GI DYSFUNCTION IN SIV-INFECTED MACAQUES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gastrointestinal disease and inflammation are common sequelae of HIV/SIV infection. Nevertheless, the molecular mechanisms that lead to GI dysfunction remain unclear. We investigated regulation of the IL-6-JAK-STAT3 pathway in jejunum and colon, collected at necropsy, from 10 SIV-infected macaques with diarrhea (group 1), 10 non-SIV infected macaques with diarrhea (group 2) and 7 control uninfected macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting and colitis but group 1 animals had more frequent and severe lesions in the jejunum. A significant increase in IL-6 and SOCS-3 gene expression along with constitutive STAT3 activation was observed in colon of all group 1 and 2 macaques and in jejunum of only group 1 macaques compared to controls. Further, in colon, histopathology severity scores correlated significantly with IL-6 (groups 1 & 2) and SOCS-3 (group 2) gene expression. In jejunum, a similar correlation was observed only in group 1 animals. Phosphorylated STAT3 (p-STAT3) was localized to lymphocytes (CD3+) and macrophages (CD68+) with, fewer CD3+ lymphocytes expressing p-STAT3 in group 1 macaques. Despite high SOCS-3 expression, STAT3 remained constitutively active providing a possible explanation for persistent intestinal inflammation and immune activation that may favor viral replication and disease progression.