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

Rhoda Tano-Menka; Nishant K Singh; Itai Muzhingi; Xiaolong Li; Michael V Mandanas; Clarety Kaseke; Charles R Crain; Angela Zhang; Funsho J Ogunshola; Liza Vecchiarello; Alicja Piechocka-Trocha; Arman Bashirova; Michael E Birnbaum; Mary Carrington; Bruce D Walker; Gaurav D Gaiha

doi:10.1016/j.str.2024.04.015

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

Structure. 2024 May 7:S0969-2126(24)00141-2. doi: 10.1016/j.str.2024.04.015. Online ahead of print.

Authors

Rhoda Tano-Menka¹, Nishant K Singh², Itai Muzhingi¹, Xiaolong Li³, Michael V Mandanas⁴, Clarety Kaseke¹, Charles R Crain¹, Angela Zhang¹, Funsho J Ogunshola⁵, Liza Vecchiarello¹, Alicja Piechocka-Trocha⁵, Arman Bashirova⁶, Michael E Birnbaum⁷, Mary Carrington⁸, Bruce D Walker⁹, Gaurav D Gaiha¹⁰

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
² 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.
³ 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.
⁴ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA.
⁵ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.

PMID: 38733995
DOI: 10.1016/j.str.2024.04.015

Abstract

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.

Keywords: CD8(+) T cells; HIV; HLA; KIR; NK cells; TCR; immunogenetics.