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Impaired replication of protease inhibitor-resistant HIV-1 in human thymus

Nature Medicine volume 7, pages 712–718 (2001)Cite this article

Abstract

Many HIV-1–infected patients treated with protease inhibitors (PI) develop PI-resistant HIV-1 variants and rebounds in viremia, but their CD4+ T-cell counts often do not fall. We hypothesized that in these patients, T-cell counts remain elevated because PI-resistant virus spares intrathymic T-cell production. To test this, we studied recombinant HIV-1 clones containing wild-type or PI-resistant protease domains, as well as uncloned isolates from patients, in activated peripheral blood mononuclear cells, human thymic organ cultures and human thymus implants in SCID-hu Thy/Liv mice. In most cases, wild-type and PI-resistant HIV-1 isolates replicated to similar degrees in peripheral blood mononuclear cells. However, the replication of PI-resistant but not wild-type HIV-1 isolates was highly impaired in thymocytes. In addition, patients who had PI-resistant HIV-1 had abundant thymus tissue as assessed by computed tomography. We propose that the inability of PI-resistant HIV-1 to replicate efficiently in thymus contributes to the preservation of CD4+ T-cell counts in patients showing virologic rebound on PI therapy.

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Figure 1: Replication of PI-resistant recombinant HIV-1 is moderately impaired in PHA-activated PBMCs.
Figure 2: Profound impairment of PI-resistant HIV-1 for replication in human thymus.
Figure 3: 210WT replicates more efficiently than does 210P in human thymic organ culture, although both viruses appear to infect similar thymocyte subpopulations.
Figure 4: Viral load, CD4+ T-cell decline, and viral replication kinetics for three patients after treatment interruption.
Figure 5: Patients exhibiting discordant responses have abundant thymus.

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Acknowledgements

We thank M.B. Moreno, C. Bare, J. Bare, K.H. Lee and D. Schmidt for expert assistance; the individuals who participated in this study, Survive AIDS, Project Inform, and other members of the San Francisco AIDS community for support; and the San Francisco General Hospital Department of Radiology for assistance with the CT scans. This work was supported by grants from the NIH to J.M.M. (AI43864 and AI65309) and to C.A.S. (AI05418). Additional funding was provided by the University of California, San Francisco Center for AIDS Research (P30 MH59037), the California Universitywide AIDS Research Program (M98-B-1100) and NIH Grant 5-MO1-RR00083 from the Division of Research Resources supported the General Clinical Research Center.

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Authors and Affiliations

  1. Gladstone Institute of Virology and Immunology, University of California at San Francisco, San Francisco, California, USA

    Cheryl A. Stoddart, Teri J. Liegler, Valerie D. Linquist-Stepps, Matthew S. Hayden, Robert M. Grant & Joseph M. McCune

  2. Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California, USA

    Steven G. Deeks, Robert M. Grant & Joseph M. McCune

  3. Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA

    Joseph M. McCune

  4. INSERM U552, Recherche Antivirale, IMEA, Hôpital Bichat-Claude Bernard, Paris, France

    Fabrizio Mammano & François Clavel

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  1. Cheryl A. Stoddart
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Correspondence to Cheryl A. Stoddart.

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Stoddart, C., Liegler, T., Mammano, F. et al. Impaired replication of protease inhibitor-resistant HIV-1 in human thymus. Nat Med 7, 712–718 (2001). https://doi.org/10.1038/89090

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