Immune control of SHIV in Macaques upon mucosal infection or immunization

In response to the increasing incidence of HIV-1 infection in women, many investigators have focused on antiviral immune responses in the female genital tract. In this dissertation, the systemic and mucosal immunity of female macaques infected with or immunized against an SIV-HIV virus (SHIV) was evaluated. The first hypothesis tested was whether systemic or intravaginal infection would lead to qualitative and quantitative differences in antiviral immune responses. Virus isolation, PBMC proviral peaks, and CD4+ cell declines were delayed in the intravaginally inoculated animals as compared to the animals infected intravenously, demonstrating delayed viral spreading to the periphery. However, mucosal anti-SHIV antibody levels were greater in magnitude and arose more rapidly and mucosal CD8+ T cell responses were enhanced in the intravaginal group animals, whereas both the magnitude and onset of systemic immune responses did not differ between the animals in both groups. These observations demonstrate that compartmentalization of viral replication and induction of local antiviral immunity occur early and locally after intravaginal but not intravenous inoculation. The second hypothesis tested was if combining systemic priming with mucosal boosting in a SHIV immunization regimen would induce mucosal immune responses protective against intravaginal SHIV challenge. Some animals were primed and boosted and others only received the boosts with adjuvant. Priming and boosting together induced systemic and mucosal antiviral IgG and IgA antibodies. Such antibodies were also induced in animals that received the boosts alone, but to a lesser degree. Anti-SHIV CD4+ and CD8+ T cell responses were induced in the PBMC of the prime-boost animals alone. All immunized animals and three controls were challenged intravaginally with SHIV and significant reductions in viral loads were observed in the primed and boosted animals and not in the boost-only animals as compared to the controls. These data suggest that cellular immunity was required for protection from intravaginal challenge. Incorporation of envelope protein or peptides may result in higher levels of neutralizing mucosal antibodies. Induction of mucosal immunity to target local replication was successful with the combination immunization regimen described here, providing a promising lead for future HIV-1 vaccine development.