A major research goal of the applicant is to understand the genetic and phenotypic changes that lead to the emergence of epidemic Venezuelan equine encephalitis viruses from enzootic progenitors. Preliminary data suggest that alterations leading to an increased charge on the surface of the E2 envelope glycoprotein of enzootic strains lead to emergence. These changes are accompanied by increased binding to glycosaminoglycans (GAGS) on the cell surface. An ultimate goal is to understand how these changes in binding affect the cost range, tissue tropisms and pathogenesis of the virus in both equine amplifying hosts and epidemic mosquito vectors. Because of the biosafety problems associated with VEE research, a model cell culture system employing Sindbis virus is being developed to investigate the effects of GAG binding on receptor utilization, host cell tropisms and fitness of alphaviruses. This proposal seeks to take advantage of the vast experience with animal RNA virus adaptation experiments and GAG binding assays in the laboratory of Dr. Esteban Domingo. Dr. Domingo is one of the world's leading investigators in mechanisms of viral adaptation, and the intellectual environment in his research group will enhance both the proposed research and the long term goals of the applicant.
