The Paramyxoviridae are the etiological agents of many important diseases of man and lower animals. Collectively, these viruses contribute significantly to worldwide morbidity and mortality. The Paramyxoviridae include mumps virus, human parainfluenza virus type 1 (hPIV1), type 2, type 3, type 5 (also know as simian virus 5 [SV5]), Sendai virus, Newcastle disease virus, measles virus, canine distemper virus, rinderpest virus, respiratory syncytial virus, human metapneumovirus and the newly emergent highly pathogenic viruses, Hendra and Nipah viruses. The focus of this study is the mechanism by which paramyxoviruses enter cells. The entry of enveloped viruses into cells requires the fusion of the viral envelope with a cellular membrane. The mechanism of viral-mediated membrane fusion is a topic of interest to cell biologists and structural biologists as well as those investigating the mechanism of virus entry. This is because membrane fusion is a process central in cell biology. The class I viral fusion proteins are trapped in a meta-stable state and on activation these proteins undergo a significant re-folding event to achieve their final folded form and this protein re-folding drives membrane merger. Thus, studies on the mechanism by which paramyxoviruses cause cell fusion are of significance for understanding the pathogenesis of other class I viral fusion proteins such as gp120/gp41 of human immunodeficiency virus. For many paramyxoviruses two proteins on the virus surface, the hemagglutinin-neuraminidase (HN) and the fusion (F) protein are responsible for receptor binding and membrane fusion. This proposal is focused on providing biochemical data to support the notion that the F protein exists in a pre-fusion and a post-fusion state, to determine if the F protein cytoplasmic tail exists as a discrete protein structure that regulates fusion activity and to understand differences in the rate of virus-cell fusion and cell-cell fusion. We will elucidate the role of mutations in the F protein in the context of a virus infection by using reverse genetics and we will study fusion activity, virus growth and virus assembly of the altered viruses.
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