Our goal is to develop a safe, effective, and inexpensive vaccine for human immunodeficiency virus (HIV) using the simian immunodeficiency virus (SIV) infection of rhesus macaques as a model. Previous attempts to protect monkeys against IV challenge with virulent SIV have been unsuccessful. However, protection against the mucosal route of infection with rVVs has been reported recently. We have developed a number of recombinant vaccinia virus (rVV) and live attenuated SIV vaccines that gave partial protection, reduced virus load, and increased survival time against AIDS in the macaque model. Cell-mediated immunity, rather than antibodies, may be primarily responsible for the initial control of acute HIV and SIV and it has been hypothesized that Type 1 immune responses are important in controlling intracellular infections by activating cell-mediated immune mechanisms. Type 1 responses are characterized by substantial production of IL-2 and IFN-gamma; in turn, high levels of IFN-gamma augment Type 1 responses. The rVVs we have developed incorporate the attenuating and immunoregulatory properties of IFN-gamma, and SIVnef along with gag and env as immunogens. Based on pilot experiments we have conducted in mice, we believe that co-expression of IFN-gamma will eliminate the virulence of VV, but maintain the cell-mediated, type 1 immune response that we hypothesize is necessary to control SIV infection. We will immunize macaques with two SIV proteins (nef and gag) that are important for the generation of CTLs, and with the main neutralizing antibody inducer (env) in its native conformation. As an added bonus, the inclusion of nef may induce an immune response that selects against nef (+) SIV so that, in case of lack of sterilizing immunity, attenuated nef(-) SIV variants will be favored. Since the mucosal route is the most common route of transmission of HIV, these animals will be challenged intravaginally to evaluate the efficacy of the vaccines.
