Role of HIV Envelope Proteins In Viral Replication and HIV Pathogenesis

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This project encompasses the role of gp120 signal transduction through multiple receptors in HIV pathogenesis. We initially evaluated the impact of gp120 signaling through CD4 and CCR5, and have expanded these studies to include signaling through integrin a4b7. A key finding of these studies is that the HIV envelope, by signaling through these receptors, can promote viral replication. This capacity can play a particularly important in viral replication in gut tissues. In the earliest stages of infection, when activated target cells are limited, signals delivered by gp120 can provide the stimulus required for productive infection. We tested this hypothesis in a non-human primate (NHP) model of HIV/SIV infection and determined that an antibody that blocks gp120 interactions with a4b7 prevents transmission in a rhesus macaque model of mucosal transmission. In our current work we are exploring the way in which gp120 V2 induces the differentiation of CD4+ T cells. We are also exploring the role of V2 costimulation in the formation of persistent HIV reservoirs.