title: Effects of a Single Escape Mutation on T Cell and HIV-1 Co-adaptation.
abstract: The mechanistic basis for the progressive accumulation of Y(135)F Nef mutant viruses in the HIV-1-infected population remains poorly understood. Y(135)F viruses carry the 2F mutation within RW8 and RF10, which are two HLA-A(∗)24:02-restricted superimposed Nef epitopes recognized by distinct and adaptable CD8(+) T cell responses. We combined comprehensive analysis of the T cell receptor repertoire and cross-reactive potential of wild-type or 2F RW8- and RF10-specific CD8(+) T cells with peptide-MHC complex stability and crystal structure studies. We find that, by affecting direct and water-mediated hydrogen bond networks within the peptide-MHC complex, the 2F mutation reduces both TCR and HLA binding. This suggests an advantage underlying the evolution of the 2F variant with decreased CD8(+) T cell efficacy. Our study provides a refined understanding of HIV-1 and CD8(+) T cell co-adaptation at the population level.
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sun
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Akahoshi
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan; Department of Biology, School of Science and Technology, Nazarbayev University, Astana 010000, Republic of Kazakhstan.
authors.forename: Christian
authors.initials: C
authors.lastname: Schönbach
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kuse
authors.affiliation: International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan; INSERM, Unité Mixte de Recherche 1135, Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Centre d'Immunologie et des Maladies Infectieuses-Paris, 75013 Paris, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Appay
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan; Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: masafumi@kumamoto-u.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D002999:Clone Cells; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology*; D015234:HLA-A Antigens / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014867:Water / Q000737:chemistry
chemical_list: D015234:HLA-A Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014867:Water