Protection against Mucosal SIV sm Challenge in Macaques Infected with a Chimeric SIV that Expresses HIV Type 1 Envelope

In a monkey model we used a chimeric SIV expressing the HIV-1 envelope gene (SHIV-4) as a live attenuated vaccine and a virulent SIV_sm as a mucosal challenge. Four cynomolgus monkeys were inoculated intravenously with SHIV-4. Virus was repeatedly isolated from blood mononuclear cells of all four animals for 2 to 7 months after the inoculation of SHIV. All monkeys developed neutralizing antibodies to HIV-1 and high antibody titers to HIV-1 envelope glycoproteins. In contrast, no neutralizing antibodies to SIV_sm were detected and cross-reacting antibodies to SIV envelope glycoproteins were demonstrable in low titers. Nine to 12 months after the SHIV inoculation the four monkeys and six naive control monkeys were challenged intrarectally with 10 monkey infectious doses of macaque cell-grown SIV_sm. After a follow-up period of 1 year, two of four SHIV-infected monkeys were completely protected against SIV_sm infection as shown by repeated negative virus isolations and negative polymerase chain reaction for SIV envelope DNA. One naive monkey that received blood from the two protected monkeys showed no signs of infection. The remaining two SHIV-infected monkeys showed an initial infection on challenge with SIV_sm, but viral replication was thereafter suppressed. Cytotoxic T lymphocytes to SIV Nef and RT were demonstrable in one of four SHIV-infected monkeys before SIV_sm challenge, but this monkey was not protected against SIV infection. All six control animals yielded virus repeatedly after SIV_sm challenge and three of them showed declining CD4 cell counts. Thus, infection with SHIV expressing HIV-1 envelope could induce cross-protection against mucosal SIV_sm challenge.