instmctions): A critical issue related to the translation of RhCMV as a vaccine vector for foreign antigens to human trials is the demonstration that the RhCMV vectors are sufficiently attenuated so as to exhibit reduced parameters of viral growth. This is particularly true for those monkeys without a fully functional immune system under clinical scenarios that recapitulate the human condition. In addition to asymptomatic infections in immune competent hosts, modified RhCMV vaccine vectors should induce less disease in monkeys that are immune deficient by coinfection with SIV or iatrogenically immunosuppressed, and fetuses with intrauterine RhCMV infection. This Core will evaluate vectors constructed as part of the parent proposal for replication and safety in two monkey models of immune compromise: immune immaturity associated with fetal development, and transplant-associated immune suppression. The mission of Core C is to define the replication and pathogenic potentials of RhCMV/SIV vectors in fetal and adult monkeys. Fetal Pathogenesis Model: HCMV has long been recognized as an infectious threat to the fetus, especially in the context of primary HCMV infection of the mother. Our work with the rhesus model of intrauterine HCMV pathogenesis has shown that fetal macaques exposed to RhCMV exhibit nearly identical developmental abnormalities as children congenitally infected with HCMV. The fetus is acutely permissive to replicating RhCMV and presents a sensitive in vivo evaluation ofthe replication and pathogenic potentials ofthe modified vectors. Adult Pathogenesis Model: HCMV is also the primary infectious cause of morbidity and mortality in solid organ and bone marrow transplant recipients. Similar to transplant-associated reactivation of HCMV, simian CMV disease has been observed in immunosuppressed nonhuman primates (NHP) receiving either allografts or xenografts. We have shown that reactivation of simian CMV following iatrogenic immunosuppression leads to severe pneumonitis and pulmonary vasculopathy. As another measure of attenuation of the RhCMV constructs of Projects 1 and 2, the pathogenic potential of vectors that are the lead candidates for human efficacy trials will be investigated in the context of depressed immune function in adult animals.
This Core will rigorously test the RhCMV vectors for residual levels of replication and pathogenesis. The results ofthis Core will be essential for moving candidate vectors forward to human clinical trials by critically evaluating the growth potential ofthe modified RhCMV vectors in vivo. Our productive history with the rhesus model of HCMV demonstrates our ability to meet the time schedule of the Project.
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