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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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.
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About this article
Nature Reviews Immunology (2019)