title: T cell receptor recognition motifs govern immune escape patterns in acute SIV infection.
abstract: Escape from adaptive T cell immunity through transmutation of viral antigenic structure is a cardinal feature in the pathogenesis of SIV/HIV infection and a major obstacle to antiretroviral vaccine development. However, the molecular determinants of this phenomenon at the T cell receptor (TCR)-antigen interface are unknown. Here, we show that mutational escape is intimately linked to the structural configuration of constituent TCR clonotypes within virus-specific CD8(+) T cell populations. Analysis of 3416 SIV-specific TCR sequences revealed that polyclonal T cell populations characterized by highly conserved TCRB CDR3 motifs were rendered ineffectual by single residue mutations in the cognate viral epitope. Conversely, diverse clonotypic repertoires without discernible motifs were not associated with viral escape. Thus, fundamental differences in the mode of antigen engagement direct the pattern of adaptive viral evolution. These findings have profound implications for the development of vaccines that elicit T cell immunity to combat pathogens with unstable genomes.
authors.affiliation: Human Immunology Section, Vaccine Research Center, NIAID/NIH, Bethesda, MD 20892, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Sadie M
authors.initials: SM
authors.lastname: West
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Laura E
authors.initials: LE
authors.lastname: Ruff
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: David R
authors.initials: DR
authors.lastname: Ambrozak
authors.forename: Yvette
authors.initials: Y
authors.lastname: Edghill-Smith
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Kuroda
authors.forename: Derek
authors.initials: D
authors.lastname: Bogdan
authors.forename: Kevin
authors.initials: K
authors.lastname: Kunstman
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
mesh_terms: D000208:Acute Disease; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000821:virology; D002999:Clone Cells / Q000166:cytology / Q000276:immunology; D022801:Complementarity Determining Regions / Q000276:immunology / Q000378:metabolism; D016056:Immunodominant Epitopes / Q000276:immunology; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D013997:Time Factors
chemical_list: D022801:Complementarity Determining Regions; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell