This proposal is designed to extend our ongoing studies by investigating immunization approaches aimed at maximizing immune responses to oral or intestinal SIV vaccination in primates. As a source of viral antigen during vaccination, we will use a SIV construct previously used in our SIV and SHIV vaccine studies: a genetically inactivated proviral genome that produces non-infectious viral particles. We achieved significant systemic and mucosal cellular responses with a SIV DNA-rMVA approach after oral cavity and intestinal immunizations. These immunizations had two important impacts on SIV exposure and infection: 1. the intestinal immunization provided significant protection from infection but no protection from disease progression; 2. the oral cavity immunization provided significant protection from disease with no AIDS development observed during the post-challenge follow up and with more than 50% of the animals controlling virus replication to undetectable blood levels after experiencing a peak of viremia, and apparently clearing the infection. The goals of this proposal are: 1. to evaluate whether an immunization consisting of SIVvaxmac/sm and cytokine DNA, matched rMVA, and gp140 SIVsmE543-3 Env administered in the oral cavity or intestinally, leads to persistent anti-Env IgG and IgA titers at mucosal sites of HIV exposure in humans and whether this addition improves protection from heterologous SIVmac251 infection and disease in Indian RM. 2. to more extensively evaluate the correlates of protection from infection and disease previously observed with the DNA+MVA oral and intestinal vaccinations; 3. to evaluate whether the best regimen identified in Aim 1 that protects after vaginal SIV exposure also provides a similar protection after rectal viral exposure in both male and female animals.