The frontline mucosal immune defenses are crucial in preventing and limiting HIV infection and controlling spread of enteric pathogens and microbial translocation. HIV causes breach in the mucosal defense leading to colonization and microbial translocation of enteric and luminal microbes. This contributes to chronic immune activation and immune dysfunction in HIV infection and supports viral persistence, although mechanisms have not been fully defined. Dendritic cells (DC) are an important component of the mucosal frontline defense but are under-investigated in HIV pathogenesis. Since the early mucosal response is well orchestrated, highly regulated and involves a rapid cross talk among the frontline mucosal cells, an experimental model representing an in vivo gut microenvironment is required to investigate early mucosal responses to HIV and microbes. We propose to utilize a novel in vivo intestinal loop model in SIV infected rhesus macaques to capture early events of host-microbe interactions at the mucosal site and characterize the responses of the key components of mucosal defense and the correlates of protection. Our previous studies identified blunted Th17 CD4+ T cell responses to Salmonella typhimurium infection in gut mucosa and systemic dissemination of the bacteria in SIV infected rhesus macaques but not in SIV-negative animals. We hypothesize that SIV infection causes DC dysfunction in the gut mucosa that leads to blunting of the Th17 CD4+ T cell response and contributes to the inability to prevent enteric pathogens and microbial translocation leading to chronic immune activation. The overall objective of this competing continuation application is to investigate HIV induced dysfunction in the frontline gut mucosal defense mechanisms to bacterial pathogens in the SIV infected rhesus macaque model. The proposal capitalizes on our experience of enteropathogenic studies in the SIV model;immunophenotypic analysis by multi-color flow cytometry;ligated intestinal loop model for in vivo studies of mucosal responses and bacterial translocation;high throughput gene expression profiling of isolated mucosal cells, and imaging technologies to visualize multiple cell types. We propose to determine the effects of SIV infection on the phenotypic and functional characteristics of DC in the gut mucosa during primary and chronic SIV infection (Specific Aim 1). Our investigation will utilize an innovative ligated ileal loop model that creates up to 12 independent, isolated in vivo experimental settings within the small intestine of the same animal to investigate the molecular mechanisms of dendritic cells and CD4+ Th17 cell responses to challenge from either enteric pathogens or luminal probiotic bacteria in SIV infected animals and healthy uninfected controls (Specific Aim 2). Proposed studies will provide important insights into molecular correlates of frontline gut mucosal responses that may identify novel targets for therapeutically enhancing DC functions and improving mucosal immunity against both virus and secondary pathogens.
The persistence of viral reservoirs and chronic immune activation pose major challenges for achieving complete immune recovery in HIV infected patients, even during long-term therapy. The frontline mucosal immune defenses are crucial in preventing and limiting HIV infection and controlling spread of enteric pathogens and microbial translocation. HIV causes breach in the mucosal defense leading to colonization and microbial translocation of enteric and luminal microbes. This contributes to chronic immune activation and immune dysfunction in HIV infection and supports viral persistence, although mechanisms have not been fully defined. The proposed studies will investigate HIV induced dysfunction in the frontline gut mucosal responses to bacterial pathogens in the SIV infected rhesus macaque model and determine the mechanisms contributing to the inability of the host to control these infections. Gaining insights into the mucosal immune defenses critical in maintaining gut mucosal health will be crucial in identifying therapeutic targets for mucosal protection against the virus and co-infections.
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