Virus-Membrane Fusion: Mechanisms and Inhibition
Wednesday, April 19, 2006
Presented by the Microbiology Section
Speaker: Margaret Kielian, Albert Einstein College of Medicine
Alphaviruses and flaviviruses infect cells through low pH-dependent membrane fusion reactions mediated by their structurally similar viral fusion proteins. During fusion these class II viral fusion proteins trimerize and refold to form hairpin-like structures with the domain III and stem regions folded back towards the target membrane-inserted fusion peptides. Using the alphavirus Semliki Forest virus and the flavivirus dengue virus, we have demonstrated that exogenous domain III can function as a specific dominant-negative inhibitor of membrane fusion and infection. Our data reveal the existence of a relatively long-lived core trimer intermediate with which domain III stably interacts to initiate membrane fusion, an interaction that can potentially serve as a new target for the development of antiviral reagents. Inhibitors and other approaches are also being used to define key functions of the class II fusion protein including target membrane insertion, trimerization, and oligomeric interactions.