Epigenetic Regulation of HIV-1 Persistence and Evolving Strategies for Virus Eradication

  • Neeru Dhamija
  • Pratima Rawat
  • Debashis MitraEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 61)


Despite the intense effort put by researchers globally to understand Human Immunodeficiency Virus (HIV-1) pathogenesis since its discovery 30 years ago, the acquired knowledge till date is not good enough to eradicate HIV-1 from an infected individual. HIV-1 infects cells of the human immune system and integrates into the host cell genome thereby leading to persistent infection in these cells. Based on the activation status of the cells, the infection could be productive or result in latent infection. The current regimen used to treat HIV-1 infection in an AIDS patient includes combination of antiretroviral drugs called Highly Active Anti-Retroviral Therapy (HAART). A major challenge for the success of HAART has been these latent reservoirs of HIV which remain hidden and pose major hurdle for the eradication of virus. Combination of HAART therapy with simultaneous activation of latent reservoirs of HIV-1 seems to be the future of anti-retroviral therapy; however, this will require a much better understanding of the mechanisms and regulation of HIV-1 latency. In this chapter, we have tried to elaborate on HIV-1 latency, highlighting the strategies employed by the virus to ensure persistence in the host with specific focus on epigenetic regulation of latency. A complete understanding of HIV-1 latency will be extremely essential for ultimate eradication of HIV-1 from the human host.


Latency Associate Transcript Latent Reservoir Histone Acetyl Transferase H3K9 Methyl Transferase Transcriptional Interference 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Research work in DM laboratory was supported by NCCS and Department of Biotechnology (DBT), Government of India. ND is a CSIR senior research fellow (SRF) and PR is a research associate (RA) in DBT funded project.


  1. Aagaard L, Laible G, Selenko P, Schmid M, Dorn R, Schotta G, Kuhfittig S, Wolf A, Lebersorger A, Singh PB, Reuter G, Jenuwein T (1999) Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31. EMBO J 18:1923–1938PubMedCrossRefGoogle Scholar
  2. Adhya S, Gottesman M (1982) Promoter occlusion: transcription through a promoter may inhibit its activity. Cell 29:939–944PubMedCrossRefGoogle Scholar
  3. Ahmad K, Henikoff S (2002) The histone variant H33 marks active chromatin by replication-independent nucleosome assembly. Mol Cell 9:191–1200CrossRefGoogle Scholar
  4. Antoni BA, Rabson AB, Kinter A, Bodkin M, Poli G (1994) NF-kappa B-dependent and -independent pathways of HIV activation in a chronically infected T cell line. Virology 202:684–694PubMedCrossRefGoogle Scholar
  5. Archin NM, Keedy KS, Espeseth A, Dang H, Hazuda DJ, Margolis DM (2009) Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. AIDS 23:1799–1806CrossRefGoogle Scholar
  6. Asin S, Taylor JA, Trushin S, Bren G, Paya CV (1999) Ikappakappa mediates NF-kappaB activation in human immunodeficiency virus-infected cells. J Virol 73:3893–3903PubMedGoogle Scholar
  7. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410:120–124PubMedCrossRefGoogle Scholar
  8. Benkirane M, Chun RF, Xiao H, Ogryzko VV, Howard BH, Nakatani Y, Jeang KT (1998) Activation of integrated provirus requires histone acetyltransferase p300 and P/CAF are coactivators for HIV-1 Tat. J Biol Chem 273:24898–24905PubMedCrossRefGoogle Scholar
  9. Bennasser Y, Le SY, Yeung ML, Jeang KT (2004) HIV-1 encoded candidate micro-RNAs and their cellular targets. Retrovirology 1:43PubMedCrossRefGoogle Scholar
  10. Bennasser Y, Yeung ML, Jeang KT (2006) HIV-1 TAR RNA subverts RNA interference in transfected cells through sequestration of TAR RNA-binding protein TRBP. J Biol Chem 281:27674–27678PubMedCrossRefGoogle Scholar
