This application for renewal of a Hepatitis C Cooperative Research Center (HCV CRC) focuses on the multicellular mechanisms employed by HCV to evade or suppress the immune response. Three highly inter-related projects from PIs who have worked closely together in a productive manner will characterize diverse components of innate and adaptive immunity that influence whether spontaneous resolution or viral persistence occurs. The proposal fulfills several of the stated aims of this RFA, including but not limited to: 1. Identify effectors of HCV-induced innate immune signaling (project 1, aim 3;project 3);describe their mechanisms in HCV control (project 1/aim 1, aim 3);explain how HCV inhibits innate immune pathways (project 1/aim 1;project 3/aim3). 2. Determine the mechanisms of the adaptive immunity in clearance of HCV infection and their functional collapse leading to virus persistence (project 1/aims 1 and 2;project 2/ alms 1, 2, and 3. Clarify how the innate and adaptive immune responses are integrated to effect clearance of HCV infection (project 1/ aim 1 .project 3/ aim 3). The overarching objective of this Center application is to understand the multi-cellular processes involved in mediating recovery from HCV infection, and conversely, why these processes often fail and lead to viral persistence, and furthermore, identify targets to rescue cells from immune exhaustion and failure. As evident from our track record, the individual projects benefit significantly from their participation in this HCV CRC since each investigator brings unique expertise and resources from substantially different yet complementary areas of research. These include clinical hepatology, cellular and molecular immunology, virology, cell biology, and systems biology.

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-BP-M (J1))
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Koshy, Rajen
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Giugliano, Silvia; Kriss, Michael; Golden-Mason, Lucy et al. (2015) Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication. Gastroenterology 148:392-402.e13
Lee, Hai-Chon; Narayanan, Sowmya; Park, Sung-Jae et al. (2014) Transcriptional regulation of IFN-? genes in hepatitis C virus-infected hepatocytes via IRF-3·IRF-7·NF-?B complex. J Biol Chem 289:5310-9
Stone, Amy E L; Mitchell, Angela; Brownell, Jessica et al. (2014) Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression. PLoS One 9:e95627
Labonte, Adam C; Tosello-Trampont, Annie-Carole; Hahn, Young S (2014) The role of macrophage polarization in infectious and inflammatory diseases. Mol Cells 37:275-85
Brownell, Jessica; Bruckner, Jacob; Wagoner, Jessica et al. (2014) Direct, interferon-independent activation of the CXCL10 promoter by NF-*B and interferon regulatory factor 3 during hepatitis C virus infection. J Virol 88:1582-90
Lee, Hai-Chon; Sung, Sung-Sang J; Krueger, Peter D et al. (2013) Hepatitis C virus promotes T-helper (Th)17 responses through thymic stromal lymphopoietin production by infected hepatocytes. Hepatology 57:1314-24
Golden-Mason, Lucy; Rosen, Hugo R (2013) Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunol Rev 255:68-81
Polyak, Stephen J; Ferenci, Peter; Pawlotsky, Jean-Michel (2013) Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology 57:1262-71
Esser-Nobis, Katharina; Romero-Brey, Ines; Ganten, Tom M et al. (2013) Analysis of hepatitis C virus resistance to silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B. Hepatology 57:953-63
Brownell, Jessica; Wagoner, Jessica; Lovelace, Erica S et al. (2013) Independent, parallel pathways to CXCL10 induction in HCV-infected hepatocytes. J Hepatol 59:701-8

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