HIV envelope proteins and their role in HIV infection

The HIV envelope proteins are critical for viral entry into the cell. There are two envelope proteins. HIV gp41 is a transmembrane protein that mediates cell fusion. HIV gp120 is a more globular protein that is non-covalently associated to HIV gp41 on the virus surface. HIV gp120 is the protein that associates to the cellular receptors. There are still many unanswered questions about how these two proteins act together to gain the virus entry into the cell. My thesis research has taken both a biophysical chemistry and a virology approach to answering some of these questions. The focus of this research has been the HIV gp41 ectodomain and its role in HIV gp120 association and in virus to cell fusion. I have shown that the HIV gp41 ectodomain, which forms a six-helix bundle in vitro, is extremely stable. This structure forms higher order oligomeric species in vitro. I have shown that the higher order oligomers are formed by a mass action nucleation event. This is similar to the protein deposition neurodegenerative diseases and HIV gp41 has thus been implicated to play a role in AIDS-related dementia. I have identified a footprint on HIV gp41 of the association of HIV gp120 and also identified other areas that effect fusion but do not affect the gp41/gp120 association. This association is shown to be very sensitive and also localized and thus is proof of concept that small molecule inhibitors could be developed to disrupt the association and consequently to inhibit fusion. The HIV envelope protein complex is an ideal target for drug development because to inhibit the function of this protein complex would be not only therapeutic but also prophylactic.