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. The objective of this project is to (a) characterize the roles of the RhCMV interleukin-10 and US28 proteins in the RhCMV replication cycle, and (b) develop novel vaccine designs against human cytomegalovirus by constructing RhCMV variants containing deletions in the viral interleukin-10 and US28 genes. Cytomegalovirus (CMV) infection in an immunocompetent individual infrequently causes clinical signs of infection. Rather, the vast majority of primary infections in those with a fully functional immune system are asymptomatic. In contrast, CMV infection in those without a functional immune system is a significant cause of morbidity and mortality. This includes CMV infections in those co-infected with HIV. Therefore, CMV vaccine strategies developed through these two grants will have direct clinical relevance to protecting those most at risk for CMV disease, including HIV AIDS patients. There are no licensed vaccines for human cytomegalovirus (HCMV). Limited clinical trials have been conducted with live attenuated and recombinant subunit vaccines. Despite partial success protecting from disease in renal transplant recipients, the goal of developing an HCMV vaccine that elicits protective immunity has not been achieved. There are impediments to the development of an HCMV vaccine. Design of an effective HCMV vaccine requires characterization of the correlates of protective immunity and a better understanding of HCMV natural history. Both aspects of HCMV are incompletely resolved and difficult to investigate in humans. Studies have suggested that two measures of humoral immunity, neutralizing antibodies and antibody avidity, and one measure of cellular immunity, CTL, are useful for assessing protective anti-HCMV immunity. The two HCMV proteins associated with protective immune responses, gB and pp65, represent starting points for any rational vaccine. Recent data on HCMV and the closely related rhesus CMV (RhCMV) strongly implicate viral modulation of host immune responses as a critical component of CMV natural history. CMV appears to have evolved strategies that alter lymphoid cell signaling and trafficking. Based on sequence homologies, it is reasonable to infer that HCMV has targeted pro-inflammatory immune responses for disruption during infection. Attenuation of HCMVs ability to modulate host immune responses should limit viral replication and disease sequelae. Accordingly, HCMV vaccines must be directed against both structural and immune modulating ORF to reduce virologic parameters of infection and/or disease. In other words, protective immunity will be enhanced when vaccination is directed against identified immunogens, such as gB and pp65, together with novel vaccine targets represented by immune modulating ORF. A successful outcome of this approach will demonstrate that attenuation of the CMV immunomodulatory ORF by immunization represents a rational vaccine strategy. This would fundamentally alter the paradigm for vaccine approaches to HCMV.
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