The Paramyxoviridae are enveloped, negative-stranded RNA viruses, including measles virus, human parainfluenza virus (hPIV) types 1-4, respiratory syncytial virus, mumps virus, Newcastle disease virus (NDV), Sendai virus, simian parainfluenza virus 5, and the newly-emerged hendra and nipah viruses. Measles remains a major killer of children worldwide, despite successful vaccination programs in industrialized countries and .along with mumps and nipah viruses, causes severe CMSdisease. HPIV types 1-3 have long been recognized as causative agents of croup and as important respiratory pathogens, especially of infants and children and hPIVS is a major cause of pneumonia and bronchitis. Recently, NDV has gained importance for its ability to selectively kill tumor cells and has potential for use as both an oncolytic agent and a vaccine vector for expression of foreign genes from other viruses, including influenza virus. The long-term objective of this project is the characterization of the structure/function of the paramyxovirus glycoproteins and their early interactions with the target cell. One of the hallmark cytopathic effects of cells infected with paramyxoviruses is the formation of multi-nucleate syncytia. This process is mediated by membrane fusion induced by a virus-specific interaction between the two viral surface glycoproteins, the attachment (HN/H) and the fusion (F) proteins. The objective of this proposal is to understand the mechanism by which the virus-specific interaction between paramyxovirus glycoproteins regulates the activation of the fusion protein at the proper time and place. A clear understanding of this process will guide anti-viral strategies, such as small molecule inhibitors, aimed at controlling these viruses through interference with the early steps in infection.
The specific aims of this proposal are to elucidate the molecular basis for the correlation between the strength of the HN-receptor interaction and the level of membrane fusion, to follow the status of the glycoprotein complex through the fusion process, to test various models proposed for the mechanism of HN-F mediated fusion and, to demonstrate the complementarity of the interacting domains on the NDV HN and F proteins.
