CYTOKINES FROM VACCINE-INDUCED HIV-1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES - EFFECTS ON VIRAL REPLICATION

Cytolytic T lymphocytes (CTLs) specific for the human immunodeficiency virus (HIV-1) envelope glycoproteins have been cloned from HIV-1-seronegative human volunteers immunized with HIV-1 gp160-based candidate vaccines. Although vaccine-induced CTLs can potentially contribute to the antiviral response by direct lysis of infected cells, these CTLs may also produce cytokines that alter HIV-1 gene expression in other infected cells present in the microenvironment where CTL-target cell interactions occur. Vaccine-induced CTL clones were therefore examined for production of cytokines that affect HIV-1 gene expression in chronically infected T lymphocytic and promonocytic cell lines. Enhancement of HIV-1 gene expression was observed with supernatants from CD4(+) CTL clones and with supernatants from a subset of CD8(+) CTL clones. For each clone studied, upregulation of HIV-1 gene expression in chronically infected T cell lines resulted from the antigen-specific release by CTLs of tumor necrosis factor alpha (TNF-alpha). CD4(+) and CD8(+) CTLs that released TNF-alpha on antigen stimulation were also shown to express a biologically active 26-kDa transmembrane form of TNF-alpha, which was sufficient to induce upregulation of HIV-1 gene expression in chronically infected T cells placed in direct contact with the CTLs. Supernatants from antigen-activated, vaccine-induced CD4(+) and CD8(+) CTLs also caused upregulation of HIV-1 gene expression in chronically infected promonocytic cells. A subset of CD8(+) CTL clones also produced a soluble factor(s) that inhibited HIV-1 replication in acutely infected autologous CD4(+) blasts. Supernatants from CD4(+) CTLs had no effect on HIV-1 replication in acutely infected CD4(+) blasts. These results suggest that cytokine production as weal as cytolytic activity should be evaluated in the analysis of the potential antiviral effects of vaccine-induced CTLs.