Journal of the Formosan Medical Association
Volume 107, Issue 12 , Pages 909-914, December 2008

Waking Up the Sleepers: HIV Latency and Reactivation

  • Hoi Ping Mok
    • ,
  • Andrew Lever

      Affiliations

    • Corresponding Author InformationCorrespondence to: Dr Andrew Lever, Level 5, Addenbrooke's Hospital, Hill's Road, Cambridge, CB2 0QQ, UK

Department of Medicine, University of Cambridge, Cambridge, UK

Received 12 August 2008; received in revised form 3 October 2008; accepted 3 October 2008.

Article Outline

In a patient infected with HIV-1, the presence of latently infected cells from which the virus can be reactivated and rekindle HIV infection in the patient necessitates lifelong administration of antiretroviral treatment. The biology of HIV latency and viral silencing is now becoming clearer at a molecular and cellular level. However, our understanding of HIV-1 latency in vivo is still inadequate. Attempts to therapeutically reactivate the virus in infected patients have yielded disappointing results. This article reviews the research and clinical findings and discusses current thinking on the subject of HIV latency and reactivation.

Key Words:  anti-HIV agents , HIV: physiology , virus latency

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References 

  1. Chun TW , Davey RT Jr , Engel D , et al.   Re-emergence of HIV after stopping therapy . Nature . 1999;401:874–875
  2. Davey RT , Bhat N , Yoder C , et al.   HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression . Proc Natl Acad Sci U S A . 1999;96:15109–15114
  3. Simon V , Ho DD . HIV-1 dynamics in vivo: implications for therapy . Nat Rev Microbiol . 2003;1:181–190
  4. Havlir DV , Strain MC , Clerici M , et al.   Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years . J Virol . 2003;77:11212–11219
  5. Petitjean G , Al Tabaa Y , Tuaillon E , et al.   Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients . Retrovirology . 2007;4:60
  6. Sharkey M , Triques K , Kuritzkes DR , et al.   In vivo evidence for instability of episomal human immunodeficiency virus type 1 cDNA . J Virol . 2005;79:5203–5210
  7. Embretson J , Zupancic M , Beneke J , et al.   Analysis of human immunodeficiency virus-infected tissues by amplification and in situ hybridization reveals latent and permissive infections at single-cell resolution . Proc Natl Acad Sci U S A . 1993;90:357–361
  8. Embretson J , Zupancic M , Ribas JL , et al.   Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS . Nature . 1993;362:359–362
  9. Patterson BK , Till M , Otto P , et al.   Detection of HIV-1 DNA and messenger RNA in individual cells by PCR-driven in situ hybridization and flow cytometry . Science . 1993;260:976–979
  10. 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;79:5185–5202
  11. Ruff CT , Ray SC , Kwon P , et al.   Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure . J Virol . 2002;76:9481–9492
  12. Parera M , Ibanez A , Clotet B , et al.   Lack of evidence for protease evolution in HIV-1-infected patients after 2 years of successful highly active antiretroviral therapy . J Infect Dis . 2004;189:1444–1451
  13. Sedaghat AR , Siliciano JD , Brennan TP , et al.   Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART . PLoS Pathog . 2007;3:e122
  14. Sedaghat AR , Siliciano RF , Wilke CO . Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART . BMC Infect Dis . 2008;8:2
  15. Ciuffi A , Bleiber G , Munoz M , et al.   Entry and transcription as key determinants of differences in CD4 T-cell permissiveness to human immunodeficiency virus type 1 infection . J Virol . 2004;78:10747–10754
  16. Vandegraaff N , Kumar R , Burrell CJ , et al.   Kinetics of human immunodeficiency virus type 1 (HIV) DNA integration in acutely infected cells as determined using a novel assay for detection of integrated HIV DNA . J Virol . 2001;75:11253–11260
  17. Weinberger LS , Burnett JC , Toettcher JE , et al.   Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity . Cell . 2005;122:169–182
  18. Mok HP , Javed S , Lever A . Stable gene expression occurs from a minority of integrated HIV-1-based vectors: transcriptional silencing is present in the majority . Gene Ther . 2007;14:741–751
  19. Jeeninga RE , Westerhout EM , van Gerven ML , et al.   HIV-1 latency in actively dividing human T cell lines . Retrovirology . 2008;5:37
  20. Lewinski MK , Bisgrove D , Shinn P , et al.   Genome-wide analysis of chromosomal features repressing human immunodeficiency virus transcription . J Virol . 2005;79:6610–6619
  21. Steger DJ , Eberharter A , John S , et al.   Purified histone acetyltransferase complexes stimulate HIV-1 transcription from preassembled nucleosomal arrays . Proc Natl Acad Sci U S A . 1998;95:12924–12929
