MODULATION OF INNATE IMMUNE RESPONSES BY CYTOMEGALOVIRUS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In a competitive supplement to the parent grant (AI070890), we examine whether RhCMV lacking pp65 and pp71 is capable of primary and re-infection in rhesus macaques. A pp65-deleted RhCMV was generated and examined for replication in vitro and in vivo. No defect was observed suggesting that, despite being a major structural component of the virion, pp65 is not essential for growth in vitro. We also showed that the pp65-deleted virus can protect against challenge with a virus that lacks T cell evasion genes. This suggests that that pp65-specific T cells are not required for protection. We also generated a pp71-deleted RhCMV. This deletion mutant is highly attenuated in vitro due to the known function of pp71 to kick-start immediate early gene expression. Interestingly, despite this major growth defect, the pp71-deleted virus induced a normal immune response against CMV as well as against heterologous antigens from SIV upon infection of rhesus macaques. However, pp71-deleted virus was undetectable in the secretions of infected animals. This result suggests that a pp71-deleted HCMV could be used as a safe alternative for live replicating vaccines and vaccine vectors.