Hepatitis C virus (HCV) often causes chronic infection that affects over 200 million people worldwide. Chronic HCV infection is associated with fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The approved therapy for HCV infection is pegylated interferon-1 (IFN- 1) in combination with ribavirin that offers limited benefit depending on the genotype of the infecting virus. However, the molecular mechanisms underlying treatment failure remain unknown. Our long-term goal is to understand how HCV causes persistent infection at the molecular level, which will help in developing effective therapeutic modalities. Studies on HCV is challenging because of its limited growth in cell culture, and lack of a convenient animal model for virus infection and disease progression. We have recently shown that HCV infection in cell culture activates interferon beta (IFN-2) expression and induces autophagy. However, we do not fully understand how HCV blunts innate immune response and establishes chronic infection. We hypothesize that HCV interacts with cellular proteins and perturb their functions for establishment of persistent infection. Three complementary approaches will be used to test our hypothesis:
Aim 1 will determine molecular processes by which HCV modulates intracellular IFN signaling pathway.
Aim 2 will determine whether HCV impairs innate immunity by induction of autophagy. Finally, Aim 3 will examine intrahepatic innate immune response in HCV infected patients to correlate with treatment outcome. The results from our proposed studies will provide molecular mechanisms for viral persistence, and will aid in devising future therapeutic strategies for treatment of chronic HCV infection.

Public Health Relevance

HCV infection affects over 200 million people worldwide. Our study will reveal the molecular mechanisms of viral persistence, which may lead to new therapeutic strategies for treatment of chronic HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081817-03
Application #
8101849
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Doo, Edward
Project Start
2009-08-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$314,429
Indirect Cost
Name
Saint Louis University
Department
Pathology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Sasaki, Reina; Devhare, Pradip B; Steele, Robert et al. (2017) Hepatitis C virus-induced CCL5 secretion from macrophages activates hepatic stellate cells. Hepatology 66:746-757
Devhare, Pradip B; Sasaki, Reina; Shrivastava, Shubham et al. (2017) Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells. J Virol 91:
Devhare, Pradip B; Ray, Ratna B (2017) Extracellular vesicles: Novel mediator for cell to cell communications in liver pathogenesis. Mol Aspects Med :
Sasaki, Reina; Devhare, Pradip; Ray, Ratna B et al. (2017) Hepatitis C virus-induced tumor-initiating cancer stem-like cells activate stromal fibroblasts in a xenograft tumor model. Hepatology 66:1766-1778
Meyer, Keith; Kwon, Young-Chan; Ray, Ratna B et al. (2017) N-terminal gelsolin fragment potentiates TRAIL mediated death in resistant hepatoma cells. Sci Rep 7:12803
Shrivastava, Shubham; Devhare, Pradip; Sujijantarat, Nanthiya et al. (2016) Knockdown of Autophagy Inhibits Infectious Hepatitis C Virus Release by the Exosomal Pathway. J Virol 90:1387-96
Bhattacharya, Sourav; Steele, Robert; Shrivastava, Shubham et al. (2016) Serum miR-30e and miR-223 as Novel Noninvasive Biomarkers for Hepatocellular Carcinoma. Am J Pathol 186:242-7
Meyer, Keith; Kwon, Young-Chan; Liu, Shuanghu et al. (2015) Interferon-? inducible protein 6 impairs EGFR activation by CD81 and inhibits hepatitis C virus infection. Sci Rep 5:9012
Mukherjee, Anupam; Di Bisceglie, Adrian M; Ray, Ratna B (2015) Hepatitis C virus-mediated enhancement of microRNA miR-373 impairs the JAK/STAT signaling pathway. J Virol 89:3356-65
Shrivastava, Shubham; Steele, Robert; Ray, Ranjit et al. (2015) MicroRNAs: Role in Hepatitis C Virus pathogenesis. Genes Dis 2:35-45

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