This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major goal of this application is to characterize the mechanism by which Rhesus Cytomegalovirus (RhCMV) interferes with activation of the innate immune response, particularly interferon-regulatory factor 3 (IRF-3) and to test the hypothesis that activation of IRF-3 by human CMV is the major event triggering the transcriptional response to HCMV in infected cells.
Specific Aim 1 : To further characterize IRF3 inhibition by RhCMV We will determine whether the inhibition of IRF3 activation requires the expression of viral gene products. We will further map the kinetic class of the inhibitory function. We will also further characterize which step of the signal transduction cascade that leads to IRF3 activation is inhibited in virally infected cells.
Specific Aim 2 : To identify open reading frames of RhCMV preventing IRF3 activation To identify genomic regions of RhCMV responsible for IRF-3 evasion, we will generate a library of RhCMV mutants in genes that differ between RhCMV and AD169. We will use a rapid mutagenesis approach based on bacterial artificial chromosome technology to generate these deletion mutants. Mutants displaying restored IRF3 activation will be further characterized by expression cloning of the gene products encoded in the deleted region and confirming the ability of these isolated ORFs to inhibit IRF3 activation.
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