Pro-fibrogenic role of alarmin high mobility group box 1 in HIV–hepatitis B virus coinfection. (1st March 2023)

• Record Type: Journal Article
• Authors: Singh, Kasha P.; Pallett, Laura J.; Singh, Harsimran; Chen, Antony; Otano, Itziar; Duriez, Marion; Rombouts, Krista; Pinzani, Massimo; Crane, Megan; Fusai, Giuseppe; Avihingsanon, Anchalee; Lewin, Sharon R.; Maini, Mala K.
• Is Part Of: AIDS. Volume 37:Number 3(2023)
• Page Start: 401
• Page End: 411
• Publication Date: 2023-03-01
• Subjects: fibrosis -- hepatitis B virus -- hepatic stellate cells -- HIV -- HIV–hepatitis B virus -- liver -- pro-fibrogenic; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000003435
• Languages: English
• ISSNs: 0269-9370

Abstract

Abstract : Objective: Liver disease is accelerated in people with HIV (PWH) with hepatitis B virus (HBV) coinfection. We hypothesized that liver fibrosis in HIV–HBV is triggered by increased hepatocyte apoptosis, microbial translocation and/or HIV/HBV viral products. Design: Sera from PWH 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 PWH 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. High mobility group box 1 (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 PWH with HBV coinfection to activate hHSC. This effect was recapitulated by lipopolysaccharide, 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 PWH 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 PWH 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.