The long term goal of this renewal application is to study in detail the involvement of host proteins in the gene expression of the respiratory pathogen human parainfluenza virus type 3 (hPIV3). HPIV3 is a common causative agent for acute respiratory tract disease of infants and children. Effective vaccines to combat hPIV3 infection are not currently available. During the continuing studies of this group in the important area of host-virus interaction, they have discovered a number of cellular proteins that interact either with virus-encoded proteins or cis-regulatory RNA elements. These include cytoskeletal protein actin, involved in transcription of virus genome RNA; cellular protein kinase C, isoform z, which specifically phosphorylated hPIV3 phosphoprotein P to activate it for eventual replication of the virus; cellular La protein and ubiquitous cellular enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which specifically interact with cis-regulatory viral RNAs. Additionally they have demonstrated that the cellular MxA protein, an interferon-inducible protein, inhibits hPIV3 replication, setting the stage to study the role of host proteins in cell defense mechanisms. They propose to study in detail the role of these cellular proteins in the hPIV3 life cycle, focussing on their actions on the virus's transcriptive and replicative pathways. They will study the molecular basis underlying such specific interactions between these host proteins and viral components. They also propose experiments to counteract some of these host-virus interactive steps that would help create an opportunity to develop antiviral agents. Understanding in detail the molecular basis of the interplay of viruses and cellular proteins would further our knowledge to understand the role of the host in promoting or abrogating virus replication and develop agents that specifically target certain host-virus interactions.
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