Hepatitis C virus (HCV) infects over 170 million people world-wide, causing a spectrum of liver disease ranging from an asymptomatic carrier state to end-stage liver disease. HCV efficiently escapes host immune responses and establishes persistence in >80% of acute cases;however the mechanism is poorly understood. Antiviral therapy with interferon (IFN)-a and ribavirin clears HCV infection in about half of those patients treated, but there is a large variation in IFN-a based treatment efficacy depending on the viral genotype. High viral genetic variation is associated with success of therapy. Persistent HCV infection is associated with hypergammaglobulinemia, high levels of antiviral antibody, circulating immune complexes, and immune complex disease. Infection of immortalized human hepatocytes (IHH) with cell culture grown HCV induces IFN expression, although virus replication is not inhibited. Modest HCV neutralizing antibody response is generated in humans from natural infection, and neutralization can be augmented in vitro by serum complement. Based on these observations, we hypothesize that HCV proteins interact with cellular proteins to promote escape from innate immunity. We will undertake an in-depth investigation of the molecular interactions of HCV or specific HCV proteins and components of the innate immune response.
Aim 1 will identify host factors involved in HCV mediated modulation of IFN signaling pathway.
Aim 2 will measure the effects of HCV genetic variation on the evasion of IFN-a responses.
Aim 3 will investigate the molecular mechanisms for HCV induced complement regulation. Studies will be performed using HCV cDNA from patient samples, replicon, and cell culture grown HCV. Together, these studies will improve our understanding of how viral infections interfere with innate immune responses to promote viral persistence, and will provide future avenues for therapeutic modalities.

Public Health Relevance

Hepatitis C virus (HCV) infects a large number of people world-wide, causing a spectrum of liver disease, including cirrhosis and hepatocellular carcinoma. We will undertake an in-depth investigation in understanding how HCV infection interferes with the innate immune responses to promote viral persistence, and to provide future avenues for therapeutic modalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057160-10
Application #
8446494
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$151,585
Indirect Cost
$38,824
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Chen, Linxiao; Valentine, Jenny L; Huang, Chung-Jr et al. (2016) Outer membrane vesicles displaying engineered glycotopes elicit protective antibodies. Proc Natl Acad Sci U S A 113:E3609-18
Ulland, Tyler K; Jain, Nidhi; Hornick, Emma E et al. (2016) Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun 7:13180
Miao, Chunhui; Li, Minghua; Zheng, Yi-Min et al. (2016) Cell-cell contact promotes Ebola virus GP-mediated infection. Virology 488:202-15
Zhao, Jincun; Vijay, Rahul; Zhao, Jingxian et al. (2016) MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis. J Virol 90:7098-108
Lubman, Olga Y; Fremont, Daved H (2016) Parallel Evolution of Chemokine Binding by Structurally Related Herpesvirus Decoy Receptors. Structure 24:57-69
Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min et al. (2016) Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger. PLoS Pathog 12:e1005373
Grinnage-Pulley, Tara; Mu, Yang; Dai, Lei et al. (2016) Dual Repression of the Multidrug Efflux Pump CmeABC by CosR and CmeR in Campylobacter jejuni. Front Microbiol 7:1097
Teijaro, John R; Studer, Sean; Leaf, Nora et al. (2016) S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification. Proc Natl Acad Sci U S A 113:1351-6
Grinnage-Pulley, Tara; Zhang, Qijing (2015) Genetic Basis and Functional Consequences of Differential Expression of the CmeABC Efflux Pump in Campylobacter jejuni Isolates. PLoS One 10:e0131534
Nukui, Masatoshi; Mori, Yasuko; Murphy, Eain A (2015) A human herpesvirus 6A-encoded microRNA: role in viral lytic replication. J Virol 89:2615-27

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