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¹ Partners AIDS Research Center, Massachusetts General Hospital, and Harvard University Center for AIDS Research, Boston, MA 02129
² Boston Biomedical Research Institute, Watertown, MA 02472
³ Department of Pathology, Cambridge University, Cambridge CB2 1TN, UK
⁴ Howard Hughes Medical Institute, Chevy Chase, MD 20815

CORRESPONDENCE Xu G. Yu: xyu{at}partners.org

Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8⁺ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide–major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705–restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1–specific CD8⁺ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1–specific CD8⁺ T cells, the HLA-B2705–KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I–specific receptor expressed on myelomonocytic cells. Binding of the B2705–KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversification.

M. Lichterfeld and D.G. Kavanagh contributed equally to this work.

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