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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000159-10
Application #
9655906
Study Section
Infectious Diseases A (INFA)
Project Start
2009-04-01
Project End
2021-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52246
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
Zhu, Zhaowen; Mathahs, M Meleah; Schmidt, Warren N (2013) Restoration of type I interferon expression by heme and related tetrapyrroles through inhibition of NS3/4A protease. J Infect Dis 208:1653-63
Schmidt, Warren N; Mathahs, M Meleah; Zhu, Zhaowen (2012) Heme and HO-1 Inhibition of HCV, HBV, and HIV. Front Pharmacol 3:129
Bandyopadhyay, Sarmistha; Friedman, Robin C; Marquez, Rebecca T et al. (2011) Hepatitis C virus infection and hepatic stellate cell activation downregulate miR-29: miR-29 overexpression reduces hepatitis C viral abundance in culture. J Infect Dis 203:1753-62
Poynard, Thierry; Munteanu, Mona; Colombo, Massimo et al. (2011) FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPICĀ³ program. J Hepatol 54:227-35
Marquez, Rebecca T; Bandyopadhyay, Sarmistha; Wendlandt, Erik B et al. (2010) Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans. Lab Invest 90:1727-36
Zhu, Zhaowen; Wilson, Anne T; Luxon, Bruce A et al. (2010) Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: mechanism for the antiviral effects of heme oxygenase? Hepatology 52:1897-905
Ali, Sobia; Stolpen, Alan H; Schmidt, Warren N (2010) Portosystemic encephalopathy due to mesoiliac shunt in a patient without cirrhosis. J Clin Gastroenterol 44:381-3
Zhu, Zhaowen; Wilson, Anne T; Gopalakrishna, Kota et al. (2010) Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells. J Med Virol 82:239-48

Showing the most recent 10 out of 11 publications