LAUSR

OBJECTIVE Liver disease is accelerated in people living with HIV (PLWH) with hepatitis B (HBV) coinfection. We hypothesised that liver fibrosis in HIV-HBV is triggered by increased hepatocyte apoptosis, microbial translocation and/or HIV/HBV viral products. DESIGN Sera from PLWH with HBV coinfection versus from those with HBV only or putative mediators were used to examine the pathogenesis of liver disease in HIV-HBV. METHODS We applied sera from PLWH and HBV coinfection versus HBV alone, or putative mediators (including HMGB1), to primary human hepatic stellate cells (hHSC) and examined pro-fibrogenic changes at the single cell level using flow cytometry. HMGB1 levels in the applied sera were assessed according to donor fibrosis stage. RESULTS Quantitative flow cytometric assessment of pro-fibrogenic and inflammatory changes at the single cell level revealed an enhanced capacity for sera from PLWH with HBV coinfection to activate hHSC. This effect was recapitulated by LPS, HIV-gp120, hepatocyte conditioned-media and the alarmin HMGB1. Induction of hepatocyte cell death increased their pro-fibrogenic potential, an effect blocked by HMGB1 antagonist glycyrrhizic acid. Consistent with a role for this alarmin, HMGB1 levels were elevated in sera from PLWH and hepatitis B coinfection compared to HBV alone and higher in those with HIV-HBV with liver fibrosis compared to those without. CONCLUSIONS Sera from PLWH and HBV coinfection have an enhanced capacity to activate primary hHSC. We identified an increase in circulating HMGB1 which, in addition to HIV-gp120 and translocated microbial products, drove pro-fibrogenic changes in hHSC, as mechanisms contributing to accelerated liver disease in HIV-HBV.