AEGiS-08IAC: Cytotoxic T lymphocytes do not select for mutations in an immunodominant epitope of SIVmac gag.

8th International AIDS Conference

Amsterdam, Netherlands — July 19-24, 1992

Cytotoxic T lymphocytes do not select for mutations in an immunodominant epitope of SIVmac gag.

Int Conf AIDS 1992 Jul 19-24; 8:We45 (abstract no. WeA 1002)
Chen ZW, Shen L, Miller MD, Hughes A, Letvin NL; Harvard Medical School, Southborough, MA.

OBJECTIVE: To determine whether cytotoxic T lymphocytes (CTL) have a role in selecting AIDS virus mutants, we examined mutations in SIVmac proviral DNA encoding a gag CTL epitope in PBL of infected rhesus monkeys.

METHODS: SIVmac-infected rhesus monkeys expressing the major histocompatibility complex (MHC) class I allele Mamu-A*01 reproducibly develop a gag-specific CTL response limited to a 9 amino acid epitope of the SIVmac gag protein (p11C, residues 182-190). Three Mamu-A*01+ rhesus monkeys were infected with SIVmac and assessed for gag- and peptide 11C-specific CTL responses. The generation of proviral gag genomic mutations was also determined by sequencing 500 bp proviral fragments amplified from fresh PBL obtained from the monkeys greater than 2 1/2 years following infection.

RESULTS: While numerous point mutations were characterized in 131 PCR-amplified clones of SIVmac gag, only 3 mutants within the gag CTL epitope-coding region of the genome were identified. Comparison of synonymous and nonsynonymous nucleotide substitutions in the regions encoding p11C and the flanking gag protein indicated a lack of selective pressure for viral mutations in the CTL epitope encoding region. Interestingly, a predominant gag mutant encoding a single amino acid change in p11C was found in a monkey which lost its CTL activity. However, even in this setting there was no evidence for selection of mutations in the CTL epitope coding region. Furthermore, mutant peptides derived from all naturally occurring variants in the gag epitope-coding region were recognized by effector cells of the infected monkeys with persistent CTL.

CONCLUSIONS: While mutations occur in proviral genomic regions encoding a SIVmac gag CTL epitope, there is no evidence for CTL-mediated selection of these mutations, and the mutants do not escape CTL recognition.

Keywords: AEGIS, Immunodominant Epitopes, T-Lymphocytes, Cytotoxic, Gene Products, gag, Epitopes, Macaca mulatta, Mutation, Major Histocompatibility Complex, Peptides, HIV-1, Animal, genetics, immunology, ICA8
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WeA1002