T cell receptor recognition motifs govern immune escape patterns in acute SIV infection.
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.
Price
David A
DA
Human Immunology Section, Vaccine Research Center, NIAID/NIH, Bethesda, MD 20892, USA.
West
Sadie M
SM
Betts
Michael R
MR
Ruff
Laura E
LE
Brenchley
Jason M
JM
Ambrozak
David R
DR
Edghill-Smith
Yvette
Y
Kuroda
Marcelo J
MJ
Bogdan
Derek
D
Kunstman
Kevin
K
Letvin
Norman L
NL
Franchini
Genoveffa
G
Wolinsky
Steven M
SM
Koup
Richard A
RA
Douek
Daniel C
DC
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
D022801:Complementarity Determining Regions; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell