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Abstract

Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir1,2, primarily in resting memory CD4+ T cells3,4. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed5 and tested both in vitro and in vivo6,7,8. A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (>98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.

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Acknowledgements

We thank all study participants. We thank J. Blankson for critical advice to the project; L. Alston and R. Hoh for coordinating patient recruitment; J. Alderman, C. Weibel and E. Henchey for technical assistance in the animal study. We thank the National Institutes of Health (NIH) AIDS Reagent Program for providing HIV-1 consensus B peptides. R.F.S. is supported by the Howard Hughes Medical Institute, by the Martin Delaney CARE and DARE Collaboratories (NIH grants AI096113 and 1U19AI096109), by an ARCHE Collaborative Research Grant from the Foundation for AIDS Research (amFAR 108165-50-RGRL), by the Johns Hopkins Center for AIDS Research (P30AI094189), and by NIH grant 43222. L.S. is supported by NIH grant T32 AI07019. R.A.F. is supported by the Bill and Melinda Gates Foundation and the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Kai Deng
    • , Mihaela Pertea
    • , Christine M. Durand
    • , Jun Lai
    • , Holly L. McHugh
    • , Janet D. Siliciano
    •  & Robert F. Siliciano
  2. Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Mihaela Pertea
    •  & Steven L. Salzberg
  3. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Anthony Rongvaux
    • , Till Strowig
    • , Richard A. Flavell
    •  & Liang Shan
  4. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA

    • Leyao Wang
  5. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Gabriel Ghiaur
  6. Deep Sequencing and Microarray Core, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Haiping Hao
  7. Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA

    • Hao Zhang
    •  & Joseph B. Margolick
  8. Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA

    • Cagan Gurer
    • , Andrew J. Murphy
    • , David M. Valenzuela
    •  & George D. Yancopoulos
  9. Department of Medicine, University of California, San Francisco, San Francisco, California 94110, USA

    • Steven G. Deeks
  10. Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Priti Kumar
  11. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Steven L. Salzberg
  12. Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA

    • Richard A. Flavell
  13. Howard Hughes Medical Institute, Baltimore, Maryland 21205, USA

    • Robert F. Siliciano

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Contributions

K.D., L.S., R.A.F. and R.F.S. conceived and designed the research studies; K.D., J.L., H.Z., J.B.M. and L.S. performed the in vitro experiments; K.D., A.R., L.W., C.G., A.J.M., D.M.V., G.D.Y., T.S., P. K. and L.S. performed animal experiments; C.M.D., G.G., H.L.M. and S.G.D. provided patient samples; K.D., M.P., L.W., H.H., J.D.S., S.L.S., L.S. and R.F.S. analysed data; K.D., L.S. and R.F.S. wrote the manuscript.

Competing interests

C.G., A.J.M., D.M.V. and G.D.Y. are employees and shareholders of Regeneron Pharmaceuticals, Inc.

Corresponding authors

Correspondence to Richard A. Flavell or Liang Shan or Robert F. Siliciano.

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DOI

https://doi.org/10.1038/nature14053

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