirus: inhibition of promoter-proximal polyadenylation by the downstream major splice donor site. Genes Dev. 1995;9(23):3008-3025.
28. Han Y, et al. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe. 2008;4(2):134-146.
29. 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.
30. Mbonye U, Karn J. Transcriptional control of HIV latency: cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology. 2014;454-455:328-339.
31. 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):16981-16988.
32. Jadlowsky JK, et al. Negative elongation factor is required for the maintenance of proviral latency but does not induce promoter-proximal pausing of RNA polymerase II on the HIV long terminal repeat. Mol Cell Biol. 2014;34(11):1911-1928.
33. Rice AP, Herrmann CH. Regulation of TAK/P-TEFb in CD4+ T lymphocytes and macrophages. Curr HIV Res. 2003;1(4):395-404.
34. Yang X, et al. 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 U S A. 1997;94(23):12331-12336.
35. Williams SA, Greene WC. Host factors regulating post-integration latency of HIV. Trends Microbiol. 2005;13(4):137-139.
36. 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.
37. Cullen BR, Lomedico PT, Ju G. Transcriptional interference in avian retroviruses - implications for the promoter insertion model of leukaemogenesis. Nature. 1984;307(5948):241-245.
38. Klaver B, Berkhout B. Comparison of 5' and 3' long terminal repeat promoter function in human immunodeficiency virus. J Virol. 1994;68(6):3830-3840.
39. Landry S, et al. Detection, characterization and regulation of antisense transcripts in HIV-1. Retrovirology. 2007;4:71.
40. Ludwig LB, et al. Human Immunodeficiency Virus-Type 1 LTR DNA contains an intrinsic gene producing antisense RNA and protein products. Retrovirology. 2006;3:80.
41. Jordan A, Bisgrove D, Verdin E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 2003;22(8):1868-1877.
42. Verdin E, Paras P Jr, Van Lint C. Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation. EMBO J. 1993;12(8):3249-3259.
43. Bartholomeeusen K, Fujinaga K, Xiang Y, Peterlin BM. Histone deacetylase inhibitors (HDACis) that release the positive transcription elongation factor b (P-TEFb) from its inhibitory complex also activate HIV transcription. J Biol Chem. 2013;288(20):14400-14407.
44. Budhiraja S, Rice AP. Reactivation of latent HIV: do all roads go through P-TEFb? Future Virol. 2013;8(7):10.2217/fvl.13.52.
45. Chiang K, Rice AP. MicroRNA-mediated restriction of HIV-1 in resting CD4+ T cells and monocytes. Viruses. 2012;4(9):1390-1409.
46. Marshall NF, Price DH. Purification of P-TEFb, a transcription factor required for the transition into productive elongation. J Biol Chem. 1995;270(21):12335-12338.
47. Zhu Y, et al. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev. 1997;11(20):2622-2632.
48. Mancebo HS, et al. P-TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro. Genes Dev. 1997;11(20):2633-2644.
49. Garber ME, 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(22):3512-3527.
50. Wei P, Garber ME, Fang SM, 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(4):451-462.
51. Cujec TP, et al. The HIV transactivator TAT binds to the CDK-activating kinase and activates the phosphorylation of the carboxy-terminal domain of RNA polymerase II. Genes Dev. 1997;11(20):2645-2657.
52. Heidemann M, Hintermair C, Voss K, Eick D. Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription. Biochim Biophys Acta. 2013;1829(1):55-62.
53. Zhou M, Deng L, Kashanchi F, Brady JN, Shatkin AJ, Kumar A. The Tat/TAR-dependent phosphorylation of RNA polymerase II C-terminal domain stimulates cotranscriptional capping of HIV-1 mRNA. Proc Natl Acad Sci U S A. 2003;100(22):12666-12671.
54. 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):2918-2927.
55. Yamaguchi Y, Shibata H, Handa H. Transcription elongation factors DSIF and NELF: promoterproximal pausing and beyond. Biochim Biophys Acta. 2013;1829(1):98-104.
56. Renner DB, Yamaguchi Y, Wada T, Handa H, Price DH. A highly purified RNA polymerase II elongation control system. J Biol Chem. 2001;276(45):42601-42609.
57. Fujinaga K, Irwin D, Huang Y, Taube R, Kurosu T, Peterlin BM. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol Cell Biol. 2004;24(2):787-795.
58. Rice AP. P-TEFb as a target to reactivate latent HIV: two Brds are now in hand. Cell Cycle. 2013;12(3):392-393.
59. Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell. 2001;8(2):327-337.
60. Chiang K, Sung TL, Rice AP. Regulation of cyclin T1 and HIV-1 Replication by microRNAs in resting CD4+ T lymphocytes. J Virol. 2012;86(6):3244-3252.
61. Zhou Q, Yik JH. The Yin and Yang of P-TEFb regulation: implications for human immunodeficiency virus gene expression and global control of cell growth and differentiation. Microbiol Mol Biol Rev. 2006;70(3):646-659.
62. Peterlin BM, Brogie JE, Price DH. 7SK snRNA: a noncoding RNA that plays a major role in regulating eukaryotic transcription. Wiley Interdiscip Rev RNA. 2012;3(1):92-103.