  11. Berger SL (2002) Histone modifications in transcriptional regulation. Curr Opin Genet Dev 12:142–148PubMedCrossRefGoogle Scholar
  12. Blankson JN, Persaud D, Siliciano RF (2002) The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med 53:557–593PubMedCrossRefGoogle Scholar
  13. Blazkova J, Trejbalova K, Gondois-Rey F, Halfon P, Philibert P, Guiguen A, Verdin E, Olive D, Van Lint C, Hejnar J, Hirsch I (2009) CpG methylation controls reactivation of HIV from latency. PLoS Pathog 5:e1000554PubMedCrossRefGoogle Scholar
  14. Bohnlein E, Lowenthal JW, Siekevitz M, Ballard DW, Franza BR, Greene WC (1988) The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell 53:827–836PubMedCrossRefGoogle Scholar
  15. Boldogh I, Albrecht T, Porter DD (1996) Persistent viral infections. In: Baron S (ed) Medical microbiology, 4th edn. University of Texas Medical Branch, GalvestonGoogle Scholar
  16. Bosque A, Planelles V (2011) Studies of HIV-1 latency in an ex vivo model that uses primary central memory T cells. Methods 53:54–61PubMedCrossRefGoogle Scholar
  17. Boulanger MC, Liang C, Russell RS, Lin R, Bedford MT, Wainberg MA, Richard S (2005) Methylation of Tat by PRMT6 regulates human immunodeficiency virus type 1 gene expression. J Virol 79:124–131PubMedCrossRefGoogle Scholar
  18. Bres V, Kiernan R, Emiliani S, Benkirane M (2002) Tat acetyl-acceptor lysines are important for human immunodeficiency virus type-1 replication. J Biol Chem 277:22215–22221PubMedCrossRefGoogle Scholar
  19. Brooks DG, Kitchen SG, Kitchen CM, Scripture-Adams DD, Zack JA (2001) Generation of HIV latency during thymopoiesis. Nat Med 7:459–464PubMedCrossRefGoogle Scholar
  20. Bukrinsky M (2006) SNFing HIV transcription. Retrovirology 3:49PubMedCrossRefGoogle Scholar
  21. Bukrinsky MI, Sharova N, Dempsey MP, Stanwick TL, Bukrinskaya AG, Haggerty S, Stevenson M (1992) Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc Natl Acad Sci U S A 89:6580–6584PubMedCrossRefGoogle Scholar
  22. Butera ST, Perez VL, Wu BY, Nabel GJ, Folks TM (1991a) Oscillation of the human immunodeficiency virus surface receptor is regulated by the state of viral activation in a CD4+ cell model of chronic infection. J Virol 65:4645–4653PubMedGoogle Scholar
  23. Butera ST, Perez VL, Besansky NJ, Chan WC, Wu BY, Nabel GJ, Folks TM (1991b) Extrachromosomal human immunodeficiency virus type-1 DNA can initiate a spreading infection of HL-60 cells. J Cell Biochem 45:366–373PubMedCrossRefGoogle Scholar
  24. Cherrier T, Suzanne S, Redel L, Calao M, Marban C, Samah B, Mukerjee R, Schwartz C, Gras G, Sawaya BE, Zeichner SL, Aunis D, Van Lint C, Rohr O (2009) p21(WAF1) gene promoter is epigenetically silenced by CTIP2 and SUV39H1. Oncogene 28:3380–3389PubMedCrossRefGoogle Scholar
  25. Chiu YL, Soros VB, Kreisberg JF, Stopak K, Yonemoto W, Greene WC (2005) Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature 435:108–114PubMedCrossRefGoogle Scholar
  26. Choudhary SK, Archin NM, Margolis DM (2008) Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells. J Infect Dis 197:1162–1170PubMedCrossRefGoogle Scholar
  27. Choudhary SK, Rezk NL, Ince WL, Cheema M, Zhang L, Su L, Swanstrom R, Kashuba AD, Margolis DM (2009) Suppression of human immunodeficiency virus type 1 (HIV-1) viremia with reverse transcriptase and integrase inhibitors CD4+ T-cell recovery and viral rebound upon interruption of therapy in a new model for HIV treatment in the humanized Rag2−/−{gamma}c−/− mouse. J Virol 83:8254–8258PubMedCrossRefGoogle Scholar
  28. Chugh P, Fan S, Planelles V, Maggirwar SB, Dewhurst S, Kim B (2007) Infection of human immunodeficiency virus and intracellular viral Tat protein exert a pro-survival effect in a human microglial cell line. J Mol Biol 366:67–81PubMedCrossRefGoogle Scholar
