We propose continuation of a highly successful Cooperative Hepatitis C Research Center involving a consortium of investigators. Project 1 is directed by Dr. S.M. Lemon (Center Director, UTMB) and focuses on the role of the NS3/4A protease in disrupting cellular signaling pathways leading to induction of type 1 interferons. The project seeks to identify novel cellular NS3/4A substrate proteins that participate in these pathways, to determine how sequence variation within NS3/4A influences its ability to disrupt signaling, and to utilize this information to develop cell lines that are more permissive for viral replication. Project 2 is directed by Dr. R.E. Lanford (SFBR) and will characterize acute and chronic infection events in the chimpanzee, including studies that integrate sophisticated immunohistochemical imaging of gene expression in situ with previous microarray analyses, and determine the rates of hepatocyte death and proliferation once the infection becomes persistent. Dr. Lanford will also characterize correlates of cross-genotype immunity and investigate the molecular basis for genotype-specific resistance to interferon-alpha. Project 3, directed by Dr. S. Ray (JHU), will characterize events during acute infection in humans that ultimately lead to T lymphocyte failure. Dr. Ray will assess molecular markers of CD8+ T cell failure in cells derived from both peripheral blood and liver and examine the role of CD4+ cells in modulating CD8+ T cell responses during acute HCV. Project 4 is directed by Dr. M. Gale (UTSW) and will investigate the role of innate intracellular defenses in regulating HCV replication, and whether viral persistence is linked to HCV disruption of the retinoic acid inducible-gene I (RIG-I) pathway signaling induction of host defenses. Core A, Administrative Core, directed by Dr. Lemon (UTMB), will provide oversight and facilitate the integration of these highly interactive and collaborative projects with the national Hepatitis C Research Center Network. Core B, Clinical Core, directed by Dr. D. L. Thomas (JHU),will prospectively follow an established cohort of HCV-naive intravenous drug users to provide unique clinical specimens to be used in each of the Center's projects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI040035-13
Application #
7475732
Study Section
Special Emphasis Panel (ZAI1-GLM-M (M1))
Program Officer
Koshy, Rajen
Project Start
1997-08-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
13
Fiscal Year
2008
Total Cost
$1,414,039
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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

Showing the most recent 10 out of 156 publications