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 acquiredimmune system in the defense against HIV infection, our knowledge of the role of innate immunityis rather limited. The Gl mucosal immune system plays a vital role in protection against infection byHIV and opportunistic pathogens, in part through mucosal secretions, containing a rich variety ofsoluble innate immune mediators. We hypothesize 1) that differences identified in the susceptibilityof mucosal infection by HIV (oral vs. rectal and vaginal) are a result of differences in the types andconcentrations of soluble innate immune mediators in their secretions, 2) that the increased riskof development of Gl opportunistic infections with immunosupression are a result of decreasedsecretion of innate immune mediators by the mucosa, 3) that immunosuppression is also associatedwith wholesale changes in the mucosal microbiota, 4) that alterations in the local microbiota contributeto alteration in the secretion of soluble mediators of innate immunity, and 4) that increased mucosalcolonization by proinflammatory bacterial species will result in secretion of mediators that stimulatemucosal HIV replication. We therefore propose to 1) to test the hypothesis that HIV nfection isassociated with depressed mucosal secretion of soluble innate immune mediators, 2) to test thehypothesis that HIV-induced immunosupression, through its effects on secretion of innate immuneproteins, results in changes in the diversity of the mucosal microbiota throughout several Gl mucosalsites, and 3) to test the hypothesis that alterations of the mucosal microbiota alter secretion ofimmune mediators, which in turn affect HIV replication in the Gl mucosa. The knowledge gainedfrom the proposed studies may lead to mechanisms to suppress HIV replication, alter the naturalhistory of HIV disease and decrease the susceptibility of mucosal sites to HIV infection.
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