Human cytomegalovirus (HCMV) is the major infectious cause of birth defects and a significant cause of morbidity and mortality in transplant and AIDS patients. Efforts to vaccinate against CMV disease have centered on a live attenuated strain Towne vaccine. The discovery that HCMV encodes four proteins that block antigen presentation by down- regulating class I expression on infected cells suggest that possibility that deleting these genes from the vaccine strain might induce a more robust immune response by enhancing presentation of viral antigens to the host immune system. However, this might also result in more rapid clearance of the virus and hence attenuate the overall immune response. Thus, the consequences of modifying the Towne vaccine are difficult to predict. Because HCMV does not infection animals, viruses such as murine, rat and guinea pig cytomegalovirus (GPCMV) have been studied as animal models; however, only GPCMV is transmitted in utero and causes birth defects similar to those of HCMV. Evidence for class I down-regulation has been reported for both the rat and murine viruses, and preliminary evidence from our laboratory suggests that GPCMV also down-regulates class I. The goals of this project are to identify the GPCMV genes responsible for class I down-regulation and characterize the mechanisms by which down-regulation occurs.. These preliminary in vitro studies will provide the basis from which to construct recombinant GPCMVs in which the class I down-regulation genes have been deleted, and this will permit future in vivo studies to test the efficacy of live vaccines based on these engineered viruses as well as the importance of these genes for viral pathogenesis. Ultimately, these results should help to guide the construction of improved HCMV vaccines.
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