부산대학교 도서관

Increased levels of systemic immune activation are strongly associated with disease progression in HIV-1 infection, but the mechanisms causing it are not well understood. This work investigated the TH17 subset in the gastrointestinal tract of HIV-1 infected patients and looked for evidence that mucosal barrier breaches and microbial translocation contribute to peripheral immune activation. We found significant disruption in the expression of mucosal tight junction proteins in HIV-1 infection that only partially resolved on ART. This mucosal damage was positively correlated to plasma HIV viral load and 16s rDNA. Increased microbial translocation in viraemic infection correlated to elevated T cell activation and viral load. We found no evidence of reduced mucosal TH17-associated cytokines (IL-17a, IL-17f and IL-22) in our HIV cohort, but did observe reduced mucosal TH17 precursor cells (CD4+CD161+) in viraemic infection. Precursor TH17 loss was associated with increased tight junction breaches and T cell activation. To investigate the dual role of TH17 cells in promoting inflammation and maintaining barrier function in the gut mucosa we also studied inflammatory bowel disease. Tight junction disruption was observed in both active ulcerative colitis (UC) and Crohn's disease (CD) and occurred at a similar level as in viraemic HIV infection. Unlike HIV patients we found no evidence of microbial products in the periphery of IBD patients. In active UC there was evidence of TH17 cytokine driven pathology with increased levels of blood and mucosal IL-22 and IL-17f production by CD4 T cells. Blood and mucosal IL-17f proportions were positively correlated to the ulcerative colitis severity score (UCSS) and blood CD4+ IL-17f levels positively correlated with T cell activation. In contrast to UC we found little evidence of TH17 dysregulation in the blood or mucosa of CD patients. In conclusion this work found that there was a reduction in mucosal integrity, loss of mucosal CD4 T cells and precursor TH17 cells in HIV-1 infection. Loss of mucosal integrity in HIV was associated with microbial translocation and systemic T cell activation. We identified a correlation between reduced levels of mucosal precursor TH17 cells and increased mucosal damage in HIV infection, supporting the theory that this subset has a role in HIV-1 pathogenesis. However in UC, the inverse observation - elevated levels of precursor TH17 cells associated with increased mucosal damage - was made, reinforcing the paradoxical theory that this subset plays directly contrasting roles in different pathogenic environments.