Heat Shock Protein Synthesis Inhibitor Treatment of Hepatitis C Viral Infection

Summary

Principal Investigator: SAMUEL WHEELER FRENCH
Abstract: DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.
Funding Period: 2010-12-01 - 2015-11-30
more information: NIH RePORT

Top Publications

  1. pmc The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production
    Oscar Gonzalez
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095 1732, USA
    Hepatology 50:1756-64. 2009
  2. pmc A cell-permeable hairpin peptide inhibits hepatitis C viral nonstructural protein 5A-mediated translation and virus production
    Ronik Khachatoorian
    Molecular Biology Interdepartmental PhD Program, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
    Hepatology 55:1662-72. 2012
  3. pmc HOXB7 promotes invasion and predicts survival in pancreatic adenocarcinoma
    Anne Nguyen Kovochich
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 1732, USA
    Cancer 119:529-39. 2013
  4. pmc Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle
    Ronik Khachatoorian
    Molecular Biology Interdepartmental Ph D Program, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, California, CA, United States
    Virology 433:346-55. 2012
  5. pmc SAMe treatment prevents the ethanol-induced epigenetic alterations of genes in the Toll-like receptor pathway
    Ronik Khachatoorian
    Molecular Biology Interdepartmental Ph D Program, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA, United States
    Exp Mol Pathol 94:243-6. 2013
  6. pmc Systematic analysis of enhancer and critical cis-acting RNA elements in the protein-encoding region of the hepatitis C virus genome
    Derrick Chu
    Department of Surgery, Cedars Sinai Medical Center, Los Angeles, California, USA
    J Virol 87:5678-96. 2013
  7. pmc The NS5A-binding heat shock proteins HSC70 and HSP70 play distinct roles in the hepatitis C viral life cycle
    Ronik Khachatoorian
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA, United States of America Electronic address
    Virology 454:118-27. 2014

Detail Information

Publications8

  1. pmc The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production
    Oscar Gonzalez
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095 1732, USA
    Hepatology 50:1756-64. 2009
    ..The marked inhibition of virus production by Quercetin may partially be related to reduction of HSP40 and HSP70 and their potential involvement in IRES translation, as well as viral morphogenesis or secretion...
  2. pmc A cell-permeable hairpin peptide inhibits hepatitis C viral nonstructural protein 5A-mediated translation and virus production
    Ronik Khachatoorian
    Molecular Biology Interdepartmental PhD Program, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
    Hepatology 55:1662-72. 2012
    ..Moreover, treatment with a 10-amino acid peptide derivative of C34 suppressed NS5A-augmented IRES-mediated translation and significantly inhibited intracellular viral protein synthesis, with no associated cytotoxicity...
  3. pmc HOXB7 promotes invasion and predicts survival in pancreatic adenocarcinoma
    Anne Nguyen Kovochich
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 1732, USA
    Cancer 119:529-39. 2013
    ..Although published microarray data suggest HOXB7 is overexpressed in pancreatic ductal adenocarcinoma (PDAC), its function in pancreatic cancer has not been studied...
  4. pmc Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle
    Ronik Khachatoorian
    Molecular Biology Interdepartmental Ph D Program, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, California, CA, United States
    Virology 433:346-55. 2012
    ..Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV...
  5. pmc SAMe treatment prevents the ethanol-induced epigenetic alterations of genes in the Toll-like receptor pathway
    Ronik Khachatoorian
    Molecular Biology Interdepartmental Ph D Program, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA, United States
    Exp Mol Pathol 94:243-6. 2013
    ....
  6. pmc Systematic analysis of enhancer and critical cis-acting RNA elements in the protein-encoding region of the hepatitis C virus genome
    Derrick Chu
    Department of Surgery, Cedars Sinai Medical Center, Los Angeles, California, USA
    J Virol 87:5678-96. 2013
    ..We have identified new enhancer RNA elements and an extended stem-loop in the NS5B coding region. Genetic modification of enhancer RNA elements can be utilized for designing attenuated HCV vaccine candidates...
  7. pmc The NS5A-binding heat shock proteins HSC70 and HSP70 play distinct roles in the hepatitis C viral life cycle
    Ronik Khachatoorian
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA, United States of America Electronic address
    Virology 454:118-27. 2014
    ..This data suggests that HSC70 and HSP70 play discrete roles in the viral life cycle. Investigation of these different functions may facilitate developing of novel strategies that target host proteins to treat HCV infection...