  29. Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF (1995) In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1:1284–1290PubMedCrossRefGoogle Scholar
  30. Chun TW, Engel D, Mizell SB, Hallahan CW, Fischette M, Park S, Davey RT Jr, Dybul M, Kovacs JA, Metcalf JA, Mican JM, Berrey MM, Corey L, Lane HC, Fauci AS (1999) Effect of interleukin-2 on the pool of latently infected resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med 5:651–655PubMedCrossRefGoogle Scholar
  31. Chun TW, Justement JS, Lempicki RA, Yang J, Dennis G Jr, Hallahan CW, Sanford C, Pandya P, Liu S, Mc Laughlin M, Ehler LA, Moir S, Fauci AS (2003) Gene expression and viral prodution in latently infected resting CD4+ T cells in viremic versus aviremic HIV-infected individuals. Proc Natl Acad Sci U S A 100:1908–1913PubMedCrossRefGoogle Scholar
  32. Col E, Caron C, Seigneurin-Berny D, GraciaJ Favier A, Khochbin S (2001) The histone acetyltransferase hGCN5 interacts with and acetylates the HIV transactivator Tat. J Biol Chem 276:28179–28184PubMedCrossRefGoogle Scholar
  33. Contreras X, Barboric M, Lenasi T, Peterlin BM (2007) HMBA releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and activates HIV transcription. PLoS Pathog 3:1459–1469PubMedCrossRefGoogle Scholar
  34. Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, Peterlin BM (2009) Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem 284:6782–6789PubMedCrossRefGoogle Scholar
  35. Coull JJ, Romerio F, Sun JM, Volker JL, Galvin KM, Davie JR, Shi Y, Hansen U, Margolis DM (2000) The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J Virol 74:6790–6799PubMedCrossRefGoogle Scholar
  36. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749PubMedCrossRefGoogle Scholar
  37. Deng L, Wang D, de la Fuente C, Wang L, Li H, Lee CG, Donnelly R, Wade JD, Lambert P, Kashanchi F (2001) Enhancement of the p300 HAT activity by HIV-1 Tat on chromatin DNA. Virology 289:312–326PubMedCrossRefGoogle Scholar
  38. Dorr A, Kiermer V, Pedal A, Rackwitz HR, Henklein P, Schubert U, Zhou MM, Verdin E, Ott M (2002) Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. EMBO J 21:2715–2723PubMedCrossRefGoogle Scholar
  39. du Chene I, Basyuk E, Lin YL, Triboulet R, Knezevich A, Chable-Bessia C, Mettling C, Baillat V, Reynes J, Corbeau P, Bertrand E, Marcello A, Emiliani S, Kiernan R, Benkirane M (2007) Suv39H1 and HP1gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency. EMBO J 26:424–435PubMedCrossRefGoogle Scholar
  40. Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB (1989) Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A 86:5974–5978PubMedCrossRefGoogle Scholar
  41. Dutton RW, Bradley LM, Swain SL (1998) T cell memory. Annu Rev Immunol 16:201–223PubMedCrossRefGoogle Scholar
  42. Efstathiou S, Preston CM (2005) Towards an understanding of the molecular basis of herpes simplex virus latency. Virus Res 111:108–119PubMedCrossRefGoogle Scholar
  43. Emiliani S, Van Lint C, Fischle W, Paras P Jr, Ott M, Brady J, Verdin E (1996) A point mutation in the HIV-1 Tat responsive element is associated with postintegration latency. Proc Natl Acad Sci U S A 93:6377–6381PubMedCrossRefGoogle Scholar
  44. Emiliani S, Fischle W, Ott M, Van Lint C, Amella CA, Verdin E (1998) Mutations in the tat gene are responsible for human immunodeficiency virus type 1 postintegration latency in the U1 cell line. J Virol 72:1666–1670PubMedGoogle Scholar
  45. Farber DL, Acuto O, Bottomly K (1997) Differential T cell receptor-mediated signaling in naive and memory CD4 T cells. Eur J Immunol 27:2094–2101PubMedCrossRefGoogle Scholar
  46. Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS (1987) Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science 238:800–802PubMedCrossRefGoogle Scholar
