VIRAL EVASION STRATEGIES: ANALYSIS OF HERPES VIRUSES HSV, VZV AND HHV-6-7

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Human Herpesviruses cause a life-long latent infection, from which reactivation can occur in the face of a fully primed immune system. This viral strategy necessitates evasion of host immune reactions. For human cytomegalovirus (HCMV), a set of genes in the unique short (US) region encode a collection of in all likelihood structurally similar-type I membrane glycoproteins. Several of these genes, notably US2, US3, US6 and US 11, are known to interfere with MHC class I restricted antigen presentation when analyzed in tissue culture systems. To complement the recent determination of the Class I-US2 structure we have initiated structural studies of the HCMV US3 product. We shall further analyze the mode of action and structure of U21, an HHV7-encoded immunoevasin that also down-regulates MHC class I molecules. Because there is no animal model for HCMV infection, the suggestions for the biological role of the immunoevasins encoded in the HCMV US cluster remain conjectural. Murine CMV recombinants equipped with the US genes, alone or in combination, will be generated, along with the flu matrix protein, which will serve as the "passenger" antigen to allow enumeration of antigen-specific T cells. With these viruses we shall infect HLA-A2 and I-ILA-B7 transgenic mice in which the endogenous H-2K and H-2D genes have been disrupted through gene targeting. These animals must rely on the human restriction elements for the generation of CD8 T cells, the presence and frequency of which will be determined with the appropriate HLA-Class I peptide tetramers. In view of the intimate connection between the US gene products and MHC class I antigens, the nucleotide sequence of the US2, US3, US6 and US 11 genes will be determined for a number of clinical HCMV isolates, to be obtained preferably from different ethnic groups with different sets and distributions of MHC class I alleles. This analysis should reveal if and to what extent the MHC alleles in the human population help shape the "repertoire" of immunoevasins.