  22. 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;74:6790–6799
  23. Lusic M , Marcello A , Cereseto A , et al.   Regulation of HIV-1 gene expression by histone acetylation and factor recruitment at the LTR promoter . EMBO J . 2003;22:6550–6561
  24. Ylisastigui L , Coull JJ , Rucker VC , et al.   Polyamides reveal a role for repression in latency within resting T cells of HIV-infected donors . J Infect Dis . 2004;190:1429–1437
  25. Quivy V , Adam E , Collette Y , et al.   Synergistic activation of human immunodeficiency virus type 1 promoter activity by NF-kappaB and inhibitors of deacetylases: potential perspectives for the development of therapeutic strategies . J Virol . 2002;76:11091–11103
  26. Lutzko C , Senadheera D , Skelton D , et al.   Lentivirus vectors incorporating the immunoglobulin heavy chain enhancer and matrix attachment regions provide position-independent expression in B lymphocytes . J Virol . 2003;77:7341–7351
  27. Rampalli S , Kulkarni A , Kumar P , et al.   Stimulation of Tatindependent transcriptional processivity from the HIV-1 LTR promoter by matrix attachment regions . Nucleic Acids Res . 2003;31:3248–3256
  28. Pereira LA , Bentley K , Peeters A , et al.   A compilation of cellular transcription factor interactions with the HIV-1 LTR promoter . Nucleic Acids Res . 2000;28:663–668
  29. Nelson DE , Ihekwaba AE , Elliott M , et al.   Oscillations in NF-kappaB signaling control the dynamics of gene expression . Science . 2004;306:704–708
  30. Mikovits JA , Young HA , Vertino P , et al.   Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-gamma production . Mol Cell Biol . 1998;18:5166–5177
  31. Klase Z , Kale P , Winograd R , et al.   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 . 2007;8:63
  32. Huang J , Wang F , Argyris E , et al.   Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes . Nat Med . 2007;13:1241–1247
  33. Han Y , Wind-Rotolo M , Yang HC , et al.   Experimental approaches to the study of HIV-1 latency . Nat Rev Microbiol . 2007;5:95–106
  34. 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;9:727–728
  35. 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;5:512–517
  36. Brenchley JM , Hill BJ , Ambrozak DR , et al.   T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis . J Virol . 2004;78:1160–1168
  37. Haase AT , Henry K , Zupancic M , et al.   Quantitative image analysis of HIV-1 infection in lymphoid tissue . Science . 1996;274:985–989
  38. Cavert W , Notermans DW , Staskus K , et al.   Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection . Science . 1997;276:960–964
  39. 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
  40. Katz RA , Jack-Scott E , Narezkina A , et al.   High-frequency epigenetic repression and silencing of retroviruses can be antagonized by histone deacetylase inhibitors and transcriptional activators, but uniform reactivation in cell clones is restricted by additional mechanisms . J Virol . 2007;81:2592–2604
  41. Williams SA , Chen LF , Kwon H , et al.   Prostratin antagonizes HIV latency by activating NF-kappaB . J Biol Chem . 2004;279:42008–42017
  42. 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;78:10507–10515
  43. Wang FX , Xu Y , Sullivan J , et al.   IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART . J Clin Invest . 2005;115:128–137
  44. Israel N , Hazan U , Alcami J , et al.   Tumor necrosis factor stimulates transcription of HIV-1 in human T lymphocytes, independently and synergistically with mitogens . J Immunol . 1989;143:3956–3960
  45. Chun TW , Engel D , Mizell SB , et al.   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 . 1999;5:651–655
  46. Lehrman G , Hogue IB , Palmer S , et al.   Depletion of latent HIV-1 infection in vivo: a proof-of-concept study . Lancet . 2005;366:549–555
  47. Siliciano JD , Lai J , Callender M , et al.   Stability of the latent reservoir for HIV-1 in patients receiving valproic acid . J Infect Dis . 2007;195:833–836
  48. Sagot-Lerolle N , Lamine A , Chaix ML , et al.   Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir . AIDS . 2008;22:1125–1129
  49. Lorincz MC , Schubeler D , Goeke SC , et al.   Dynamic analysis of proviral induction and de novo methylation: implications for a histone deacetylase-independent, methylation densitydependent mechanism of transcriptional repression . Mol Cell Biol . 2000;20:842–850

PII: S0929-6646(09)60013-9

doi:10.1016/S0929-6646(09)60013-9

Journal of the Formosan Medical Association
Volume 107, Issue 12 , Pages 909-914, December 2008

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