Influenza virus remains one of the uncontrolled pathogens of man. This proposal is aimed at understanding the biosynthesis, structure and function of the hemagglutinin (HA) glycoprotein, the major component of the influenza virus envelope. In studies pertaining directly to the life cycle of the virus, techniques of molecular genetics will be used to analyze the biological roles of HA in the infectivity and entry of the virion into the host cell and in the host organism's immune response to infection. Studies of the biosynthesis of HA will elucidate the cellular mechanisms that underly the processing, maturation and intracellular transport of eukaryotic glycoproteins in general.
The specific aims of these studies are: 1. To identify individual amino acids in HA that contribute to the low pH-induced membrane fusion activity of the molecule. 2. To analyze the role of conserved amino acids in the cytoplasmic tail of HA in the budding of influenza virions. 3. To analyze the role of protein structure in the proteolytic activation of HA and to investigate the location of cellular proteases that carry out this cleavage. 4. To investigate the cellular immune response to influenza virus infection by analyzing different modes of presentation of the HA antigen to cytotoxic lymphocytes. 5. To continue to study the role of protein folding in the intracellular transport of HA. 6. To identify and characterize compartments of the exocytotic pathway in which HA mutants become arrested.