  47. Folks TM, Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, Fauci AS (1989) Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A 86:2365–2368PubMedCrossRefGoogle Scholar
  48. Gallastegui E, Millan-Zambrano G, Terme JM, Chavez S, Jordan A (2011) Chromatin reassembly factors are involved in transcriptional interference promoting HIV latency. J Virol 85:3187–3202PubMedCrossRefGoogle Scholar
  49. Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR, Klomp LW, Wijmenga C, Duckett CS, Nabel GJ (2003) The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 426:853–857Google Scholar
  50. Gao L, Cueto MA, Asselbergs F, Atadja P (2002) Cloning and functional characterization of HDAC11 a novel member of the human histone deacetylase family. J Biol Chem 277:25748–25755PubMedCrossRefGoogle Scholar
  51. Garriga J, Peng J, Parreno M, Price DH, Henderson EE, Grana X (1998) Upregulation of cyclin T1/CDK9 complexes during T cell activation. Oncogene 17:3093–3102PubMedCrossRefGoogle Scholar
  52. Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC (2001) HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature 410:834–838PubMedCrossRefGoogle Scholar
  53. Giri MS, Nebozyhn M, Raymond A, Gekonge B, Hancock A, Creer S, Nicols C, Yousef M, Foulkes AS, Mounzer K, Shull J, Silvestri G, Kostman J, Collman RG, Showe L, Montaner LJ (2009) Circulating monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance. J Immunol 182:4459–4470PubMedCrossRefGoogle Scholar
  54. Greenway AL, McPhee DA, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S, Lambert P (2002) Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol 76:2692–2702PubMedCrossRefGoogle Scholar
  55. Grewal SI, Moazed D (2003) Heterochromatin and epigenetic control of gene expression. Science 301:798–802PubMedCrossRefGoogle Scholar
  56. Guillemard E, Jacquemot C, Aillet F, Schmitt N, Barre-Sinoussi F, Israel N (2004) Human immunodeficiency virus 1 favors the persistence of infection by activating macrophages through TNF. Virology 329:371–380PubMedCrossRefGoogle Scholar
  57. Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A, Filipowicz W (2005) TRBP a regulator of cellular PKR and HIV-1 virus expression interacts with Dicer and functions in RNA silencing. EMBO Rep 6:961–967PubMedCrossRefGoogle Scholar
  58. Han Y, Lassen K, Monie D, Sedaghat AR, Shimoji S, Liu X, Pierson TC, Margolick JB, Siliciano RF, Siliciano JD (2004) 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 78:6122–6133PubMedCrossRefGoogle Scholar
  59. Hargreaves DC, Crabtree GR (2011) ATP-dependent chromatin remodeling: genetics genomics and mechanisms. Cell Res 21:396–420PubMedCrossRefGoogle Scholar
  60. Hazuda DJ, Young SD, Guare JP, Anthony NJ, Gomez RP, Wai JS, Vacca JP, Handt L, Motzel SL, Klein HJ, Dornadula G, Danovich RM, Witmer MV, Wilson KA, Tussey L, Schleif WA, Gabryelski LS, Jin L, Miller MD, Casimiro DR, Emini EA, Shiver JW (2004) Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 305:528–532PubMedCrossRefGoogle Scholar
  61. He LM, Hsu J, Xue Y, Chou S, Burlingame A, Krogan NJ, Alber T, Zhou Q (2010) HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell 38:428–438PubMedCrossRefGoogle Scholar
  62. Henikoff S, Furuyama T, Ahmad K (2004) Histone variants nucleosome assembly and epigenetic inheritance. Trends Genet 20:320–326PubMedCrossRefGoogle Scholar
  63. Herrmann CH, Carroll RG, Wei P, Jones KA, Rice AP (1998) Tat-associated kinase TAK activity is regulated by distinct mechanisms in peripheral blood lymphocytes and promonocytic cell lines. J Virol 72:9881–9888PubMedGoogle Scholar
  64. Hofman MJ, Higgins J, Matthews TB, Pedersen NC, Tan C, Schinazi RF, North TW (2004) Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1. Antimicrob Agents Chemother 48:3483–3490PubMedCrossRefGoogle Scholar
