Persistent infection with hepatitis C virus (HCV) is of global significance. HCV infection renders health complications ranging from mild liver dysfunction to hepatocellular carcinoma and end-stage liver disease. The virus-host interactions and molecular mechanisms that support persistent HCV replication and chronic infection are not understood. We hypothesize that innate intracellular immune defenses play an essential role in regulating HCV replication and that viral persistence is linked to HCV control of innate defense processes. Our preliminary studies have identified the cellular RNA helicase, RIG-I as an essential transducer of signaling actions that direct the downstream activation of interferon regulatory factor-3 (IRF-3), nuclear facotor-kappa B (NF-KB) and induction of interferon defenses that can limit HCV replication. These proceses are antagonized by the protease action of the HCV NS3/4A protein complex. We have now defined the cellular RIG-I pathway/NS3/4A interface as a novel therapeutic target in which RIG-I signaling of interferon immune defenses can be restored through inhibition of NS3/4A protease function. We have therefore incorporated molecular-genetic, biochemical and pharmacologic approaches to investigate processes and outcomes RIG-I signaling and host defense regulation by HCV. Studies within our Specific Aims will: 1) Determine the molecular processes by which HCV activates the cellular RIG-I pathway, 2) Define the mechanisms by which RIG-I and NS3/4A regulate virus signaling to IRF-3 and NF-KB, 3) Identify host defense genes whose expression is controlled through the RIG-I pathway and determine their potential to regulate HCV replication, 4) Characterize and validate the status/activity of the RIG-I pathway in vivo from existing liver biopsy specimen derived from HCV-infected patients or chimpanzees experimentally infected with HCV. Our studies will be closely linked with Projects 1-3 of this U19 proposal, and will utilize liver biopsy specimen from both our clinical cohort ( Project 3) and chimpanzee studies (project 2). NS3/4A regulation of the RIG-I pathway will evaluated through interactions with Project 1. This work will define the role of innate intracellular immune defense and the RIG-I pathway-NS3/4A interface in controlling HCV infection, and will provide molecular basis for understanding how NS3 protease inhbibitor therapy may contribute to interferon defenses through restoration of RIG-I signaling.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of Texas Medical Br Galveston
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Jarret, Abigail; McFarland, Adelle P; Horner, Stacy M et al. (2016) Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nat Med 22:1475-1481
Hong, MeeAe; Schwerk, Johannes; Lim, Chrissie et al. (2016) Interferon lambda 4 expression is suppressed by the host during viral infection. J Exp Med 213:2539-2552
Yi, MinKyung; Hu, Fengyu; Joyce, Michael et al. (2014) Evolution of a cell culture-derived genotype 1a hepatitis C virus (H77S.2) during persistent infection with chronic hepatitis in a chimpanzee. J Virol 88:3678-94
Li, Kui; Lemon, Stanley M (2013) Innate immune responses in hepatitis C virus infection. Semin Immunopathol 35:53-72
Wilkins, Courtney; Woodward, Jessica; Lau, Daryl T-Y et al. (2013) IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology 57:461-9
Horner, Stacy M; Park, Hae Soo; Gale Jr, Michael (2012) Control of innate immune signaling and membrane targeting by the Hepatitis C virus NS3/4A protease are governed by the NS3 helix ?0. J Virol 86:3112-20
Welsch, Christoph; Schweizer, Sabine; Shimakami, Tetsuro et al. (2012) Ketoamide resistance and hepatitis C virus fitness in val55 variants of the NS3 serine protease. Antimicrob Agents Chemother 56:1907-15
Zhou, Yan; Callendret, BenoƮt; Xu, Dan et al. (2012) Dominance of the CD4(+) T helper cell response during acute resolving hepatitis A virus infection. J Exp Med 209:1481-92
Grebely, Jason; Prins, Maria; Hellard, Margaret et al. (2012) Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of injecting drug users: towards a vaccine. Lancet Infect Dis 12:408-14
Shimakami, Tetsuro; Yamane, Daisuke; Jangra, Rohit K et al. (2012) Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. Proc Natl Acad Sci U S A 109:941-6

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