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MHC class I immunogenetics and CTL escape in a family of MHC-defined macaques infected with SIV.
Evans D; Jing P; O'Connor D; Allen T; Venham J; Rudersdorf R; Dasilva J;
June 30, 2000
Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:116

MHC class I-restricted CTL responses are important in the resolution of primary viremia, and in the control of HIV replication prior to the onset of AIDS. To explore the influence of MHC class I polymorphism on disease progression, we infected five Mamu-DRB-identical members of a family of MHC-defined rhesus macaques intravenously with SIVmac251. Two animals rapidly progressed to disease (survived < 80 days), whereas the other three animals followed either slow (survived > 500 days) or intermediate (survived 299 days) courses of disease progression. The MHC alleles of the rapid progressors were identical, and differed from those of one slow progressor by only a single MHC class I haplotype. Remarkably, this haplotype was shared by both slow progressors, and encoded two molecules used to present three different CTL epitopes derived from the SIV env and nef proteins. Similarly, two MHC class I molecules encoded on the same haplotype of the intermediate progressor bound two additional env and nef epitopes. To determine if the CTL responses of these macaques were exerting selective pressure on the virus, we sequenced regions of the env and nef genes encoding each CTL epitope at selected time points after infection. Prior to their decline in health, amino acid replacements were found in all five epitopes. Comparison of the rates of silent and replacement nucleotide substitutions in the epitope coding regions versus the flanking regions revealed unequivocal evidence of CTL selective pressure. Furthermore, multiple changes within three of the five epitopes were found to reduce or abrogate CTL recognition. These results suggest that virus-specific CTL responses select for escape mutations in SIV-infected macaques, and are entirely consistent with the hypothesis that allelic differences at the MHC class I loci and CTL escape contribute to the variable pathology among AIDS-virus infected individuals.

ABSTRACT Animal *Cytotoxicity, Immunologic Epitopes, T-Lymphocyte Genes, MHC Class I/*GENETICS/IMMUNOLOGY Genes, env Genes, nef Macaca mulatta SIV/GENETICS/*IMMUNOLOGY Simian Acquired Immunodeficiency Syndrome/GENETICS/*IMMUNOLOGY T-Lymphocytes, Cytotoxic/*IMMUNOLOGY

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