PROGRESSIVE LOSS OF IL-2-EXPANDABLE HIV-1-SPECIFIC CYTOTOXIC T-LYMPHOCYTES DURING ASYMPTOMATIC HIV-INFECTION

In HIV-I infection, circulating HIV-l-specific cytotoxic T lymphocytes (CTL) exist in different states of activation, including activated cy totoxic cells and memory cells. We report that a subpopulation of HIV- I-specific CTL is capable of clonal expansion upon culture with IL-2 w ithout exogenous antigen. The IL-il-expandable HIV-l-specific CTL prec ursor frequency was reduced in patients with advancing infection, alth ough HIV-l-specific memory CTL could still be detected by stimulation in vitro with allele-specific HIV-1 peptide. Longitudinal analysis dur ing advancing infection showed a progressive decline in the IL-2-expan dable HIV-I-specific CTL precursor (CTLp) frequency without a decline in Epstein-Barr virus (EBV)-specific or allo-specific CTLp frequencies . To address mechanisms that may contribute to the decline in the IL-2 -expandable HIV-specific CTL response, the requirements for in vitro g eneration of HIV-1-specific and EBV-specific effector CTL were examine d. In the absence of exogenous IL-2 in limiting dilution, generation o f EBV-specific CD8(+) effector CTL was dependent upon help from CD4(+) cells. CD4(+) help for EBV-specific CD8(+) CTL was observed in asympt omatic HIV infection but not in advanced infection. In the presence of exogenous IL-2, CD4(+) cells could also provide help for the optimal generation of HIV-1 peptide-specific CD8(+) CTL, because in vitro depl etion of CD4(+) cells prior to culture using stimulation with an MHC c lass I-restricted HIV-1 peptide reduced the peptide-specific CD8(+) CT L response. We conclude that there is a decline in the IL-2-expandable HIV-I-specific CTL response during advancing infection. There are a n umber of possible mechanisms for this decline, including a reduction i n CD4(+) T cell help for in viva antigen-activated CD8(+) T cells.