Sexual transmission is the major route for the spread of the human immunodeficiency virus (HIV) in the AIDS pandemic progression. Most attempts to develop a protective HIV vaccine have failed despite eliciting strong systemic immune responses. The basic hypothesis of our poliovirus vaccine vector strategy is that essential requirements for protective immunization against HIV and other related lentiviruses may involve (1) induction of mucosal immunity and (2) immunological responses against multiple viral antigens. To test this hypothesis, we have developed replication-competent poliovirus recombinants, based on the Sabin poliovirus vaccine strain viruses, that carry and express antigens derived from the simian immunodeficiency virus (SIV). Because there are no good immunological correlates for complete protection against SIV infection, we have elected to express the entire SIV genome in defined, discrete overlapping fragments. With this approach all the potentially important antigenic sequences can be effectively expressed at local mucosal sites by the inoculation of a cocktail of recombinant polioviruses that carries a complete set of SIV antigens. Infection of susceptible mice and cynomolgus monkeys with poliovirus-SIV cocktails elicits serum and secretory humoral responses, as well as a strong cellular immunity to the inserted sequences. Most importantly, we have demonstrated that vaccination of cynomolgus monkeys with poliovirus-SIV cocktails protects against infection and AIDS after intravaginal challenge with highly pathogenic SIV(mac)251.