Chronic hepatitis C infection (HCV) is a worldwide health problem that can lead to cirrhosis, end stage liver disease, and hepatocellular carcinoma (HCC). Because of the HCV epidemic, the incidence of HCC is rising at an alarming rate and US veterans with cirrhosis have 5-8% lifetime risk of developing hepatocellular carcinoma (HCC). New, highly effective, antiviral therapies for HCV have recently become available, but these have had little impact on development of HCC and it is virtually unknown how the virus causes cancer. Our group has been studying the effects of HCV on the host cellular enzyme telomerase, which is a reverse transcriptase (RT) that repairs short chromosomal DNA 3' ?telomeric? ends in dividing cells. Adequate telomere lengths must be maintained to avoid chromosomal injury and to support continuous cellular replication. Consequently, telomerase is induced or upregulated in the majority of malignant cells and has proven to be a valuable cellular target enzyme for cancer detection and anticancer therapy. Our laboratory has recently shown that HCV induces telomerase early after infection and we hypothesize that this behavior contributes to the virus' oncogenicity. Induction of telomerase is likely facilitated in part through the actions of HCV proteins core, NS5A and NS3-4A in the host hepatocyte. We have also demonstrated that HCV core and NS5A proteins transcriptionally activate TERT promoter and that NS3-4A, the viral protease-helicase complex, binds specifically to TERT and stimulates telomerase catalytic activity. Our data are the first to show that HCV can induce TERT expression as well as catalytically activate host telomerase. The overlying hypothesis of this application is that HCV reactivates telomerase through initial interactions with the Wnt/?-catenin signaling system which then drives TERT promoter to open transcription. This is likely accomplished by core and NS5A which have been shown to stabilize activated Wnt/?-catenin signaling complexes. We also hypothesize that NS3-4A, a multifunctional protease-helicase, increases telomerase catalytic activity by optimizing the enzyme's type II processivity. By increasing telomerase processivity, NS3-4A thus promotes efficiency of telomere repair and facilitates neoplastic progression. Collectively, the actions of the virus upregulate chromosomal maintenance and repair mechanisms and promote hepatocarcinogenesis. The long term goals of our work are two-fold: we wish to determine the mechanisms of how the virus induces telomerase expression and increases telomerase catalytic activity. Achievement of both of these goals will lead to the identification of cellular events that are undoubtedly important for HCC development and ultimately treatment. This approach is highly relevant for understanding how HCV promotes liver cancer and the data will lay a firm foundation for eventual drug targeting of telomerase or the viral helicase with anticancer agents.

Public Health Relevance

Hepatitis C virus (HCV) is a major cause of cirrhosis and cause of liver cancer in US veterans and around the world. This grant will study how viral enzymes change normal livers to cancer. It will also provide new information on how liver cancer can be detected early, more effectively treated and prevented. The goals of this project, if achieved, will certainly benefit numerous US veterans as well as millions of patients worldwide with chronic HCV infection.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Infectious Diseases A (INFA)
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Iowa City VA Medical Center
Iowa City
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Schmidt, Warren N; Nelson, David R; Pawlotsky, Jean-Michel et al. (2014) Direct-acting antiviral agents and the path to interferon independence. Clin Gastroenterol Hepatol 12:728-37
Kayali, Zeid; Schmidt, Warren N (2014) Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med 7:387-98
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