Using an in vitro model system that reflects the cellular interactions occurring in the microenvironment of lymphoid organs (i.e., the interaction between dendritic cells (DC) and CD4+ T lymphocytes), the ability of CD8+ T cells to inhibit HIV replication was investigated. DC, the most potent APC in the paracortical region of lymphoid organs, were cocultured with autologous, unstimulated CD4+ T cells resulting in viral replication in the absence of exogenous stimulation. Using two variations of DC cocultures, one an acute infection system and the other an endogenous infection system, two sets of activities were identified. One activity was expressed in both HIV-infected and -uninfected individuals, and a second was found only in HIV-infected individuals. These activities can be differentiated further by their evolution or lack thereof with disease progression in infected individuals and their sensitivity to gamma irradiation. Furthermore, the results indicate that CD8+ T cell modulation of HIV replication in CD4+ T cells is a multifactorial phenomenon involving both inhibitory and stimulatory effects on HIV replication.