title: 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.
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Masao
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Maria Candela
authors.initials: MC
authors.lastname: Iglesias
authors.forename: Pascal G
authors.initials: PG
authors.lastname: Wilmann
authors.forename: James E
authors.initials: JE
authors.lastname: McLaren
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gras
authors.forename: Takayuki
authors.initials: T
authors.lastname: Chikata
authors.forename: Nozomi
authors.initials: N
authors.lastname: Kuse
authors.forename: Solène
authors.initials: S
authors.lastname: Fastenackels
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: John S
authors.initials: JS
authors.lastname: Bridgeman
authors.forename: Vanessa
authors.initials: V
authors.lastname: Venturi
authors.forename: Zaïna Aït
authors.initials: ZA
authors.lastname: Arkoub
authors.forename: Henri
authors.initials: H
authors.lastname: Agut
authors.forename: David J
authors.initials: DJ
authors.lastname: van Bockel
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Almeida
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Laurence
authors.initials: L
authors.lastname: Meyer
authors.forename: Alain
authors.initials: A
authors.lastname: Venet
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Victor
authors.initials: V
authors.lastname: Appay
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D016655:HIV Core Protein p24; C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; C514799:p24 protein, Human Immunodeficiency Virus Type 1