Skip to main content

Advertisement

Log in

Confronting proviral HIV infection

  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

The course of HIV infection is arrested by antiretroviral therapy (ART). However, life-long ART is undesirable. To eradicate infection, strategies are needed to deplete the rare population of proviral genomes that persist and reemerge if ART is interrupted. Proviral HIV persists due to the simultaneous deficiency of factors required to allow proviral expression and virion production, and a predominance of factors that obstruct proviral expression. Combining ART with global inducers of T-cell activation has so far failed to eradicate HIV infection. One approach to the selective removal of obstacles to proviral expression, inhibition of the chromatin remodeling enzyme histone deacetylase, has entered clinical testing. Additional approaches may be needed. Ultimately, therapies that eliminate rare cells that persistently express HIV and interrupt low levels of viremia that persist in some patients may be required to render depletion of proviral HIV infection clinically relevant, and lead to the clearance of HIV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Joint Untied Nations Programme on HIV/AIDS/World Health Organization: AIDS Epidemic Update: December 2006. http://www.unaids.org/en/HIV_data/epi2006/default.asp. Accessed on January 26, 2007.

  2. Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 2004. Volume 16. Atlanta, GA: Department of Health and Human Services; 2005.

    Google Scholar 

  3. Letvin NL: Progress and obstacles in the development of an AIDS vaccine. Nat Rev Immunol 2006, 6:930–939.

    Article  PubMed  CAS  Google Scholar 

  4. Chen RY, Accortt NA, Westfall AO, et al.: Distribution of health care expenditures for HIV-infected patients. Clin Infect Dis 2006, 42:1003–1010.

    Article  PubMed  CAS  Google Scholar 

  5. Carr A: Toxicity of antiretroviral therapy and implications for drug development. Nat Rev Drug Discov 2003, 2:624–634.

    Article  PubMed  CAS  Google Scholar 

  6. Chun TW, Finzi D, Margolick J, et al.: In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med 1995, 1:1284–1290.

    Article  PubMed  CAS  Google Scholar 

  7. Chun TW, Carruth L, Finzi D, et al.: Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997, 387:183–188.

    Article  PubMed  CAS  Google Scholar 

  8. Chun TW, Stuyver L, Mizell SB, et al.: Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 1997, 94:13193–13197.

    Article  PubMed  CAS  Google Scholar 

  9. Finzi D, Hermankova M, Pierson T, et al.: Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997, 278:1295–1300.

    Article  PubMed  CAS  Google Scholar 

  10. Wong JK, Hezareh M, Gunthard HF, et al.: Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997; 278:1291–5.

    Article  PubMed  CAS  Google Scholar 

  11. Williams SA, Greene WC: Host factors regulating post-integration latency of HIV. Trends Microbiol 2005, 13:137–139.

    Article  PubMed  CAS  Google Scholar 

  12. Swiggard WJ, Baytop C, Yu JJ, et al.: Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. J Virol 2005, 79:14179–14188.

    Article  PubMed  CAS  Google Scholar 

  13. Swingler S, Brichacek B, Jacque JM, et al.: HIV-1 Nef intersects the macrophage CD40L signaling pathway to promote resting-cell infection. Nature 2003, 424:213–219.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    Article  PubMed  CAS  Google Scholar 

  15. 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.

    Article  PubMed  CAS  Google Scholar 

  16. 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, 70:646–659.

    Article  PubMed  CAS  Google Scholar 

  17. Martin-Serrano J, Li K, Bieniasz PD: Cyclin T1 expression is mediated by a complex and constitutively active promoter and does not limit human immunodeficiency virus type 1 Tat function in unstimulated primary lymphocytes. J Virol 2002, 76:208–219.

    Article  PubMed  CAS  Google Scholar 

  18. Lassen KG, Ramyar KX, Bailey JR, et al.: Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog 2006, 2:e68.

    Article  PubMed  Google Scholar 

  19. Schroer AR, Shinn P, Chen H, et al.: HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002, 110:521–529.

    Article  Google Scholar 

  20. Van Lint C, Emiliani S, Ott M, et al.: Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J 1996, 15:1112–1120.

    PubMed  Google Scholar 

  21. Sheridan PL, Mayall TP, Verdin E, et al.: Histone acetyltransferases regulate HIV-1 enhancer activity in vitro. Genes Dev 1997, 11:3327–3340.

    PubMed  CAS  Google Scholar 

  22. Jenuwein T, Allis CD: Translating the histone code. Science 2001, 293:1074–1080.

    Article  PubMed  CAS  Google Scholar 

  23. Romerio F, Gabriel MN, Margolis DM: Repression of HIV-1 through the novel cooperation of the human factors YY1 and LSF. J Virol 1997, 71:9375–9382.

