Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: Inverse relationship of degree of protection with level of attenuation

Three different deletion mutants of simian immunodeficiency virus (SIV) that vary in their levels of attenuation were tested for the ability to protect against mucosal challenge with pathogenic SIV. Four female rhesus monkeys were vaccinated by intravenous inoculation with SIVmac239 Delta 3, four with SIVmac239 Delta 3X, and four with SIVmac239 Delta 4. These three vaccine strains exhibit increasing levels of attenuation: Delta 3 < Delta 3X < Delta 4. The vaccinated monkeys were challenged by vaginal exposure to uncloned, pathogenic SIVmac251 at 61 weeks after the time of vaccination. On the basis of viral RNA loads in plasma, cell-associated virus loads in peripheral blood, and CD4 cell counts, strong protective effects were observed in all three groups of vaccinated monkeys. However, the degree of protection correlated inversely with the level of attenuation; the least-attenuated strain, SIVmac239 Delta 3, gave the greatest protection. One monkey in the Delta 3X group and two in the Delta 4 group clearly became superinfected by the challenge virus, but these animals had levels of SIV RNA in plasma that were considerably lower than those of naive animals that were challenged in parallel. Protection against vaginal challenge appears easier to achieve than protection against intravenous challenge, since four other SIVmac239 Delta 4-vaccinated monkeys showed no protection, when challenged intravenously with a much lower inoculum of the same challenge virus stock Protection against vaginal challenge in the Delta 4-vaccinated group occurred in the absence of detectable serum neutralizing activities and appeared to be associated with the development of an early SIV-specific cytotoxic-T-lymphocyte response. Our results demonstrate that mucosal protection can be achieved by systemic immunization with the highly attenuated SIVmac239 Delta 4 more than 1 year prior to the time of challenge.