A novel vaccine strategy: Replication-defective pseudotyped SIVs expressing IFN-gamma

Our long-term goal is to develop safe and efficacious vaccines for human immunodeficiency virus and AIDS using the simian immunodeficiency virus (SIV) infection of rhesus macaques as a model. Our previous efforts showed promising results using live attenuated SIV vaccines to reduce viral loads and increase resistance to challenge with virulent SIVmac251. The inclusion of interferon-gamma (IFN-gamma), an immuno-modulatory molecule, into the live attenuated virus genome rendered this vaccine safer and more effective. As a step toward improving both safety and efficacy of live attenuated vaccines, this thesis now develops vesicular stomatitis virus glycoprotein pseudotyped replication-defective SIVs expressing different levels of IFN-gamma as an AIDS vaccine candidate and to optimize the cytokine's immunomodulatory effects. IFN-gamma co-expression did not alter levels of viral gene expression within a single round of infection in cell lines susceptible or non-susceptible to IFN-gamma and in primary non-dividing monocyte-derived dendritic cells. In an in vitro model, stimulation of naive macaque T cells with dendritic cells transduced by constructs expressing IFN-gamma resulted in significantly higher-levels of IFN-gamma secreting cells as measured by ELISPOT assays compared to the construct lacking IFN-gamma. In vivo, rats immunized with the construct expressing lower levels of IFN-gamma developed significantly higher antigen-specific cell mediated immunity and humoral responses and greater resistance against the surrogate challenge compared to those immunized with the construct lacking IFN-gamma. The construct expressing higher levels of IFN-gamma did not further enhance cell-mediated immunity. These results suggest that IFN-gamma functions as an adjuvant to augment antigen-specific immune responses in a dose, time, and cell type-dependent manner, and our approach may represent a safer and more efficacious strategy towards developing an AIDS vaccine in the experimental nonhuman primate model.