Hepatitis C virus (HCV) infection has a worldwide prevalence of 3% and is the main entity responsible for liver transplantation in developed countries for treatment of cirrhosis. In the United States, HCV is the most common chronic blood borne infection affecting 1.8% of the population and appears to be the major etiologic factor responsible for the recent doubling of HCC in the United States. Current therapy consists of pegylated interferon-1 (PEG-IFN) and ribavirin (RBV). 70% of patients in the United States are infected with genotype 1 for which sustained virologic response (SVR) is only 42-46%. Generally, therapy of all genotypes can be accompanied by adverse effects and contraindications to therapy are not infrequent. For these reasons there is the need to develop additional therapies that are less toxic and result in higher SVR either as adjuncts or replacement therapies. We have identified the heat shock proteins (HSP)s HSP40 and HSP70 in complex with the HCV encoded protein NS5A through mass spectrometric analysis. We confirmed an NS5A/HSP interaction by confocal microscopy and coimmunoprecipitation. HSP40 and HSP70 knockdown both reduced infectious viral particle production in a HCV cell culture system. Treatment with the heat shock protein synthesis inhibitors Quercetin and KNK437 reduced infectious particle production at non-toxic concentrations. This striking inhibition of virus production combined with its known low toxicity and use in previous and ongoing clinical trials serves to motivate this bench to bedside proposal to study treat HCV infected patients with Quercetin. In this proposal, our goals are to further understand the impact of HSP40 and HSP70 and heat shock protein synthesis inhibitors on HCV infection and determine Quercetin's safety and antiviral activity in patients suffering from chronic HCV infection in a phase I clinical trial. To achieve this we propose three interrelated specific aims: 1. We will determine the importance of heat shock proteins 40 and 70 in hepatitis C virus production in the HCVcc model. 2. We will determine the impact of heat shock protein synthesis inhibitors on hepatitis C viral infection in the HCVcc model. We will test the clinical feasibility of the heat shock protein synthesis inhibitor Quercetin on patients with chronic hepatitis C viral infection through a phase I trial. Further understanding of heat shock proteins and heat shock protein synthesis inhibition in HCV infection may allow for successful treatment of chronic hepatitis C and reduce the incidence of cirrhosis and hepatocellular carcinoma.
Chronic hepatitis C viral (HCV) infection is the number one causative agent of cirrhosis necessitating liver transplantation and is the major cause of the recent doubling of hepatocellular carcinoma in the United States. We have identified heat shock proteins (HSP)s 40 and 70 as cellular proteins that are important for HCV infection. We propose to study HSP40, HSP70 and HSP synthesis inhibitors effect on HCV infection in this bench to beside proposal that could lead to treatment of chronic HCV infection thereby reducing the incidence of cirrhosis and hepatocellular carcinoma.
|Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2017) Pyroptosis by Caspase11/4-Gasdermin-D Pathway in Alcoholic Hepatitis. Hepatology :|
|Lu, Nu T; Crespi, Catherine M; Liu, Natalie M et al. (2016) A Phase I Dose Escalation Study Demonstrates Quercetin Safety and Explores Potential for Bioflavonoid Antivirals in Patients with Chronic Hepatitis C. Phytother Res 30:160-8|
|Lu, Nu T; Liu, Natalie M; Vu, James Q et al. (2016) Phospho-Network Analysis Identifies and Quantifies Hepatitis C Virus (HCV)-induced Hepatocellular Carcinoma (HCC) Proteins Regulating Viral-mediated Tumor Growth. Cancer Genomics Proteomics 13:339-57|
|Khachatoorian, Ronik; French, Samuel W (2016) Chaperones in hepatitis C virus infection. World J Hepatol 8:9-35|
|Khachatoorian, Ronik; Riahi, Rana; Ganapathy, Ekambaram et al. (2016) Allosteric heat shock protein 70 inhibitors block hepatitis C virus assembly. Int J Antimicrob Agents 47:289-96|
|Khachatoorian, Ronik; Ruchala, Piotr; Waring, Alan et al. (2015) Structural characterization of the HSP70 interaction domain of the hepatitis C viral protein NS5A. Virology 475:46-55|
|Ignatius Irudayam, Joseph; Contreras, Deisy; Spurka, Lindsay et al. (2015) Profile of Inflammation-associated genes during Hepatic Differentiation of Human Pluripotent Stem Cells. Data Brief 5:871-8|
|Irudayam, Joseph Ignatius; Contreras, Deisy; Spurka, Lindsay et al. (2015) Characterization of type I interferon pathway during hepatic differentiation of human pluripotent stem cells and hepatitis C virus infection. Stem Cell Res 15:354-364|
|Buzzanco, A; Gomez, A; Rodriguez, E et al. (2014) Digital quantitation of HCC-associated stem cell markers and protein quality control factors using tissue arrays of human liver sections. Exp Mol Pathol 97:399-410|
|Khachatoorian, Ronik; Ganapathy, Ekambaram; Ahmadieh, Yasaman et al. (2014) The NS5A-binding heat shock proteins HSC70 and HSP70 play distinct roles in the hepatitis C viral life cycle. Virology 454-455:118-27|
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