HIV-1 envelope glycoprotein-mediated fusion and pathogenesis: Implications for therapy and vaccine development

Our overall goal is to understand how viral envelope proteins mediate membrane fusion and pathogenesis. Membrane fusion is a crucial step in the delivery of the viral genome into the cell resulting in infection. On the other hand, fusion activity of viral envelope glycoproteins expressed in infected cells may cause the demise of uninfected bystander cells by apoptosis. Our general approach is to kinetically resolve steps in the pathway of viral. envelope glycoprotein-mediated membrane fusion and to uncover physical parameters undertying those steps using a variety of biochemical, biophysical, virological, and molecular and cell biotogical. techniques. Since HIV fusion involves a comptex cascade of interactions of the envelope glycoprotein with two receptors, membrane organization plays an important rote and interfering with it may modulate entry. To study this phenomenon, we have either examined cell, lines with differential expression of sphingolipids (such as GM3), or altered membrane organization by modifying levels of cholesterol, ceramides, or gtycosphingolipids. We show that the localized plasma membrane lipid microenvironment (and not the specific membrane lipids) in the vicinity of CD4 controls receptor mobitity and HIV-1 fusion. The complex cascade of