A Molecular Basis for the Control of Preimmune Escape Variants by HIV-Specific CD8+ T Cells

Abstract

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)-B∗2705. 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-B∗2705+ 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.

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

“…Under selection pressure from the immune system, HIV-1 also mutates rapidly to evade cytotoxic T lymphocyte responses. These epitopecentric escape mutations typically alter the conformation of exposed residues that interact with the T-cell receptor 50,51,52,53 or abrogate peptide presentation via effects on antigen processing or HLA-I binding 54,55 . Here, we report a novel mode of escape whereby the common T3N mutant exploits the P-1 overhang of TW10 and the anchor residue preferences in the A and B pockets to shift the register of the peptide within HLA-B*57:01.…”

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…Furthermore, special thymic selection inducing a larger B27-driven CD8 1 T cell precursor repertoire, preferential usage of certain T cell receptor (TCR) clonotypes associated with higher cross-reactive and, finally, better capacity of evasion from regulatory T cell (T reg )-mediated suppression have also been documented [55][56][57][58].…”

A Molecular Basis for the Interplay between T Cells, Viral Mutants, and Human Leukocyte Antigen Micropolymorphism

“…However, to escape immune surveillance, viruses have deployed a wide range of strategies, including interfering with the Ag-processing machinery and mutating T cell epitopes (13,14). Mutations within major histocompatibility complex (MHC)-bound peptides can potentially impact on MHC binding or TCR recognition, which can subsequently lead to immune escape.…”