THE ROLE OF CYTOMEGALOVIRUS PHOSPHOPROTEIN 65 IN VIRUS REPLICATON IN VIVO

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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. Cytomegalovirus (CMV) protein pp65 modulates the host immune response yet simultaneously is the primary antiviral target of cellular immunity. pp65 is the most abundant component of the Rhesus CMV (RhCMV) and human CMV (HCMV) tegument, a protein-rich layer between the capsid and the envelope that is released into the cytoplasm. Interestingly, pp65 is not required for in vitro growth of either virus. This allowed us to generate a pp65-deficient RhCMV to examine whether 1) pp65's immunomodulatory functions are critical for virus survival in vivo; or 2) pp65 immunogenicity limits virus replication in healthy animals. Infection of rhesus macaques (RMs) with mutant RhCMV will allow examination of the importance of pp65 for CMV infection in vivo. We will infect CMV-na¿ve macaques with pp65-deleted RhCMV and evaluate whether this virus is able to establish primary and chronic infection and, if so, how virological and immunological parameters compare to previous observations made during infection with wild type RhCMV. Depending on the outcome, we will evaluate whether pp65-deleted virus is able to re-infect these animals. If pp65-encoded functions are required for productive infection, we expect replication of the mutant to be either undetectable or diminished. Conversely, if pp65 immunogenicity is crucial to the ability of the host immune response to control virus infection we predict that replication of the pp65-deleted virus will be greater than that for wild type. The outcome has implications both for the design of CMV vaccines and antivirals as well as the development of CMV as a vaccine vector.