BRIDGING THE GAP: THE ROLE OF HEPATITIS C VIRUS NONSTRUCTURAL PROTEIN 5A IN THE INHIBITION OF INTRACELLULAR ANTIVIRAL PATHWAYS

• Main Author: Gleaton, Samuel James
• Other Authors: Giridhar R Akkaraju
• Format: Others
• Language: en
• Published: Texas Christian University 2011
• Subjects: College of Science and Engineering
• Online Access: http://etd.tcu.edu/etdfiles/available/etd-05032011-113713/

It is estimated that approximately over two hundred million people worldwide are infected with hepatitis C virus (HCV), far more than HIV/AIDS, and that number grows by three to four million each year. It is a leading cause of cirrhosis, replacement of the liver tissue by fibrosis, or scar tissue, and is consequently the primary reason for liver transplantation in the United States. It is an enveloped, positive single stranded RNA virus and is the most common chronic blood-borne infection in the United States. The stages of hepatitis C virus infection are divided into acute and chronic. While infection clearance rates vary from patient to patient, approximately eighty-five percent of patients will go on to develop chronic hepatitis C infection. Liver inflammation results in death of the tissue (necrosis) and replacement by scar tissue (fibrosis). Death of hepatocytes leads to regeneration of the liver by activating the cell cycle in quiescent liver cells. This can increase the chances of errors during DNA replication. In addition, the liver processes many toxins present in the body including possible mutagens. Both of these factors increase the chance of cellular mutation, which can lead to various forms of cancer (including hepatocellular carcinomas) should this occur in the coding or regulatory regions of a cell cycle regulatory protein. Currently, no vaccine is available for the virus. The only treatment is a combination of IFN-<em>f</em>Ñ and ribavirin. However, the treatment lasts for extended periods, has serious side effects, and because the virus is constantly mutating during viral genome replication, resistant strains are predominant. Because of these combined factors, treatment has a very low success rate. The viral genome consists of three structural proteins and seven nonstructural ones. One of the nonstructural proteins, NS5A, has been attributed to the blocking of the cellular antiviral response including the apoptotic pathway. It is known to inhibit RNA-activated protein kinase R (PKR). The objective of this project was to understand the role played by NS5A in inhibiting two aspects of the host antiviral response ¡V gene expression and apoptosis. In this study we show that NS5A affects gene expression by inhibiting production of the antiviral protein IFN-<em>f</em>Ò. Additionally, NS5A inhibits degradation of procaspase 3, a protein in the caspase pathway for apoptosis, whose degradation is required for the pathway to continue. NS5A may do the above by inhibiting PKR, which is known to be involved in both apoptosis and the regulation of gene expression.