# T cell Immunity and the Outcome of Acute HCV Infection

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2020 · $714,861

## Abstract

Abstract.
The hepatitis C virus (HCV) has infected about 2 percent of the world's population and is a major cause of
chronic liver diseases. Treatment of chronic hepatitis C has improved dramatically with the introduction of
highly effective direct acting antivirals (DAA). At the same time, HCV transmission is increasing globally. In the
United States, infection rates have doubled in many regions. Most of these new infections are undiagnosed
and so new infections may occur at a faster rate than detection and treatment. There is an emerging
consensus that a vaccine may be needed to prevent new HCV infections, and perhaps second infections in
those cured with costly DAA. Considerable evidence supports a role for T cell immunity in protection from
HCV persistence. Indeed, the only vaccine to enter phase I/II testing in humans incorporates only non-
structural HCV proteins, with the objective of priming T cell immunity to prevent HCV persistence. There is still
uncertainty, however, about mechanisms of CD4+ and CD8+ T cell failure during acute hepatitis C and the risk
posed to vaccine development. The central hypothesis of the proposed research is that comparison of T cell
responses in acute HCV infections will reveal mechanisms leading to exhaustion and persistence, or memory
and life-long protection from chronic hepatitis C. Two aspects of the application are innovative. First, human
liver biopsies are not medically justified during acute infection and so very little is known about intrahepatic T
cell responses during this critical phase when infection outcome is determined. The proposed research will fill
this gap in knowledge using archived blood and liver mononuclear cells from acutely infected chimpanzees
with different infection outcomes. Second, cutting edge technologies to profile gene expression and TcR
affinity have been adapted to study HCV-specific T cells. These technologies are innovative as they require
very few HCV-specific CD8+ T cells to accomplish study goals. When combined with established flow
cytometric methods, they will provide a comprehensive view of how transcriptional pathways, effector
functions, and TcR affinity differ in resolving and persisting infections. These unique samples and technologies
will be used to address two specific aims. Specific Aim 1 will identify early differences in HCV-specific CD8+
T cells associated with resolution versus persistence of infection. CD8+ T cells undergo functional exhaustion
and select for HCV escape variants in infections that persist. Our objective is to understand how transcription
factor networks, TcR affinity for antigen, and alterations in effector function contribute to this outcome. Specific
Aim 2 is to identify mechanism(s) of CD4+ T cell failure in acute HCV infections that persist. CD4+ T cell help
is essential for antiviral CD8+ T cell activity in HCV infection. There is to date no explanation for spontaneous
loss of CD4+ T cell activity infections that persist, in part ...

## Key facts

- **NIH application ID:** 9932322
- **Project number:** 5R01AI126890-05
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Arash Grakoui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $714,861
- **Award type:** 5
- **Project period:** 2016-06-25 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932322

## Citation

> US National Institutes of Health, RePORTER application 9932322, T cell Immunity and the Outcome of Acute HCV Infection (5R01AI126890-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932322. Licensed CC0.

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