The objectives of this research are to study the role of dendritic cells (DC) in initiating and propagating HIV disease and to identify other immunologic activities, such as cytokines, chemokines, and other immune cell functions, that affect viral replication, T cell activation, and DC function. Using two variations of co-cultures of DC and CD4+ T cells (termed the acute and endogenous infection systems), we identified two activities that can inhibit HIV replication; these differ in their expression in HIV-infected versus uninfected people, in stage of HIV disease progression, and in sensitivity to gamma-irradiation. Recently, the beta-chemokines MIP-1alpha, MIP-1beta, and RANTES were observed to suppress viral replication in T cell blasts. A similar effect was noted in the endogenous culture system while no effect was observed in the acute system. The addition of neutralizing antibodies to these factors to endogenous DC CD4+ T cell cultures containing CD8+ T cells did not abrogate the CD8+ T cell mediated suppression of HIV. These observations suggest that CD8+ T cell mediated suppression is multifactorial. The mechanism of beta-chemokine mediated suppression of HIV replication has also been studied. Initial studies using pertussis toxin which blocks signal transduction through beta-chemokine receptors did not abrogate RANTES mediated suppression of HIV replication. Given the recent identification of fusin and CC-CKR5 as the co-receptors for T cell tropic and monocytotropic viruses, respectively, these findings strongly suggest that the mechanism of inhibition of viral replication by ligands for these receptors is independent of receptor-mediated signal transduction, and involves receptor occupancy and blockage of virus entry into its target cell. Langerhans cells (LC) are the first cell to encounter SIV after vaginal inoculation of virus and are likely involved in heterosexual transmission of HIV. The difference in heterosexual transmission observed between clade B viruses, mainly found in the US and Europe, and other clades, found in Africa, Asia, and India, is significant (<10% versus >90%, respectively). We are studying DC and LC expression of HIV coreceptors and the HIV infectability of epidermal and dermal DC/LC with clade B and E viruses. We have identified an additional chemokine receptor on DC; its structure and function are being studied.
