The objective of this proposal is to enable the applicant to develop expertise as an independent medical research scientist in the fields of virology and molecular genetics. Phase I will be devoted to full time graduate course work and preliminary laboratory training. The focus of Phase II will be the investigation of host-virus interactions during acute and persistent infections with vesicular stomatitis virus (VSV). The leader RNA transcript from the exact 3' end of the genome has been implicated in the shut-off of host cell macromolecular synthesis. The leader RNA also associates with the host protein La, which is identifiable with antiseral derived from patients with autoimmune disorders. The research phase of this project will address the following specific questions: 1) Does the inhibition of cell macromolecular synthesis by VSV result from competition by the leader RNA for host factors that influence RNA transcription or processing? 2) Do interactions between leader RNAs of VSV and/or rabies and the LA protein block the assembly of U1 and U2 small nuclear ribonucleoproteins? 3) Can the inhibition of cell macromolecular synthesis by VSV be overcome by the overproduction of La protein in vivo using mammalian cell expression vectors? The long-term goal of this research is to identify viral functions that promote cell killing and virulence during acute infections. Studies concerning virus-host interactions may provide new knowledge regarding targets for antiviral therapy.