    PubMed  CAS  Google Scholar 

  24. Coull J, Romerio F, Sun J-M, 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.

    Article  PubMed  CAS  Google Scholar 

  25. Coull JJ, He G, Melander C, et al.: Targeted derepression of the human immunodeficiency type 1 long terminal repeat by pyrrole-imidazole polyamides. J Virol 2002, 76:12349–12354.

    Article  PubMed  CAS  Google Scholar 

  26. Ylisastigui L, Coull JJ, Rucker V, et al.: Polyamides reveal a role for repression in viral latency within HIV-infected donors’ resting CD4+ cells. J Infect Dis 2004, 190:1429–1437.

    Article  PubMed  CAS  Google Scholar 

  27. Kovacs JA, Lempicki RA, Sidorov IA, et al.: Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. J Clin Invest 2005, 115:2139–2148.

    Article  PubMed  CAS  Google Scholar 

  28. 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 antive antiretroviral therapy. Nat Med 1999, 5:651–655.

    Article  PubMed  CAS  Google Scholar 

  29. Dybul M, Hidalgo B, Chun TW, et al.: Pilot study of the effects of intermittent interleukin-2 on human immunodeficiency virus (HIV)-specific immune responses in patients treated during recently acquired HIV infection. J Infect Dis 2002, 185:61–68.

    Article  PubMed  CAS  Google Scholar 

  30. Stellbrink HJ, van Lunzen J, Westby M, et al.: Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS 2002, 16:1479–1487. [Published erratum appears in AIDS 2002, 16:2103.]

    Article  PubMed  CAS  Google Scholar 

  31. Prins JM, Jurriaans S, van Praag RM, et al.: Immunoactivation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 1999, 13:2405–2410.

    Article  PubMed  CAS  Google Scholar 

  32. van Praag RM, Prins JM, Roos MT, et al.: OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. J Clin Immunol 2001, 21:218–226.

    Article  PubMed  Google Scholar 

  33. Kulkosky J, Nunnari G, Otero M, et al.: Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J Infect Dis 2002, 186:1403–1411.

    Article  PubMed  CAS  Google Scholar 

  34. Fraser C, Ferguson NM, Ghani AC, et al.: Reduction of the HIV-1 infected T cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS 2002, 14:659–669.

    Article  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. Warrilow D, Gardner J, Darnell GA, et al.: HIV type 1 inhibition by protein kinase C modulatory compounds. AIDS Res Hum Retroviruses 2006, 22:854–864.

    Article  PubMed  CAS  Google Scholar 

  37. Kulkosky J, Culnan DM, Roman J, et al.: Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 2001, 98:3006–3015.

    Article  PubMed  CAS  Google Scholar 

  38. Williams SA, Chen LF, Kwon H, et al.: Prostratin antagonizes HIV latency by activating NF-kappaB. J Biol Chem 2004, 279:42008–42017.

    Article  PubMed  CAS  Google Scholar 

  39. 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.

    Article  PubMed  Google Scholar 

  40. Hamer DH, Bocklandt S, McHugh L, et al.: Rational design of drugs that induce human immunodeficiency virus replication. J Virol 2003, 77:10227–10236.

    Article  PubMed  CAS  Google Scholar 

  41. Zeichner SL, Hirka G, Andrews PW, et al.: Differentiation-dependent human immunodeficiency virus long terminal repeat regulatory elements active in human teratocarcinoma cells. J Virol 1992, 66:2268–2273.

    PubMed  CAS  Google Scholar 

  42. Klichko V, Archin N, Kaur R, et al.: Hexamethylbisacetamide remodels the human immunodeficiency virus type 1 (HIV-1) promoter and induces Tat-independent HIV-1 expression but blunts cell activation. J Virol 2006, 80:4570–4579.

    Article  PubMed  CAS  Google Scholar 

  43. Andreeff M, Stone R, Michaeli J, et al.: Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation-inducing agent. Blood 1992, 80:2604–2609.

    PubMed  CAS  Google Scholar 

  44. Ylisastigui L, Archin NM, Lehrman G, et al.: Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS 2004, 18:1101–1108.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. Archin N, Harmann Duff A, Eron J, et al.: Attacking latent HIV: towards eradication of HIV infection [abstract TUPE0059]. Presented at the XVI International AIDS Conference. Toronto, Canada; August 13–18, 2006.

  47. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al.: Phase 1/2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia. Blood 2006, 108:3271–3279.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David M. Margolis MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Margolis, D.M. Confronting proviral HIV infection. Curr HIV/AIDS Rep 4, 60–64 (2007). https://doi.org/10.1007/s11904-007-0009-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-007-0009-6

Keywords

Navigation