Abstract
Patients living with human immunodeficiency virus 1 (PLWH) develop accelerated liver fibrosis, but the exact mechanism remains unknown. Activation of hepatic stellate cells (HSCs)-a central driver of hepatic fibrogenesis-is influenced by various factors, including viral infection, hepatocellular injury, chronic immune activation, gut barrier dysfunction, and microbial translocation. The role of gram-positive microbial products in human immunodeficiency virus 1 (HIV-1) infection-associated liver inflammation and fibrosis remains poorly understood. This study investigates the effect of lipoteichoic acid (LTA), a major gram-positive bacterial component, on HSCs in the context of HIV-1 infection. Human primary HSCs (pHSCs) were isolated from liver tissues of HIV-1-infected and uninfected individuals undergoing hepatic resection. Inflammatory responses of HSCs to LTA stimulation were measured via ELISA in patient-derived HSCs, and in vitro Lx2 cells (a human HSC line) before and after HIV-1BaL exposure. Western blotting, ChIP-qPCR and RNA-seq were used on Lx2 cells to explore relevant gene associations. LTA modestly induced interleukin-8/CXCL8 (IL-8) production in HSCs, but this response was heightened in both patient-derived HIV-1 exposed pHSCs and in vitro HIV-1BaL exposed Lx2 cells. IL-8 mRNA levels were higher in HIV-1-infected tissues compared to uninfected controls. LTA exposure increased IL-8 mRNA in LX2 cells, and IL-8 treatment of Lx2 cells increased α-SMA and COL1A1 expression. Transcriptomic analysis on Lx2 cells co-exposed to LTA and HIV-1BaL suggested a link between histone acetylation and IL-8. HIV-1 exposure in patient-derived pHSCs and Lx2 cells was linked to increased IL-8 response of HSCs to LTA. In vitro IL-8 treatment of Lx2 cells supports a role of IL-8 in pro-fibrogenic signaling in HSCs. These findings link gut-derived gram-positive microbial products and IL-8 activation in HSCs, providing important insights to guide future mechanistic studies and potential therapeutic targets for managing HIV-associated liver disease.