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<p>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-1<sub>BaL</sub> 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-1<sub>BaL</sub> 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-1<sub>BaL</sub> 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.</p>

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Role of HIV-1 in IL-8 response of human stellate cells to gram-positive microbial products

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Rabab O. Ali,
  • Lumin Zhang,
  • Naichaya Chamroonkul,
  • Parissa Tabrizian,
  • Myron Schwartz,
  • Ganesh Gunasekaran,
  • Thomas Schiano,
  • Maria Isabel Fiel,
  • Steven C. Ward,
  • Meena B. Bansal

摘要

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.