Impact of Gag Sequence Variability on Level,Phenotype,and Function of Anti-HIV Gag-Specific CD8 + Cytotoxic T Lymphocytes in Untreated Chronically HIV-Infected Patients

Abstract

The role of cytotoxic T lymphocyte responses in controlling viral replication during chronic HIV infection remains controversial. Viral escape mutations driven by immune pressure have been postulated to be an important mechanism contributing to the evasion of CD8⁺ T cell responses. To explore this issue in more detail, HIV-1 p17 sequence variability was examined in chronically HIV-infected patients, in parallel with the level, phenotype, and function of HIV-SL9-specific CD8⁺ T cell. Thirty-one HLA-A*0201⁺ (A2⁺) and 10 HLAA* 02^– (A2^–) patients were included. The phenotype of SL9-specific CD8⁺ T cell and their ability to produce IFN-γ were analyzed by multiparameter flow cytometry. The HIV Gag p17 was sequenced and the mean variability score for each residue within SL9 and the two epitope flanking regions were calculated using Shannon entropy. The mean variability of SL9 and the proportion of patients with amino acid changes within SL9 were similar in A2⁺ and A2^– patients. Patients without Tet⁺ cells had a significantly higher prevalence of aminoacid changes in SL9 than patients with Tet⁺ cells. Interestingly, in patients with Tet⁺ cells, the Y79F mutation within SL9 tended to be associated with lower levels of Tet⁺ cells. We did not find any association between amino acid changes within SL9 and the differentiation stage of Tet⁺ cells, or with IFN-γ production. A similar analysis within the epitope flanking sequences did not reveal differences in the variability of these regions. These results suggest that viral mutations driven by immune selection pressure may play an important role in evading the immunological response in chronically HIV-infected individuals.