  65. Huang J, Wang F, Argyris E, Chen K, Liang Z, Tian H, Huang W, Squires K, Verlinghieri G, Zhang H (2007) Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 13:1241–1247PubMedCrossRefGoogle Scholar
  66. Imai K, Okamoto T (2006) Transcriptional repression of human immunodeficiency virus type 1 by AP-4. J Biol Chem 281:12495–12505PubMedCrossRefGoogle Scholar
  67. Imai K, Togami H, Okamoto T (2010) Involvement of histone H3 lysine 9 (H3K9) methyltransferase G9a in the maintenance of HIV-1 latency and its reactivation by BIX01294. J Biol Chem 285:16538–16545PubMedCrossRefGoogle Scholar
  68. Janicki SM, Tsukamoto T, Salghetti SE, Tansey WP, Sachidanandam R, Prasanth KV, Ried T, Shav-Tal Y, Bertrand E, Singer RH, Spector DL (2004) From silencing to gene expression: real-time analysis in single cells. Cell 116:683–698PubMedCrossRefGoogle Scholar
  69. Jenkins MK, Khoruts A, Ingulli E, Mueller DL, McSorley SJ, Reinhardt RL, Itano A, Pape KA (2001) In vivo activation of antigen-specific CD4 T cells. Annu Rev Immunol 19:23–45PubMedCrossRefGoogle Scholar
  70. Jiang G, Espeseth A, Hazuda DJ, Margolis DM (2007) c-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter. J Virol 81:10914–10923PubMedCrossRefGoogle Scholar
  71. Jin C, Zang C, Wei G, Cui K, Peng W, Zhao K, Felsenfeld G (2009) H3.3/H2AZ double variant-containing nucleosomes mark ‘nucleosome-free regions’ of active promoters and other regulatory regions. Nat Genet 41:941–945PubMedCrossRefGoogle Scholar
  72. Jordan A, Bisgrove D, Verdin E (2003) HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J 22:1868–1877PubMedCrossRefGoogle Scholar
  73. Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G (1996) Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator. Virology 216:357–366PubMedCrossRefGoogle Scholar
  74. Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E (2009) Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog 5:e1000495PubMedCrossRefGoogle Scholar
  75. Keedy KS, Archin NM, Gates AT, Espeseth A, Hazuda DJ, Margolis DM (2009) A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression. J Virol 83:4749–4756Google Scholar
  76. Kiernan RE, Vanhulle C, Schiltz L, Adam E, Xiao H, Maudoux F, Calomme C, Burny A, Nakatani Y, Jeang KT, Benkirane M, Van Lint C (1999) HIV-1 tat transcriptional activity is regulated by acetylation. EMBO J 18:6106–6118PubMedCrossRefGoogle Scholar
  77. Klase Z, Kale P, Winograd R, Gupta MV, Heydarian M, Berro R, McCaffrey T, Kashanchi F (2007) HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol Biol 8:63PubMedCrossRefGoogle Scholar
  78. Klase Z, Winograd R, Davis J, Carpio L, Hildreth R, Heydarian M, Fu S, McCaffrey T, Meiri E, Ayash-Rashkovsky M, Gilad S, Bentwich Z, Kashanchi F (2009) HIV-1 TAR miRNA protects against apoptosis by altering cellular gene expression. Retrovirology 6:18PubMedCrossRefGoogle Scholar
  79. Klichko V, Archin N, Kaur R, Lehrman G, Margolis D (2006) Hexamethylbisacetamide remodels the human immunodeficiency virus type 1 (HIV-1) promoter and induces Tat-independent HIV-1 expression but blunts cell activation. J Virol 80:4570–4579PubMedCrossRefGoogle Scholar
  80. Korin YD, Zack JA (1999) Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0 lymphocytes. J Virol 73:6526–6532PubMedGoogle Scholar
  81. Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, Boyd MR, Pomerantz RJ (2001) Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 98:3006–3015PubMedCrossRefGoogle Scholar
  82. Kwon H, Imbalzano AN, Khavari PA, Kingston RE, Green MR (1994) Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370:477–481PubMedCrossRefGoogle Scholar
  83. Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM (2005) Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366:549–555PubMedCrossRefGoogle Scholar
  84. Lenasi T, Contreras X, Peterlin BM (2008) Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe 4:123–133PubMedCrossRefGoogle Scholar
