Hepatitis C virus (HCV) is a hepatotropic virus that mediates a persistent infection and chronic liver disease in millions of people worldwide. HCV persistence is associated with viral strategies to evade innate antiviral immune defenses and a/? interferon (IFN) immune actions that normally limit infection. We have identified HCV genome RNA and the cellular RIG-I protein as the viral pathogen-associated molecular pattern (PAMP) and host factors that trigger innate immunity and IFN production in HCV-infected hepatocytes. Our studies show that in order to evade innate immunity, HCV blocks RIG-I signaling induced by HCV PAMP RNA during the early stages of infection through viral NS3/4A protease cleavage and inactivation of the IPS-1 adaptor protein of the RIG-I pathway. Our research defines the virus/RIG-I pathway interface as a major point of control over HCV infection and immunity. We hypothesize that the processes of viral triggering and control of the RIG-I pathway regulate innate immunity and HCV infection outcome. To investigate this hypothesis we will 1) Determine the nature of the HCV PAMP RNA and signaling mechanisms that trigger the RIG-I pathway and innate immunity in infected cells;2) Define the domains and cofactor components of IPS-1 that direct innate immune actions and are controlled by the HCV NS3/4A protease;and 3) Define the molecular mechanisms of HCV NS3/4A protease targeting and interaction with IPS-1. Our studies will feature virologic, genetic, biochemical, bioinformatics, and pharmacologic approaches to define the virus-host interactions and therapeutic strategies that regulate innate immunity and HCV infection. Public Health Relevance: Hepatitis C virus (HCV) infects million of people around the world. The virus usually mediates a persistent infection of the liver and is the leading cause of liver disease, liver cancer, and liver transplant. Our work has linked HCV persistence with viral strategies that control innate immunity against infection. The proposed studies will define the virus and host cell processes that trigger and control innate immunity and HCV infection outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060389-11
Application #
8242806
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
2003-09-30
Project End
2013-08-31
Budget Start
2012-04-01
Budget End
2013-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$374,928
Indirect Cost
$129,903
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Pattabhi, Sowmya; Wilkins, Courtney R; Dong, Ran et al. (2016) Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway. J Virol 90:2372-87
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
Altfeld, Marcus; Gale Jr, Michael (2015) Innate immunity against HIV-1 infection. Nat Immunol 16:554-62
Horner, Stacy M; Wilkins, Courtney; Badil, Samantha et al. (2015) Proteomic analysis of mitochondrial-associated ER membranes (MAM) during RNA virus infection reveals dynamic changes in protein and organelle trafficking. PLoS One 10:e0117963
Ireton, Reneé C; Gale Jr, Michael (2014) Pushing to a cure by harnessing innate immunity against hepatitis C virus. Antiviral Res 108:156-64
McFarland, Adelle P; Horner, Stacy M; Jarret, Abigail et al. (2014) The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs. Nat Immunol 15:72-9
Horner, Stacy M; Gale Jr, Michael (2013) Regulation of hepatic innate immunity by hepatitis C virus. Nat Med 19:879-88
Negash, Amina A; Ramos, Hilario J; Crochet, Nanette et al. (2013) IL-1β production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog 9:e1003330
Ireton, Reneé C; Gale Jr, Michael (2013) Systems biology analyses to define host responses to HCV infection and therapy. Curr Top Microbiol Immunol 363:143-67
Stone, Amy E L; Giugliano, Silvia; Schnell, Gretja et al. (2013) Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells. PLoS Pathog 9:e1003316

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