The primary objectives of this project are to define and characterize the consequences of HIV-1 envelope/receptor interactions with respect to the function of CD4+ T cells as well as the replication of HIV-1. With the discovery of a new family of HIV co-receptors that function coordinately with the CD4 molecule in HIV infection of cells, we can now delineate the functional consequence of envelope interactions with these receptors. To this end we have designed, expressed, and characterized recombinant, multimeric envelope proteins that mimic the spike architecture found on the surface of an HIV virion. Because envelope proteins of different isolates of HIV utilize different co-receptors we will determine whether envelopes from different isolates differ with respect to their ability to transduce signals through the CD4 molecule. To the extent that envelopes do differ in their CD4 signaling capacity we will address the basis for those difference at the molecular level. We will address the possibility of envelope mediated signal transduction on CD4- cells and the functional consequences of such signals. Finally, we have demonstrated that both T- and macrophage-tropic envelope proteins induce beta-chemokine production by macrophages. When co-stimulated with CD4, T-tropic envelope-induced chemokine secretion is suppressed while M-tropic-induced chemokine secretion is enhanced. Finally, supernatants from envelope stimulated macrophage cultures differentially affect the replication of M- or T-tropic viruses in CD4+ T cells.
