Research Project 4

Molecular Mechanisms of RSV F Activation and Inhibition

Jason McLellan, PhD

Respiratory syncytial virus (RSV) causes respiratory tract infections that result in substantial morbidity and mortality in infants and the elderly. RSV entry into host cells is facilitated by an attachment protein (G) and a fusion protein (F) that in its active form adopts a metastable prefusion conformation. After attachment of RSV to cells, it is hypothesized that host-factors trigger the conformational rearrangement of F that results in fusion of the viral and cellular membranes. The prefusion conformation of F is therefore considered an ideal vaccine antigen, and antibodies and small molecules that disrupt its structure and function are actively being pursued. Development of effective therapeutics will be greatly enhanced by a molecular understanding of how the F glycoprotein interacts with host-cell factors to promote entry, and how neutralizing antibodies inhibit one or more steps in the entry process. For this project, we will test two hypotheses: first, that specific host-cell factors enhance the rate of RSV F triggering; and second, that the most potent neutralizing antibodies target receptor-binding sites and block conformational changes. We expect that the results from these studies will fill important gaps in our understanding of RSV entry and provide a molecular basis for RSV F activation and inhibition.

Schematic of RSV F-mediated membrane fusion. Host-cell factors promote entry, whereas neutralizing monoclonal antibodies block the function of RSV F.

Schematic of RSV F-mediated membrane fusion. Host-cell factors promote entry, whereas neutralizing monoclonal antibodies block the function of RSV F.