title: HIV and HCV cooperatively promote hepatic fibrogenesis via induction of reactive oxygen species and NFkappaB.
abstract: HIV/HCV coinfection leads to accelerated hepatic fibrosis progression, with higher rates of cirrhosis, liver failure, and liver death than does HCV mono-infection. However, the profibrogenic role of HIV on hepatocytes and hepatic stellate cells (HSC) has not been fully clarified. We hypothesized that HIV, HCV induce liver fibrosis through altered regulation of the production of extracellular matrix and matrix metalloproteinases. We examined the fibrogenesis- and fibrolysis-related gene activity in LX2 HSC and Huh7.5.1 cells in the presence of inactivated CXCR4 and CCR5 HIV, as well as HCV JFH1 virus. The role of reactive oxygen species (ROS) upon fibrosis gene expression was assessed using the ROS inhibitor. Fibrosis-related transcripts including procollagen α1(I) (CoL1A), TIMP1, and MMP3 mRNA were measured by qPCR. TIMP1 and MMP3 protein expression were assessed by ELISA. We found that inactivated CXCR4 HIV and CCR5 HIV increased CoL1A, and TIMP1 expression in both HSC and Huh7.5.1 cells; the addition of JFH1 HCV further increased CoL1A and TIMP1 expression. CXCR4 HIV and CCR5 HIV induced ROS production in HSC and Huh7.5.1 cells which was further enhanced by JFH1 HCV. The ROS inhibitor DPI abrogated HIV-and HCV-induced CoL1A and TIMP1 expression. HIV and HCV-induced CoL1A and TIMP1 expression were also blocked by NFκB siRNA. Our data provide further evidence that HIV and HCV independently regulate hepatic fibrosis progression through the generation of ROS; this regulation occurs in an NFκB-dependent fashion. Strategies to limit the viral induction of oxidative stress are warranted to inhibit fibrogenesis.
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Lin
authors.forename: Guoyang
authors.initials: G
authors.lastname: Wu
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Li
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Weinberg
authors.forename: Kattareeya
authors.initials: K
authors.lastname: Kumthip
authors.forename: Lee F
authors.initials: LF
authors.lastname: Peng
authors.forename: Jorge
authors.initials: J
authors.lastname: Méndez-Navarro
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Chen
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Jilg
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Kaku
authors.initials: K
authors.lastname: Goto
authors.forename: Leiliang
authors.initials: L
authors.lastname: Zhang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
mesh_terms: D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006678:HIV / Q000378:metabolism*; D015658:HIV Infections / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species