Creative and Novel Ideas in HIV Research (CNIHR) Program

Despite the remarkable success of ART, HIV patients still experience excess mortality and morbidities. Persistent inflammation strongly predicts these complications and is likely an important mediator of disease hampering efforts towards a functional cure. While the etiology of persistent immune activation is incompletely understood, compromised mucosal barrier function and increased translocation of immunostimulatory microbial products from the gut lumen into the systemic circulation have been implicated. And while the specific cause of mucosal barrier dysfunction is unclear, one mechanism likely involves failure to reconstitute Th17 and Th22 cells in the GALT, cells principally associated with maintenance of epithelial homeostasis and integrity and in clearance of translocated microbial products. Mucosal barrier dysfunction and an inflammatory microenvironment in the GALT may also trigger a vicious cycle of microbial translocation via activation of latently infected CD4+ T cells in GALT leading to HIV RNA transcription, and potentially propagate epithelial injury and microbial translocation. To address these issues, we propose to study treated HIV-infected individuals in the context of a cross-sectional study employing mucosal sampling via sigmoidoscopy. Our hypothesis is that compromised gut mucosal integrity will be associated with microbial dysbiosis, and together, they have a deleterious effect by increasing the level of HIV RNA and DNA in mucosal tissues along with mucosal immune activation. The study will leverage resources of the NIH-sponsored SCOPE cohort of over 1500 chronically HIV-infected+ individuals, the applicant's K23 award, and expertise of the DARE U19 collaboratory. Indeed, the proposal will bridge disciplines linking clinic-based translational investigators with immunologists, microbiologists, and epithelial cell biologists, taking advantage of the rich institutional environment at UCSF. As an institutional recipient of the DARE U19 and with a culture of collaboration between clinical and bench scientists, the proposal is positioned to meet the challenge of investigating how gut mucosal barrier dysfunction and microbial dysbiosis contribute to HIV persistence while also addressing another major agenda in HIV research, immune activation.