Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations

Kai Deng, Mihaela Pertea, Anthony Rongvaux, Leyao Wang, Christine M. Durand, Gabriel Ghiaur, Jun Lai, Holly L. McHugh, Haiping Hao, Hao Zhang, Joseph B. Margolick, Cagan Gurer, Andrew J. Murphy, David M. Valenzuela, George D. Yancopoulos, Steven G. Deeks, Till Strowig, Priti Kumar, Janet D. Siliciano, Steven L. SalzbergRichard A. Flavell, Liang Shan, Robert F. Siliciano

Research output: Contribution to journalArticlepeer-review

384 Scopus citations

Abstract

Despite antiretroviral therapy (ART),humanimmunodeficiency virus (HIV)-1 persists in a stable latent reservoir1,2, primarily in resting memory CD41 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 vivo6-8. A key remaining question is whether virusspecific 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 escapemutations that render infectedcells insensitive toCTLsdirected at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes fromlatent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived fromthe latent reservoir, bothinvitro andinpatient-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.

Original languageEnglish
Pages (from-to)381-385
Number of pages5
JournalNature
Volume517
Issue number7534
DOIs
StatePublished - Jan 15 2015

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