  85. Levy DN, Refaeli Y, Weiner DB (1995) Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency. J Virol 69:1243–1252PubMedGoogle Scholar
  86. Lewinski MK, Yamashita M, Emerman M, Ciuffi A, Marshall H, Crawford G, Collins F, Shinn P, Leipzig J, Hannenhalli S, Berry CC, Ecker JR, Bushman FD (2006) Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog 2:e60PubMedCrossRefGoogle Scholar
  87. Liu H, Dow EC, Arora R, Kimata JT, Bull LM, Arduino RC, Rice AP (2006) Integration of human immunodeficiency virus type 1 in untreated infection occurs preferentially within genes. J Virol 80:7765–7768PubMedCrossRefGoogle Scholar
  88. MacNeil A, Sankale JL, Meloni ST, Sarr AD, Mboup S, Kanki P (2006) Genomic sites of human immunodeficiency virus type 2 (HIV-2) integration: similarities to HIV-1 in vitro and possible differences in vivo. J Virol 80:7316–7321PubMedCrossRefGoogle Scholar
  89. Mahmoudi T, Parra M, Vries RG, Kauder SE, Verrijzer CP, Ott M, Verdin E (2006) The SWI/SNF chromatin-remodeling complex is a cofactor for Tat transactivation of the HIV promoter. J Biol Chem 281:19960–19968PubMedCrossRefGoogle Scholar
  90. Maison C, Almouzni G (2004) HP1 and the dynamics of heterochromatin maintenance. Nat Rev Mol Cell Biol 5:296–304PubMedCrossRefGoogle Scholar
  91. Marban C, Suzanne S, Dequiedt F, de Walque S, Redel L, Van Lint C, Aunis D, Rohr O (2007) Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J 26:412–423PubMedCrossRefGoogle Scholar
  92. Marzio G, Tyagi M, Gutierrez MI, Giacca M (1998) HIV-1 tat transactivator recruits p300 and CREB-binding protein histone acetyltransferases to the viral promoter. Proc Natl Acad Sci U S A 95:13519–13524PubMedCrossRefGoogle Scholar
  93. Matalon S, Rasmussen TA, Dinarello CA (2011) Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med 17:466–472PubMedCrossRefGoogle Scholar
  94. McElhinny JA, MacMorran WS, Bren GD, Ten RM, Israel A, Paya CV (1995) Regulation of I kappa B alpha and p105 in monocytes and macrophages persistently infected with human immunodeficiency virus. J Virol 69:1500–1509PubMedGoogle Scholar
  95. Meyerhans A, Vartanian JP, Hultgren C, Plikat U, Karlsson A, Wang L, Eriksson S, Wain-Hobson S (1994) Restriction and enhancement of human immunodeficiency virus type 1 replication by modulation of intracellular deoxynucleoside triphosphate pools. J Virol 68:535–540PubMedGoogle Scholar
  96. Nabel G, Baltimore D (1987) An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326:711–713PubMedCrossRefGoogle Scholar
  97. Nathans R, Chu CY, Serquina AK, Lu CC, Cao H, Rana TM (2009) Cellular microRNA and P bodies modulate host-HIV-1 interactions. Mol Cell 34:696–709PubMedCrossRefGoogle Scholar
  98. Niederman TM, Thielan BJ, Ratner L (1989) Human immunodeficiency virus type 1 negative factor is a transcriptional silencer. Proc Natl Acad Sci U S A 86:1128–1132PubMedCrossRefGoogle Scholar
  99. North BJ, Verdin E (2004) Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol 5:224PubMedCrossRefGoogle Scholar
  100. O’Brien SK, Cao H, Nathans R, Ali A, Rana TM (2010) P-TEFb kinase complex phosphorylates histone H1 to regulate expression of cellular and HIV-1 genes. J Biol Chem 285:29713–29720PubMedCrossRefGoogle Scholar
  101. Ott M, Schnolzer M, Garnica J, Fischle W, Emiliani S, Rackwitz HR, Verdin E (1999) Acetylation of the HIV-1 Tat protein by p300 is important for its transcriptional activity. Curr Biol 9:1489–1492PubMedCrossRefGoogle Scholar
  102. Ouellet DL, Plante I, Landry P, Barat C, Janelle ME, Flamand L, Tremblay MJ, Provost P (2008) Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element. Nucleic Acids Res 36:2353–2365PubMedCrossRefGoogle Scholar
