Influence of intestinal microbiota on HIV pathogenesis
HIV infection can result in a breakdown in intestinal immunity associated with the translocation of immunostimulatory microbial products from the gut lumen to systemic circulation, which initiates and sustains the persistent inflammation that drives progression to AIDS 1 . In particular, we and others have shown that HIV infection induces a significant loss of IL-17-producing cells, including TH17 cells, that are critical for maintaining the mucosal barrier 2,3 . Recent work in mice has revealed the capacity for specific gut commensal microorganisms to induce the differentiation and maintenance of T cell subsets, including TH17 4-6 and regulatory T (Treg) cells 7,8 . The importance of the human gut microbiota in HIV has been implied by clinical trials investigating the use of antibiotics 9,10 probiotics 11,13 , and prebiotics 14,15 in HIV patient groups. However, putative microbial drivers of pathology versus recovery have not yet been identified. The objective of this proposal is to investigate the composition of gut microbiota in HIV-infected subjects in varying stages of disease progression and treatment, and to establish whether a relationship exists between changes in gastrointestinal microbiota composition and intestinal immune function. Specifically, we will interrogate the bacterial compartment of HIV patient microbiota (using in-depth profiling via 454 pyrosequencing and PhyloChip G3 technology) and relate these findings to analysis of the intestinal immune system (using cellular immunological assays coupled with multiparameter flow cytometry). The data generated in Aim 1 will be analyzed using comparative and correlative statistical tools in the R analysis environment and compared, in Aim 2, to immunologic data previously acquired using advanced multi-comparison techniques and multiparameter modeling. The data generated from the proposed multi-disciplinary study, lasting twelve months in duration, are expected to serve as the basis for future grant applications and collaborations as I begin my path toward independent investigation.