# Hepatitis C virus genome structure: dynamic roles in replication and infectivity

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $553,036

## Abstract

Project Summary
Hepatitis C virus (HCV) infects a large population within the United States (~2%), where it remains a
major cause of chronic liver disease and cancer. While potent antiviral drugs have recently become
available, long-term success in combating HCV-related disease requires a clear understanding of viral
replication mechanisms. Furthermore, HCV provides an essential model system for understanding
the replication of many related positive-strand RNA viruses, including dengue virus and other unmet
threats to human and animal health. To date, most work on HCV replication has focused on activities
of the viral nonstructural (NS) proteins or the role of host factors in this process. Very little has been
done on role of the HCV RNA genome in replication or on the functional interactions between the viral
genome and NS proteins. This is a critical gap, since the interaction between HCV RNA and viral
proteins is literally where the “rubber hits the road”, and the key events in viral replication occur. We
will leverage our recent success in defining molecular networks among the NS proteins, and in
characterizing RNA and RNA-protein complexes, and we will exploit new approaches for monitoring
RNA interactions in vivo in order to achieve the following three aims: (A) Determine the functional
RNA structures within the HCV genome; (B) Define the molecular interactions between NS proteins
and the RNA genome, establishing their interaction sites and functional relevance during sequential
phases of the viral lifecycle; (C) Define the structural features and functional attributes of the
Replication Pre-initiation Complexes (RPIC), which initiates the entire process of virus propagation.
These objectives will be accomplished by integrating innovative approaches for studying viral
genetics, RNA crosslinking and sequencing, enzymology and crystallography, and capitalizing on our
respective strengths in virology and RNA biochemistry. By focusing on the molecular interplay
between genomic RNA and NS proteins, the work is conceptually innovative. In developing the tools
needed to advance this research, the project is also technologically innovative, resulting in methods
and reagents that will be of widespread utility to the RNA virus research community.

## Key facts

- **NIH application ID:** 9980781
- **Project number:** 5R01AI131518-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Brett D. Lindenbach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $553,036
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980781

## Citation

> US National Institutes of Health, RePORTER application 9980781, Hepatitis C virus genome structure: dynamic roles in replication and infectivity (5R01AI131518-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9980781. Licensed CC0.

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