This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The major goal of this proposal is to identify and characterize cytomegaloviral immunomodulatory functions in vitro and to define their role for immune evasion in vivo. The recent completion of the RhCMV genomic sequence revealed a conservation of many immunomodulators identified in HCMV. Among those are viral genes preventing antigen presentation to T cells by major histocompatibility complex class I (MHC I) molecules. Work in several laboratories, including ours, previously uncovered that four glycoproteins of the US6-family (US2, US3, US6 and US11) inhibit assembly and transport of MHC I in HCMV-infected cells. We demonstrated that RhCMV encodes functional homologues for each of these four immunomodulators, (Rh182, Rh184, Rh185 and Rh189). In the course of these studies we made the unexpected and exciting discovery that RhCMV encodes an additional mechanism which intercepts biosynthesis of MHC I heavy chains (HC), but not light chains (beta2m), at a step that precedes the interference by US6-family proteins. This novel mechanism, termed viral interference with HC expression (VIHCE), has so far not been observed in HCMV-infected cells. The goals of this application are a) to examine whether MHC I interference mechanisms are important for evading CD8+ T cell control in vivo, b) to examine the importance of US6-related and -unrelated genes in immune evasion in vivo and c) to characterize the molecular mechanism of VIHCE.
Specific Aim 1 : Identification of the gene encoding VIHCE. The goal of this specific aim is to identify which open reading frame in the RhCMV-genome encodes the gene responsible for the VIHCE phenotype.
Specific Aim 2 : Functional characterization of VIHCE. The goal of this specific aim is to further characterize the VIHCE mechanism in cells infected with wildtype or VIHCE-deleted RhCMV.
Specific Aim 3 : The role of MHC I modulators for establishment and maintenance of persistent infection by RhCMV. We will examine the role of VIHCE and US6-related genes for viral immune evasion in a re-infection model in rhesus macaques.
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