  103. Pagans S, Kauder SE, Kaehlcke K, Sakane N, Schroeder S, Dormeyer W, Trievel RC, Verdin E, Schnolzer M, Ott M (2010) The Cellular lysine methyltransferase Set7/9-KMT7 binds HIV-1 TAR RNA monomethylates the viral transactivator Tat and enhances HIV transcription. Cell Host Microbe 7:234–244PubMedCrossRefGoogle Scholar
  104. Palmer DK, O’Day K, Trong HL, Charbonneau H, Margolis RL (1991) Purification of the centromere-specific protein CENP-A and demonstration that it is a distinctive histone. Proc Natl Acad Sci U S A 88:3734–3738PubMedCrossRefGoogle Scholar
  105. Parker R, Sheth U (2007) P bodies and the control of mRNA translation and degradation. Mol Cell 25:635–646PubMedCrossRefGoogle Scholar
  106. Pearson R, Kim YK, Hokello J, Lassen K, Friedman J, Tyagi M, Karn J (2008) 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 82:12291–12303PubMedCrossRefGoogle Scholar
  107. Pomerantz RJ, Trono D, Feinberg MB, Baltimore D (1990) Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell 61:1271–1276PubMedCrossRefGoogle Scholar
  108. Pomerantz RJ, Seshamma T, Trono D (1992) Efficient replication of human immunodeficiency virus type 1 requires a threshold level of Rev: potential implications for latency. J Virol 66:1809–1813PubMedGoogle Scholar
  109. Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406:593–599PubMedCrossRefGoogle Scholar
  110. Reuse S, Calao M, Kabeya K, Guiguen A, Gatot JS, Quivy V, Vanhulle C, Lamine A, Vaira D, Demonte D, Martinelli V, Veithen E, Cherrier T, Avettand V, Poutrel S, Piette J, de Launoit Y, Moutschen M, Burny A, Rouzioux C, De Wit S, Herbein G, Rohr O, Collette Y, Lambotte O, Clumeck N, Van Lint C (2009) Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One 4:e6093PubMedCrossRefGoogle Scholar
  111. Rosenberg N, Jolicoeur P (1997) Retroviral pathogenesis. In: Coffin JM, Hughes SH, Varmus HE (eds) Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring HarborGoogle Scholar
  112. Ruddle NH, Armstrong MK, Richards FF (1976) Replication of murine leukemia virus in bone marrow-derived lymphocytes. Proc Natl Acad Sci U S A 73:3714–3718PubMedCrossRefGoogle Scholar
  113. Saleh S, Solomon A, Wightman F, Xhilaga M, Cameron PU, Lewin SR (2007) 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 110:4161–4164PubMedCrossRefGoogle Scholar
  114. Sahu GK, Cloyd MW (2011) Latent HIV in primary T lymphocytes is unresponsive to histone deacetylase inhibitors. Virol J 8:400Google Scholar
  115. Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110:521–529PubMedCrossRefGoogle Scholar
  116. Schwartz O, Marechal V, Le Gall S, Lemonnier F, Heard JM (1996) Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med 2:338–342PubMedCrossRefGoogle Scholar
  117. Scripture-Adams DD, Brooks DG, Korin YD, Zack JA (2002) Interleukin-7 induces expression of latent human immunodeficiency virus type 1 with minimal effects on T-cell phenotype. J Virol 76:13077–13082PubMedCrossRefGoogle Scholar
  118. Sung TL, Rice AP (2006) Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4+ T cells. Retrovirology 3:66PubMedCrossRefGoogle Scholar
  119. Swingler S, Mann AM, Zhou J, Swingler C, Stevenson M (2007) Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein. PLoS Pathog 3:1281–1290PubMedCrossRefGoogle Scholar
  120. Tong-Starksen SE, Luciw PA, Peterlin BM (1987) Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc Natl Acad Sci U S A 84:6845–6849PubMedCrossRefGoogle Scholar
  121. Treand C, du Chéné I, Bres V, Kiernan R, Benarous R, Benkirane M, Emiliani S (2006) Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediated activation of the HIV-1 promoter. EMBO J 25:1690–1699PubMedCrossRefGoogle Scholar
  122. Triboulet R, Mari B, Lin YL, Chable-Bessia C, Bennasser Y, Lebrigand K, Cardinaud B, Maurin T, Barbry P, Baillat V, Reynes J, Corbeau P, Jeang KT, Benkirane M (2007) Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 315:1579–1582PubMedCrossRefGoogle Scholar
