# A sequence-independent approach for attenuating hepaciviruses

> **NIH NIH R21** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2024 · $234,000

## Abstract

Abstract
Human hepacivirus or hepatitis C virus (HCV) establishes chronic hepatotropic infection in ~70% of infected
individuals. In this project, the central question is: Can we mutate a hepacivirus genome to generate an
attenuated virus to use as a vaccine? Serial passaging of pathogenic viruses in vitro or in vivo biological systems
followed by the selection of less-pathogenic viral strains is the traditional way to generate an attenuated virus
vaccine. HCV attenuation remained inconceivable since an efficient cell culture system was unavailable for
decades after virus discovery, and an animal model is still elusive. Similarly, for many other chronic human
viruses, their species specificity restricts the development of immunocompetent animal models critical for
meaningful studies of immunity and pathogenesis. This project will use a rodent hepacivirus (RHV) that shares
the hallmarks of HCV infection in humans. We will use a bioinformatics approach to alter the dinucleotide
frequencies in RHV genomes to generate attenuated variants. Our preliminary results provided a solid
rationale for the project and assured its feasibility. We determined that the RHV variant with high frequencies
of UpA (uracil followed by adenine) failed to develop a chronic infection in rats. We propose two aims to refine
our strategy of generating attenuated hepaciviruses and characterize the innate and adaptive immunity
induced by their infection. Aim-1 is to optimize the design of the hepacivirus mutants that produce high-titer
viremia and fail to develop chronic infection. Aim-2 is to characterize the innate and adaptive immunity
induced by attenuated hepacivirus mutants. Since we will use a sequence-independent approach (only
synonymous mutations) to attenuate RHV, the results can inform the design of an HCV vaccine. Additionally,
successful attenuation of a chronic virus in its natural host will open new research avenues and yield new viral
variants to define immune responses associated with viral clearance and persistence and immune correlates of
protection for chronic viruses.

## Key facts

- **NIH application ID:** 10735885
- **Project number:** 5R21AI171928-02
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Amit Kapoor
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,000
- **Award type:** 5
- **Project period:** 2022-11-07 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10735885

## Citation

> US National Institutes of Health, RePORTER application 10735885, A sequence-independent approach for attenuating hepaciviruses (5R21AI171928-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10735885. Licensed CC0.

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