To test the protection afforded by a weakly pathogenic HIV-2 isolate against the superinfection or development of SIV-induced disease, we intrarectally challenged six HIV-P-preinfected rhesus monkeys with a pathogenic Isolate of SIVmac251. At the time of SIV challenge, none of these HIV-2-infected animals was positive for virus isolation, p27-Gag antigenemla, or HIV-2 provirus detection in PBMCs or peripheral lymph nodes. However, all monkeys exhibited anti-HIV-2 antibody titers ranging from 10(2) to 10(3). Neutralizing antibodies against the challenge SIV strain were also detected in two animals. After rectal exposure to SIVmac251, five of the six HIV-2-preinfected macaques were superinfected. SIVmac251 DNA sequences were detected repeatedly in the PBMCs of the five superinfected animals and the two controls, whereas no HIV-2 provirus was detected for 14 months postchallenge. The one monkey that resisted superinfection was negative for all SIV infection criteria. This monkey exhibited the highest anti-SIV ELISA and cross-neutralizing antibody titers on the day of SIV challenge. Preinfection with a weakly pathogenic HIV-2 ROD isolate protected one of six macaques from infection with the closely related pathogenic SIVmac251 isolate, but no protection from the progression of disease was evidenced in the other five. (C) 1996 Academic Press, Inc.