PATHOGENESIS OF PARAMYXOVIRUSES

The paramyxoviruses comprise a large group of negative-strand RNA viruses, many of which are significant causes of disease both in humans and in agriculturally important animals. Paramyxoviruses, like other enveloped viruses, spread from one host to another in the form of particles. The particles bud from the plasma membranes of virus-infected cells, allowing the transfer of infectious material to uninfected cells. The process of particle assembly and release is one of the least-understood aspects of the paramyxovirus lifecycle. Improved knowledge of the particle formation process will contribute to the development of effective antiviral strategies aimed at blocking the late steps of paramyxovirus replication. Paramyxovirus particle formation is driven by the viral M (matrix) proteins. One of the key protein interactions mediated by M proteins involves the viral nucleocapsid protein, NP. NP protein functions to bind and encapsidate the viral genomic RNA. The interaction between the viral M protein (located at virus budding sites) and NP protein (complexed with viral RNA) is the driving force that allows for the selective packaging of viral genomes into budding virions. Here, experiments are proposed that will characterize the binding interface between paramyxovirus M and NP proteins. This will set the stage for future efforts aimed at disrupting the M-NP interaction. Impaired M-NP interaction would be devastating to the virus, because viruses would no longer be able to incorporate their genomes into the particles that spread the infection. Experiments are also proposed that will characterize interactions between viral M proteins and two different host proteins: 14-3-3 and AP-3. This will facilitate the development of antiviral strategies aimed at blocking the interactions between M proteins and host proteins that are critical for proper virus assembly and particle formation.