Transmission through mucosal surfaces constitutes the major route of infection with HIV-1 worldwide. It is thought that anti-HIV-1 immunity at the mucosal sites will reduce such transmission and thereby contribute to protection from infection. There are several methods through which mucosal immunity can be induced and specifically some bacterial toxins have been shown to be potent mucosal adjuvants. This proposal aims at exploiting these adjuvants to induce protection from mucosal challenge with SIV/HIV-1 recombinants (SHIVs) in macaques. Initially the optimal mucosal adjuvant as well as the most potent challenge virus will be selected, and subsequently mucosal immunity will be induced in macaques using the selected adjuvant and this immunity will then be tested for it's ability to confer protection from mucosal and systemic challenges with the selected SHIVs. The following questions will be addressed. 1) Are in vitro biological properties of HIV-1 predictive for in vitro properties of SHIVs constructed with HIV-1 envelope genes, and does this predictive power extend to in vivo properties like transmission across mucosal surfaces? 2) Can nontoxic mutants of E. coli heat-labile enterotoxin (LT) be used to induce anti-HIV mucosal immunity in mice and is mutant LT(R192G) a superior mucosal adjuvant? 3)Is a regimen of systemic priming followed by mucosal boosting a superior method to induce mucosal immunity? 4) Can a regimen of repeated mucosal immunization induce protection from mucosal infection or even from systemic infection? The answers to these questions will ultimately determine whether mucosal immunization of humans using HIV-1 antigens and nonoxic mutants of LT can provide protection from HIV-1 infection