The overall goal of this program is to define the mechanisms by which prior infection with a virulence-attenuated lentivirus (SHIV 89.6) confers protection to rhesus macaques from subsequent intravaginal challenge with highly pathogenic SIVmac239. In previous studies, we have shown that approximately 60% of rhesus macaques infected with attenuated SHIV 89.6 are protected from subsequent intravaginal challenge with pathogenic SIVmac239. Further we have demonstrated that the route of immunization is not a factor in the observed protection from vaginal SIV challenge. A unique strength of this vaccine/challenge model is that not all vaccinated monkeys are protected and thus rigorous comparisons of immune responses in protected versus unprotected animals should provide significant insights into the mechanisms that are responsible for vaccine-mediated protection. Using this approach we found that protected monkeys had stronger anamnestic SIY-specific CD8+ T cell responses and higher levels of IFN-alpha mRNA expression in PBMC and in the acute post-challenge period than unprotected animals. However, immune responses in the blood may not accurately reflect the antiviral effector mechanisms in the mucosal and lymphoid tissues. Because the genital mucosa and lymphoid tissues are the sites of viral transmission and replication it is likely that mechanisms that are responsible for controlling challenge virus replication cannot be fully assessed by analysis of peripheral blood. Further, while informative, studies cataloguing and comparing immune responses in protected and unprotected monkeys only identify effector mechanisms that are associated with protection and they cannot prove that identified responses are responsible for the observed protection.
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