The structure and function of the genes of influenza virus will be investigated. Influenza continues to be a regular epidemic, and occasionally pandemic, disease which ranks among the leading causes of morbidity and mortality throughout the world, particularly in the elderly and in individuals with heart and lung disease. The design of better vaccines and chemotherapeutic approaches is dependent on a greater understanding of the genome of the virus, how it is expressed during replication and the mechanism by which it damages cells. We have identified two previously unrecognized integral membrane proteins of influenza viruses: M2 of influenza A virus and the NB glycoprotein of influenza B virus. The structure, mode of synthesis, expression and function of these proteins forms the focus of our work. We will investigate if the NB glycoprotein is expressed on the infected cell surface and determine its orientation in membranes. We will analyze the precise glycosylation sites used and measure the effect of glycosylation on transport of NB in the cell. We shall learn about the nucleotide sequences important for initiating two proteins (NB and NA) on a functionally active bicistronic mRNA. We will examine the mode of synthesis of M2 to investigatie how it initially becomes inserted into membrane vesicles and analyze the amino acids that are necessary for anchoring M2 in membranes. The geographic distribution of M2 on the infected cell surface will be investigated by immune electron microscopy using site-specific antisera. The effect of amantadine hydrochloride on inhibiting viral replication and its specific effect on the amino acids in the M2 membrane anchorage domain will be investigated particularly with respect to the involvement of M2 with HA in forming virus particles.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Virology Study Section (VR)
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Wu, Yibing; Canturk, Belgin; Jo, Hyunil et al. (2014) Flipping in the pore: discovery of dual inhibitors that bind in different orientations to the wild-type versus the amantadine-resistant S31N mutant of the influenza A virus M2 proton channel. J Am Chem Soc 136:17987-95
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