Immunity
Volume 38, Issue 3, 21 March 2013, Pages 425-436
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Article
A Molecular Basis for the Control of Preimmune Escape Variants by HIV-Specific CD8+ T Cells

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Summary

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8+ T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B2705. We found that cross-reactive CD8+ T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B2705+ individuals. A protective CD8+ T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.

Highlights

► New T cell clonotypes are recruited to counter TCR-accessible HIV mutations ► These T cells express TCRs that crossrecognize wild-type and mutant epitopes ► Crossreactive CD8+ T cells underpin anti-HIV efficacy in HLA-B27+ patients ► T cell efficacy ultimately drives escape mutations that impact antigen presentation

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11

These authors contributed equally to this work

12

These authors contributed equally to this work