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.
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.
|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|
|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|
|Kwon, Young-Chan; Bose, Sandip K; Steele, Robert et al. (2015) Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes. J Virol 89:11549-56|
|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|
|Meyer, Keith; Kwon, Young-Chan; Liu, Shuanghu et al. (2015) Interferon-Î± inducible protein 6 impairs EGFR activation by CD81 and inhibits hepatitis C virus infection. Sci Rep 5:9012|
|Shrivastava, Shubham; Steele, Robert; Ray, Ranjit et al. (2015) MicroRNAs: Role in Hepatitis C Virus pathogenesis. Genes Dis 2:35-45|
|Mukherjee, Anupam; Shrivastava, Shubham; Bhanja Chowdhury, Joydip et al. (2014) Transcriptional suppression of miR-181c by hepatitis C virus enhances homeobox A1 expression. J Virol 88:7929-40|
|Chowdhury, Joydip Bhanja; Kim, Hangeun; Ray, Ranjit et al. (2014) Hepatitis C virus NS5A protein modulates IRF-7-mediated interferon-* signaling. J Interferon Cytokine Res 34:16-21|
|Shrivastava, Shubham; Petrone, Jessica; Steele, Robert et al. (2013) Up-regulation of circulating miR-20a is correlated with hepatitis C virus-mediated liver disease progression. Hepatology 58:863-71|
|Bittar, Cintia; Shrivastava, Shubham; Bhanja Chowdhury, Joydip et al. (2013) Hepatitis C virus NS2 protein inhibits DNA damage pathway by sequestering p53 to the cytoplasm. PLoS One 8:e62581|
Showing the most recent 10 out of 19 publications