HCMV is remarkably successful as demonstrated by (i) its ubiquity within the human population, (ii) periodic shedding of infectious virus in the presence of host immune responses, and (iii)its ability to infect previously immune hosts. These facts are not surprising considering the evolutionary genealogy of HCMV and the other members of Herpesviridae. Since viruses are obligate intracellular pathogens, the herpesviruses must have evolved comlex mechanisms to maintain themselves in host populations in the face of innate and adaptive barriers to viral replication. HCMV encodes a highly choreographed strategy of attenuating host immune responses to overcome the stringent requirements imposed by the viral life cycle. For any HCMV vaccine to be effective, it must elicit a level of protective immunity that is greater than that generated following primary infection with wild-type virus by impeding the virus'ability to manipulate host immune responses. We previously proposed that HCMV immunomodulatory proteins should be included as vaccine targets since these proteins mediate the establishment of persistence. Results during the funding period demonstrate that cmvlL-10 treatment induces changes in dendritic cells (DC) functions in vitro. Inoculation of macaques with an IL-10-deleted variant of rhesus CMV (RhCMV) results in marked changes in the innate and adaptive immune responses. The results support the interpretation that cmvll_-10acts as an anti- inflammatory cytokine that skews host immunity at the earliest stage of viral infection. The hypothesis is presented that HCMV stimulates immune responses that, while protecting against disease, are insufficient to prevent persistence or protect against reinfection due to the actions of cmvll_-10. The hypothesis will be tested in rhesus macaques through the following Aims. (1) Immunization and challenge of macaques by a cmvlL-10 DMA priming/protein boost strategy followed by wild-type RhCMV challenge. (2) Immunization of macaques with RhCMVAILIO followed by RhCMV challenge. (3) Double immunization strategy of cmvlL-10 DMA priming/protein boosting and inoculation with RhCMVAILIO,followed by RhCMV challenge. (4) Site- directed mutation of the cmvll_-10 gene and protein. It is reasonable to expect that a successful HCMV vaccine strategy has to the match the complexity of HCMV natural history. This application seeks to demonstrate that a vaccine directed against cmvlL-10 should be included as one of the components.
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