# Neoplastic interactions of hepatitis C virus with telomerase.

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

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/β-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/β-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.

## Key facts

- **NIH application ID:** 9815411
- **Project number:** 5I01BX000159-11
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** WARREN N SCHMIDT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815411

## Citation

> US National Institutes of Health, RePORTER application 9815411, Neoplastic interactions of hepatitis C virus with telomerase. (5I01BX000159-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815411. Licensed CC0.

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