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 HTV-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 α (TNF-α). CD4⁺ and CD8⁺ CTLs that released TNF-α on antigen stimulation were also shown to express a biologically active 26-kDa transmembrane form of TNF-α, 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 well as cytolytic activity should be evaluated in the analysis of the potential antiviral effects of vaccine-induced CTLs.