63. Muniz L, Egloff S, Ughy B, Jady BE, Kiss T. Controlling cellular P-TEFb activity by the HIV-1 transcriptional transactivator Tat. PLoS Pathog. 2010;6(10):e1001152.
64. Liu P, et al. Release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein (snRNP) activates hexamethylene bisacetamide-inducible protein (HEXIM1) transcription. J Biol Chem. 2014;289(14):9918-9925.
65. He N, Pezda AC, Zhou Q. Modulation of a P-TEFb functional equilibrium for the global control of cell growth and differentiation. Mol Cell Biol. 2006;26(19):7068-7076.
66. Berro R, et al. CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing. J Virol. 2008;82(14):7155-7166.
67. Yu W, Ramakrishnan R, Wang Y, Chiang K, Sung TL, Rice AP. 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.
68. Pak V, Eifler TT, Jäger S, Krogan NJ, Fujinaga K, Peterlin BM. CDK11 in TREX/THOC regulates HJIV mRNA 3' end processing. Cell Host Microbe. 2015;18(5):560-570.
69. Liang K, et al. Characterization of human cyclindependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing. Mol Cell Biol. 2015;35(6):928-938.
70. Trembley JH, Hu D, Slaughter CA, Lahti JM, Kidd VJ. Casein kinase 2 interacts with cyclindependent kinase 11 (CDK11) in vivo and phosphorylates both the RNA polymerase II carboxylterminal domain and CDK11 in vitro. J Biol Chem. 2003;278(4):2265-2270.
71. Dai Q, et al. Primordial dwarfism gene maintains Lin28 expression to safeguard embryonic stem cells from premature differentiation. Cell Rep. 2014;7(3):735-746.
72. Castelo-Branco G, et al. The non-coding snRNA 7SK controls transcriptional termination, poising, and bidirectionality in embryonic stem cells. Genome Biol. 2013;14(9):R98.
73. Laird GM, et al. Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J Clin Invest. 2015;125(5):1901-1912.
74. Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014;20(4):425-429.
75. Li N, et al. HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen. Proc Natl Acad Sci U S A. 2008;105(12):4796-4801.
76. 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):9105-9114.
77. Narayanan A, et al. Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. J Biol Chem. 2013;288(27):20014-20033.
78. Gallastegui E, et al. Combination of biological screening in a cellular model of viral latency and virtual screening identifies novel compounds that reactivate HIV-1. J Virol. 2012;86(7):3795-3808.
79. Fujinaga K, Luo Z, Schaufele F, Peterlin BM. Visualization of positive transcription elongation factor b (P-TEFb) activation in living cells. J Biol Chem. 2015;290(3):1829-1836.
80. Kerppola TK. Bimolecular fluorescence complementation (BiFC) analysis as a probe of protein interactions in living cells. Annu Rev Biophys. 2008;37:465-487.
81. Mbonye UR, et al. Phosphorylation of CDK9 at Ser175 enhances HIV transcription and is a marker of activated P-TEFb in CD4(+) T lymphocytes. PLoS Pathog. 2013;9(5):e1003338.
82. Geng X, Doitsh G, Yang Z, Galloway NL, Greene WC. Efficient delivery of lentiviral vectors into resting human CD4 T cells. Gene Ther. 2014;21(4):444-449.
83. Beans EJ, et al. Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo. Proc Natl Acad Sci U S A. 2013;110(29):11698-11703.
84. 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):8118-8123.
85. Perez M, et al. Bryostatin-1 synergizes with histone deacetylase inhibitors to reactivate HIV-1 from latency. Curr HIV Res. 2010;8(6):418-429.
86. Jiang G, et al. Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase CΔ-NF-κB signaling. AIDS. 2014;28(11):1555-1566.
87. Pandelo Jose D, et al. Reactivation of latent HIV-1 by new semi-synthetic ingenol esters. Virology. 2014;462-463:328-339.
88. Hori T, et al. Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus. Biochem Biophys Res Commun. 2015;459(2):288-293.
89. Abreu CM, et al. Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR. PLoS One. 2014;9(5):e97257.
90. Gama L, et al. Latency reversing agents activate latent reservoirs in the brain of SIV-infected macaques. Presented at: Conference on Retroviruses and Opportunistic Infections; February 23-26, 2015; Seattle, Washington, USA. Abstract 416.
91. Darcis G, et al. An in-depth comparison of latencyreversing agent combinations in various in vitro and ex vivo HIV-1 latency models identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently reactivate viral gene expression. PLoS Pathog. 2015;11(7):e1005063.
92. Bartholomeeusen K, Xiang Y, Fujinaga K, Peterlin BM. Bromodomain and extra-terminal (BET) bromodomain inhibition activate transcription via transient release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein. J Biol Chem. 2012;287(43):36609-36616.
93. Contreras X, et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem. 2009;284(11):6782-6789.
94. Rasmussen TA, et al. Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother. 2013;9(5):993-1001.
95. Wei DG, et al. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog. 2014;10(4):e1004071.