Protective immunity requires interaction between the acquired and the innate immune systems. While great advances have been made towards understanding the critical role of the acquired immune system in the defense against HIV infection, our knowledge of the role of innate immunity is rather limited. The Gl mucosal immune system plays a vital role in protection against infection by HIV and opportunistic pathogens, in part through mucosal secretions, containing a rich variety of soluble innate immune mediators. We hypothesize 1) that differences identified in the susceptibility of mucosal infection by HIV (oral vs. rectal and vaginal) are a result of differences in the types and concentrations of soluble innate immune mediators in their secretions, 2) that the increased risk of development of Gl opportunistic infections with immunosupression are a result of decreased secretion of innate immune mediators by the mucosa, 3) that immunosuppression is also associated with wholesale changes in the mucosal microbiota, 4) that alterations in the local microbiota contribute to alteration in the secretion of soluble mediators of innate immunity, and 4) that increased mucosal colonization by proinflammatory bacterial species will result in secretion of mediators that stimulate mucosal HIV replication. We therefore propose to 1) to test the hypothesis that HIV nfection is associated with depressed mucosal secretion of soluble innate immune mediators, 2) to test the hypothesis that HIV-induced immunosupression, through its effects on secretion of innate immune proteins, results in changes in the diversity of the mucosal microbiota throughout several Gl mucosal sites, and 3) to test the hypothesis that alterations of the mucosal microbiota alter secretion of immune mediators, which in turn affect HIV replication in the Gl mucosa. The knowledge gained from the proposed studies may lead to mechanisms to suppress HIV replication, alter the natural history of HIV disease and decrease the susceptibility of mucosal sites to HIV infection.