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Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy

Nature Medicine volume 6, pages 76–81 (2000)Cite this article

Abstract

Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays1,2. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells3,4 and from semen5. A reservoir of latently infected cells established early in infection6 may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy3,4,5. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of ‘covert’ virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.

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Figure 1: Detection of 2-LTR replication intermediates of HIV-1.
Figure 2: Stability of 2-LTR circles in vitro and in vivo.
Figure 3: Relationship between 2-LTR circle frequency and interval during which plasma viral RNA was undetectable in plasma (fewer than 50 copies/ml).
Figure 4: High-input virus co-culture assays for replication-competent HIV-1.

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References

  1. Perelson, A.S., Neumann, A.U., Markowtiz, M., Leonard, J.M. & Ho, D.D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582–1586 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  2. Gulick, R.M. et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy . N. Engl. J. Med. 337, 734– 739 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Wong, J.K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291– 1227 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Finzi, D., et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Zhang, H., et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N. Engl. J. Med. 339, 1803–1809 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Chun, T.W. et al. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc. Natl. Acad. Sci. USA 95, 8869–8873 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stevenson, M., et al. Integration is not necessary for expression of human immunodeficiency virus type 1 protein products. J. Virol. 64, 2421–2425 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang, L., et al. Rapid clearance of simian immunodeficiency virus particles from plasma of rhesus macaques. J. Virol. 73, 855–860 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang, L., et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N. Engl. J. Med. 340, 1605–1613 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Furtado, M.R. et al. Persistence of HIV-1 transcription in peripheral blood mononuclear cells in patients receiving potent antiretroviral therapy. N. Engl. J. Med. 340, 1614–1622 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  11. Brown, P.O., Bowerman, B., Varmus, H.E. & Bishop, J.M. Correct integration of retroviral DNA in vitro. Cell 49, 347–356 (1987).

    Article  CAS  PubMed  Google Scholar 

  12. Bukrinsky, M.I., Stanwick, T.L., Dempsey, M.P. & Stevenson, M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection . Science 254, 423–427 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Zack, J.A., et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 61, 213–222 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Stevenson, M., Stanwick, T.L., Dempsey, M.P. & Lamonica, C.A. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 9, 1551– 1560 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sonza, S., et al. Human immunodeficiency virus type 1 replication is blocked prior to reverse transcription and integration in freshly isolated peripheral blood monocytes. J. Virol. 70, 3863– 3869 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Livingstone, W.J., Moore, M., Innes, D., Bell, J.E. & Simmonds, P. Frequent infection of peripheral blood CD8-positive T-lymphocytes with HIV-1. Edinburgh Heterosexual Transmission Study Group . Lancet 348, 649–654 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Chun, T.W. et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183–188 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Spina, C.A., Prince, H.E. & Richman, D.D. Preferential replication of HIV-1 in the CD45RO memory cell subset of primary CD4 lymphocytes in vitro. J. Clin. Invest. 99, 1774–1785 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Riley, J.L., et al. Naive and memory CD4 T cells differ in their susceptibilities to human immunodeficiency virus type 1 infection following CD28 costimulation: implications for transmission and pathogenesis. J. Virol. 72, 8273–8280 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Finzi, D., et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Med. 5, 512– 517 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Cowan, N.J., Dobner, P.R., Fuchs, E.V. & Cleveland, D.W., Expression of human alpha-tubulin genes: interspecies conservation of 3′ untranslated regions. Mol. Cell. Biol. 3, 1738–1745 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank P. Himlan, L. Mangini, C. Jaffarian, B. Cullen and L. O'Reilly for patient recruitment and scheduling; M. McManus for data management; C. Waterworth and G. Sontag of Imperial College and research associates in the laboratory of pediatric immunology at UMass Medical School for technical assistance; N. Bakker for manuscript preparation; and B. Mellor for assistance in preparation of the figures. Jurkat-CCR5 cells were obtained from M. Emerman. This work was supported in part by National Institutes of Health grants RR11589, HL57880 (M.S.) AI 32391 (K.L.), and AI32907 (J.L.S.). M. Sharkey is the recipient of a National Institutes of Health training grant (T32 AI07272). K. Luzuriaga is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation.

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Authors and Affiliations

  1. University of Massachusetts Medical School, Program in Molecular Medicine, 373 Plantation Street, Suite 319, Worcester, 01605, Massachusetts, USA

    Mark E. Sharkey, Natalia Sharova & Mario Stevenson

  2. Department of Infectious Diseases, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK

    Ian Teo, Claire Veryard & Sunil Shaunak

  3. Department of Pediatrics, University of Massachusetts Medical School, 373 Plantation Street, Suite 318, Worcester, 01605, Massachusetts, USA

    Thomas Greenough, Katherine Luzuriaga & John L. Sullivan

  4. Department of Pathology, University of Alabama at Birmingham, SW W287, 619 South 19thStreet, Birmingham, 35233, Alabama, USA

    R. Pat Bucy

  5. Aaron Diamond AIDS Research Center, Rockefeller University, 455 First Avenue, New York, 10016, New York, USA

    Leondios G. Kostrikis

  6. Department of Microbiology, University of Minnesota, 420 Delaware Street, S.E. Box 196, Minneapolis, 55455, Minnesota, USA

    Ashley Haase

  7. Division of Infectious Diseases, University of Massachusetts/Memorial Health Care, 55 Lake Avenue North, Worcester, 01655, Massachusetts, USA

    Raul E. Davaro, Sarah H. Cheeseman, Jennifer S. Daly, Carol Bova, Richard T. Ellison III, Brian Mady & Kwan Kew Lai

  8. Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK

    Graeme Moyle, Mark Nelson & Brian Gazzard

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Correspondence to Mario Stevenson.

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Sharkey, M., Teo, I., Greenough, T. et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nat Med 6, 76–81 (2000). https://doi.org/10.1038/71569

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