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

Three different deletion mutants of simian immunodeficiency virus (SIV) tha t vary in their levels of attenuation were tested for the ability to protec t against mucosal challenge with pathogenic SIV. Four female rhesus monkeys were vaccinated by intravenous inoculation with SIVmac239 Delta 3, four wi th SIVmac239 Delta 3X, and four with SIVmac239 Delta 4. These three vaccine strains exhibit increasing levels of attenuation: Delta 3 < Delta 3X < Del ta 4. The vaccinated monkeys were challenged by vaginal exposure to unclone d, pathogenic SIVmac251 at 61 weeks after the time of vaccination. On the b asis of viral RNA loads in plasma, cell-associated virus loads in periphera l blood, and CD4 cell counts, strong protective effects were observed in al l three groups of vaccinated monkeys. However, the degree of protection cor related inversely with the level of attenuation; the least-attenuated strai n, 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 wer e considerably lower than those of naive animals that were challenged in pa rallel. 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 w ith a much lower inoculum of the same challenge virus stock Protection agai nst vaginal challenge in the Delta 4-vaccinated group occurred in the absen ce of detectable serum neutralizing activities and appeared to be associate d with the development of an early SIV-specific cytotoxic-T-lymphocyte resp onse. Our results demonstrate that mucosal protection can be achieved by sy stemic immunization with the highly attenuated SIVmac239 Delta 4 more than 1 year prior to the time of challenge.