The primary goal of my dissertation research is to investigate mechanisms of reovirus cell entry and disassembly. Reoviruses are nonenveloped viruses that enter cells by receptor-mediated endocytosis. In the endocytic pathway, reovirus virions undergo acid-dependent proteolytic disassembly. The proposed experiments will allow an identification of viral genes that carry mutations responsible for growth in the presence of disassembly inhibitor ammonium chloride, elucidate the biological and structural alterations associated with ammonium-chloride resistance, and provide new insights into the molecular basis of acid-induced disassembly events required for reovirus entry into cells. The powerful reovirus genetics system, a rich panel of mutants, an existing knowledge of protein structure and function, and techniques available to advance this work offer assurance that these problems can be solved. This research will enhance an understanding of the role of endosomal acidification in reovirus cell entry and contribute new information about the physiology of the endocytic pathway.