# Persistence of HCV-Induced Perturbations of Cellular Pathways Post DAA Cure in Advanced Liver Disease

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2020 · $478,533

## Abstract

ABSTRACT
In the era of interferon (IFN)-alpha plus ribavirin therapy, a subset of Hepatitis C Virus (HCV) infected patients
were cured of their virus but some patients still developed hepatocellular carcinoma (HCC). While Directly Acting
Antiviral (DAA) drugs are now able to cure the majority of HCV infections, even in subjects with advanced liver
disease, what happens to liver disease upon DAA-induced cure of viremia is only beginning to emerge. After
curing HCV in patients who had previously treated HCC, it has been conclusively shown that HCC recurrence
does not increase. However, just like the IFN treatment era, patients with advanced liver disease still remain at
risk for developing HCC even when the original insult, the virus, is eliminated by DAAs.
This revised application seeks to define the molecular underpinnings for the liver disease risk that persists after
DAA cure of HCV infection. Our guiding idea is that the liver remains abnormal after DAA cure of HCV.
Indeed, our recently published and new preliminary data indicate that HCV-induced epigenetic, signaling and
gene expression perturbations persist after DAA cure of HCV. The data derive from DAA-HCV-cure studies in
cell culture, human liver slice cultures, mice, and humans. Moreover, these epigenetic changes confer changes
in hepatic gene expression and signal transduction pathways known to promote liver cancer. We hypothesize
that in the liver, following DAA cure of HCV, persistence of epigenetic changes activates the
phosphoinositol 3 kinase (PI3K) signaling pathway to promote progression of liver disease. The
hypothesis will be tested in three Specific Aims that will deploy HCV-infectivity studies on human hepatoma cells,
a mouse model where the combination of HCV and diet induce liver disease, on 3D human liver slice cultures,
and in human liver tissue. This comprehensive and complementary approach will be used to define how 1) HCV
engages the epigenetic machinery, 2) DAA cure of HCV promotes PI3K signaling pathway, and 3) How the
combination of virus and diet induced HCC is modulated by DAA cure of HCV infection in vivo.
This R01 brings together investigators with experience in HCV-host interactions, clinical HCV virology, and liver
immunology. It will provide timely insight into a clinically important issue in the new era of rapid cure of HCV
infection. Potential outcomes include the addition of pathway-focused (e.g. PI3K) therapies to DAA regimens to
reduce the risk of liver disease in the DAA era. Such drugs are already in development for other indications, so
a clear outcome from our research may be clinically actionable.

## Key facts

- **NIH application ID:** 10118278
- **Project number:** 1R56AI143683-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** STEPHEN J. POLYAK
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $478,533
- **Award type:** 1
- **Project period:** 2020-04-07 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118278

## Citation

> US National Institutes of Health, RePORTER application 10118278, Persistence of HCV-Induced Perturbations of Cellular Pathways Post DAA Cure in Advanced Liver Disease (1R56AI143683-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10118278. Licensed CC0.

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