# T Cell Immunity and HCV Infection Outcome

> **NIH NIH U01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2020 · $270,376

## Abstract

The hepatitis C virus (HCV) remains an important cause of liver disease globally. New direct acting
antivirals provide effective therapy but there is no vaccine to prevent transmission. The need for a vaccine is
highlighted by a sharp increase in the number of new HCV infections in the United States associated with
unsafe injection drug use. Studies of HCV infection and immunity have provided evidence for protective
immunity that might be replicated by vaccination. Spontaneous resolution of acute hepatitis C provides long-lived
protection against persistent infection upon re-exposure to the virus. Moreover, antibody-mediated
depletion of CD4+ or CD8+ T cells from immune chimpanzees resulted in persistent or prolonged infection
after rechallenge with the virus. These studies provided conceptual support for “T-cell” vaccines against HCV,
including one that is now in Phase I/II clinical trials. However, our poor understanding of how HCV evades T
cell immunity poses a potential risk for vaccine development. Failure of CD4+ T cells is the best predictor of a
chronic outcome but is unexplained. How CD8+ T cells transition from a partially effective state during acute
infection to full exhaustion has also not been defined. Studies in Project 1 are designed to test the
Programmatic central hypothesis that comparison of T cell responses in acute persisting and resolving HCV
infections will reveal unique molecular pathways leading to exhaustion or memory, respectively. Analysis of
antiviral T cell immunity is hampered by lack of access to liver in human subjects with acute hepatitis C. To
address this issue, we will make use of archived liver and blood samples from chimpanzees with acute
hepatitis C to define mechanisms of CD4+ and CD8+ T cell failure. These findings will then be translated to
humans with acute hepatitis C. Our preliminary data suggest that many acute phase intrahepatic CD4+ and
CD8+ T cells are not functional even in infections that spontaneously resolve. This suggests that control of
infection is a more stochastic or random process than previously appreciated. Two specific aims are proposed.
The first is to compare the frequency, breadth, and transcriptional profile of CD4+ T cells in the blood and liver
of chimpanzees with acute resolving and persisting infections. Transcriptional analysis of CD4+ T cells is
expected to reveal molecular pathways leading to deletion or exhaustion of HCV-specific populations
characteristic of acute persisting infections. Innovative microfluidic PCR technology will be used as it is well-adapted
for analysis of gene expression in small numbers of virus-specific CD4+ T cells. Our preliminary data
also show that CD8+ T cells provide partial control of HCV replication for several months before persistence is
established. Transcriptional analysis is proposed to determine how these cells transition from this partially
effective state to full exhaustion, and to define epigenetic modifications to regulatory genes ...

## Key facts

- **NIH application ID:** 10000824
- **Project number:** 5U01AI131313-05
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Christopher M. Walker
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $270,376
- **Award type:** 5
- **Project period:** 2016-09-06 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000824

## Citation

> US National Institutes of Health, RePORTER application 10000824, T Cell Immunity and HCV Infection Outcome (5U01AI131313-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000824. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*