Evasion of intrinsic antiviral host cell responses by herpesviruses

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Promyelocytic nuclear bodies (PML NBs) are 0.2-1um nuclear organelles that mediate an intrinsic cellular host defense response against virus infections. Herpesviruses express proteins that modulate PML or PML-associated proteins by a variety of strategies, including degradation of PML or relocalization of PML NB proteins. The consequences of PML-herpesvirus interactions during infection in vivo have yet to be investigated in detail, largely because of the species-specific tropism of many human herpesviruses. Murine gammaherpesvirus 68 (γHV68) is emerging as a suitable model to study basic biological questions of virus host interactions because it naturally infects mice. Recently we have found that γHV68 induces PML degradation through a proteasome-dependent mechanism and that loss of PML results in more robust virus replication in mouse fibroblasts. Surprisingly, we found that γHV68-mediated PML degradation is mediated by the virion tegument protein ORF75c, which shares homology with the cellular formylglycinamide ribotide amidotransferase (FGARAT) enzyme. In addition, we have shown that ORF75c is essential for production of infectious virus. ORF75 homologs are conserved in all rhadinoviruses but so far have no assigned functions. Our studies shed light on a potential role for this unusual protein in rhadinovirus biology and suggest that γHV68 will be a useful model for investigation of PML-herpesvirus interactions in vivo. The goals of this research project are to: 1) determine the mechanism by which ORF75c mediates PML degradation, 2) to determine how ORF75c contributes to the viral replication cycle, and 3) to determine the role of PML in modulating the kinetics and amplitude of acute and chronic herpesvirus infection in vivo. The information generated from our studies will address two fundamental questions. First, what is the function of the viral FGARAT proteins for gammaherpesvirus biology and second, what role does PML have in modulating acute and/or chronic herpesvirus infections in vivo? γHV68 will be a rewarding model system to address these questions in ways that would be significantly more difficult or impossible with human herpesviruses and gammaherpesviruses in particular. Practical applications from this research might support the notion that PML-deficient systems can offer a very sensitive readout for viral infection in experimental or diagnostic work. In addition, antiviral therapies that enhance PML activities could conceivably be developed. Finally, targeting ORF75 for developing novel anti-gammaherpesvirus therapeutics might be a rewarding strategy, especially if it is found to possess intrinsic enzymatic functions.