Polymorphic residues in HLA-B that mediate HIV control distinctly modulate peptide interactions with both TCR and KIR molecules.

Autor:	Tano-Menka R; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Singh NK; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Muzhingi I; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Li X; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; The First Affiliated School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China., Mandanas MV; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA., Kaseke C; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Crain CR; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Zhang A; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Ogunshola FJ; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Vecchiarello L; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Piechocka-Trocha A; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Bashirova A; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA., Birnbaum ME; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Carrington M; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA., Walker BD; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Institute for Medical Engineering and Science and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Gaiha GD; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: ggaiha@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2024 Aug 08; Vol. 32 (8), pp. 1121-1136.e5. Date of Electronic Publication: 2024 May 10.
DOI:	10.1016/j.str.2024.04.015
Abstrakt:	Immunogenetic studies have shown that specific HLA-B residues (67, 70, 97, and 156) mediate the impact of HLA class I on HIV infection, but the molecular basis is not well understood. Here we evaluate the function of these residues within the protective HLA-B ∗ 5701 allele. While mutation of Met67, Ser70, and Leu156 disrupt CD8 + T cell recognition, substitution of Val97 had no significant impact. Thermal denaturation of HLA-B ∗ 5701-peptide complexes revealed that Met67 and Leu156 maintain HLA-peptide stability, while Ser70 and Leu156 facilitate T cell receptor (TCR) interactions. Analyses of existing structures and structural models suggested that Val97 mediates HLA-peptide binding to inhibitory KIR3DL1 molecules, which was confirmed by experimental assays. These data thereby demonstrate that the genetic basis by which host immunity impacts HIV outcomes occurs by modulating HLA-B-peptide stability and conformation for interaction with TCR and killer immunoglobulin receptor (KIR) molecules. Moreover, they indicate a key role for epitope specificity and HLA-KIR interactions to HIV control. Competing Interests: Declaration of interests B.D.W. and G.D.G have filed patent application PCT/US2020/022403. G.D.G. also reports research funding from Moderna and Merck. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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