  123. Tyagi M, Karn J (2007) CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J 26:4985–4995PubMedCrossRefGoogle Scholar
  124. Tyagi M, Pearson RJ, Karn J (2010) Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J Virol 84:6425–6437PubMedCrossRefGoogle Scholar
  125. Van Duyne R, Easley R, Wu W, Berro R, Pedati C, Klase Z, Kehn-Hall K, Flynn EK, Symer DE, Kashanchi F (2008) Lysine methylation of HIV-1 Tat regulates transcriptional activity of the viral LTR. Retrovirology 5:40PubMedCrossRefGoogle Scholar
  126. Varier RA, Kundu TK (2006) Chromatin modifications (acetylation/ deacetylation/ methylation) as new targets for HIV therapy. Curr Pharm Des 12:1975–1993PubMedCrossRefGoogle Scholar
  127. Verdin E, Dequiedt F, Kasler HG (2003) Class II histone deacetylases: versatile regulators. Trends Genet 19:286–293PubMedCrossRefGoogle Scholar
  128. Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD (2007) HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res 17:1186–1194PubMedCrossRefGoogle Scholar
  129. Wang X, Ye L, Hou W, Zhou Y, Wang YJ, Metzger DS, Ho WZ (2009) Cellular microRNA expression correlates with susceptibility of monocytes/macrophages to HIV-1 infection. Blood 113:671–674PubMedCrossRefGoogle Scholar
  130. Weissman JD, Brown JA, Howcroft TK, Hwang J, Chawla A, Roche PA, Schiltz L, Nakatani Y, Singer DS (1998) HIV-1 tat binds TAFII250 and represses TAFII250-dependent transcription of major histocompatibility class I genes. Proc Natl Acad Sci U S A 95:11601–11606PubMedCrossRefGoogle Scholar
  131. Weissman JD, Hwang JR, Singer DS (2001) Extensive interactions between HIV TAT and TAF(II)250. Biochim Biophys Acta 1546:156–163PubMedCrossRefGoogle Scholar
  132. Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC (2006) NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J 25:139–149PubMedCrossRefGoogle Scholar
  133. Williams SA, Kwon H, Chen LF, Greene WC (2007) Sustained induction of NF-kappa B is required for efficient expression of latent human immunodeficiency virus type 1. J Virol 81:6043–6056PubMedCrossRefGoogle Scholar
  134. Wong K, Sharma A, Awasthi S, Matlock EF, Rogers L, Van Lint C, Skiest DJ, Burns DK, Harrod R (2005) HIV-1 Tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB. J Biol Chem 280:9390–9399PubMedCrossRefGoogle Scholar
  135. Xie B, Invernizzi CF, Richard S, Wainberg MA (2007) Arginine methylation of the human immunodeficiency virus type 1 Tat protein by PRMT6 negatively affects Tat Interactions with both cyclin T1 and the Tat transactivation region. J Virol 81:4226–4234PubMedCrossRefGoogle Scholar
  136. Yang HC, Xing S, Shan L, O’Connell K, Dinoso J, Shen A, Zhou Y, Shrum CK, Han Y, Liu JO, Zhang H, Margolick JB, Siliciano RF (2009) Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J Clin Invest 119:3473–3486PubMedGoogle Scholar
  137. Yeung ML, Bennasser Y, Myers TG, Jiang G, Benkirane M, Jeang KT (2005) Changes in microRNA expression profiles in HIV-1-transfected human cells. Retrovirology 2:81PubMedCrossRefGoogle Scholar
  138. Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM (2004) Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS 18:1101–1108PubMedCrossRefGoogle Scholar
  139. Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS (1990) HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile latent viral structure. Cell 61:213–222PubMedCrossRefGoogle Scholar
  140. Zhang H (2009) Reversal of HIV-1 latency with anti-microRNA inhibitors. Int J Biochem Cell Biol 41:451–454PubMedCrossRefGoogle Scholar
  141. Zhou M, Halanski MA, Radonovich MF, Kashanchi F, Peng J, Price DH, Brady JN (2000) Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription. Mol Cell Biol 20:5077–5086PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.National Centre for Cell SciencePuneIndia

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