Phenotype and Functional Characteristics of HIV-Specific Cytotoxic CD8+ T Cells in Chronically Infected Patients

BACKGROUND: Cytotoxic CD8+ T cells (CTLs) are critical for the control of viral infections. Although these cells can be recognized in most HIV-infected individuals, they fail to successfully control HIV replication. Distinct functional defects seem to limit their efficacy in HIV infection, although they have been not fully elucidated. PATIENTS AND METHODS: Blood lymphocytes collected from 61 HLA-A0201+, untreated, chronically HIV-infected individuals were examined for the presence of CTLs against epitopes from HIV Gag and Pol proteins, using tetrameric complexes. Several functional aspects of these cells were further analyzed (immunophenotype; ability to produce interferon-gamma (IFN-gamma) in response to the specific peptide; proliferative capacity; and cytolytic activity). Lymphoproliferative responses of these cells confronting different stimulus were also evaluated. A longitudinal analysis was carried out in a subgroup who underwent antiretroviral therapy and were followed for 6 months. RESULTS: CD8+ T cells staining with the tetramer complexes (Tet+) were detected in 44% of patients, with TetGag+ cells being more frequently detected and at higher levels than TetPol+ cells. Most Tet+ cells expressed a memory phenotype, showed an impaired ability to produce IFN-gamma when stimulated with the cognate peptide, and showed a very low expansion when cultured in the presence of the peptide. There was a negative correlation between the proportion of Tet+ cells producing IFN-gamma and plasma HIV-RNA. Although Tet+ cells diminished in most individuals after beginning antiretroviral therapy, some patients showed de novo appearance of Tet+ cells. CONCLUSIONS: Most Tet+ cells in chronic HIV-infected individuals express a memory phenotype and show an impaired production of IFN-gamma and a lower proliferative response to specific HIV antigens. Interestingly, some individuals under successful antiretroviral therapy may show de novo appearance of specific CTLs. The implications of these findings are relevant for a better understanding of virus-host interactions.