Regulation of West Nile virus replication.

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DESCRIPTION (provided by applicant): Viruses alter cellular pathways to create an environment conducive for their replication cycles as well as to inactivate or escape cellular antiviral responses. Viruses also utilize cell proteins to facilitate or enhance virus-specific molecular processes essential for their life cycles. Little is currently known about the mechanisms used by flaviviruses, such as West Nile virus, to regulate or facilitate their synthetic processes, to remodel host cell or to suppress cell stress/defense responses. Recent data obtained by the investigator's lab show that the highly conserved cell stress granule proteins, TIAR and TIA-1, facilitate flavivirus plus strand RNA synthesis by interacting with the 3' terminal stem loop of the viral complementary RNA. The interaction between these cell proteins and the viral 3'(-) SL RNA is also involved in suppressing the cell stress granule response. TIAR and TIA-1 are multifunctional RNA binding, nucleo-cytoplasmic shuttling proteins that mediate alternative RNA splicing, translational silencing and stress granule formation. To more fully understand flavivirus-mediated suppression of a host stress response, more information must first be obtained. The cell and viral components and domains involved in colocalization of TIAR and TIA-1 with flavivirus viral replication complexes and the functional consequences of this colocalization will be analyzed. In addition to the relocation of TIAR and TIA-1 to viral replication complexes in infected cells, suppression of eIF21 phosphorylation is observed even though PRK is up-regulated suggesting that additional mechanisms are involved in virus suppression of the cell SG response. Experiments are proposed to obtain insights about how the phosphorylation of eIF21 is suppressed in infected cells. Structural studies of the interaction between the 3'(-) SL RNA and TIAR/TIA-1 will provide insights about how the viral 3'(-) SL RNA out competes AU-rich sequences in cell mRNAs for TIAR/TIA-1 binding. This information will be relevant to the future development of novel antivirals. PUBLIC HEALTH RELEVANCE: The long term goal of this research is to delineate the mechanisms involved in the use by flaviviruses, such as West Nile virus, of cell proteins to positively regulate steps in their replication cycles and to remodel or suppress cellular pathways to create an environment that is conducive for efficient virus replication. These studies will lead to the discovery of new targets for the future development of novel antiviral therapies.