Hepatitis C virus (HCV) often causes a prolonged and persistent infection, and an association between hepatocellular carcinoma (HCC) and HCV infection has been noted. HCV has evolved one or more strategies to suppress the host protective immune responses during acute infection; thereby facilitating the development ofviral persistence. We have identified a number of important functional properties of the HCV core protein. These include a trans-regulatory role on a number of cellular promoters, regulation of cell growth, an inhibitory role in programmed cell death (apoptosis) under certain conditions, and failure to induce a strong cytotoxic T lymphocyte response in immunized animals. While all of these functional activities are well established, there are critical gaps in our understanding of the mechanisms by which core protein exerts these functions. Together these observations provide a compelling reason to focus and design studies which will further our understanding of the cellular targets and molecular mechanisms associated with the functional effects of HCV core protein. This research proposal is designed to: (1) identify and characterize the core protein interacting cellular factors, (2) characterize the mechanism of core protein mediated apoptotic inhibition, and (3) determine the effect of core protein on MHC class II antigen expression. The core protein from HCV genotype la, one of the predominant genotypes seen in patients with chronic HCV infection in the United States, will be used in this study. The results from the proposed study will extend our understanding of the molecular mechanisms of core protein mediated functional activities and may lead to intervention strategies or the design of appropriate therapeutic modalities against HCV infection.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology Study Section (VR)
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Read-Connole, Elizabeth Lee
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Saint Louis University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Kim, Hangeun; Ray, Ranjit (2014) Evasion of TNF-?-mediated apoptosis by hepatitis C virus. Methods Mol Biol 1155:125-32
Banerjee, Sutapa; Saito, Kousuke; Ait-Goughoulte, Malika et al. (2008) Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol 82:2606-12
Kanda, Tatsuo; Steele, Robert; Ray, Ranjit et al. (2007) Hepatitis C virus infection induces the beta interferon signaling pathway in immortalized human hepatocytes. J Virol 81:12375-81
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Kanda, Tatsuo; Basu, Arnab; Steele, Robert et al. (2006) Generation of infectious hepatitis C virus in immortalized human hepatocytes. J Virol 80:4633-9
Meyer, Keith; Basu, Arnab; Saito, Kousuke et al. (2005) Inhibition of hepatitis C virus core protein expression in immortalized human hepatocytes induces cytochrome c-independent increase in Apaf-1 and caspase-9 activation for cell death. Virology 336:198-207
Basu, Arnab; Steele, Robert; Ray, Ranjit et al. (2004) Functional properties of a 16 kDa protein translated from an alternative open reading frame of the core-encoding genomic region of hepatitis C virus. J Gen Virol 85:2299-306

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