# Project 2: Durable impact of HCV on innate and adaptive immunity

> **NIH NIH U19** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $638,169

## Abstract

Project Summary/Abstract
Chronic viral infections are associated with functional impairment of innate and adaptive immunity, including the
development of T cell exhaustion. We and others recently showed that these functional defects persist even after
cure of chronic viremia and are associated with irreversible molecular and epigenetic “scars”. With the rise of
treatment options, ranging from antivirals to immunomodulatory therapies or even therapeutic vaccines, attention
in biomedical research has shifted to understanding the long-term immune sequelae of chronic infection: how
does the irreversible regulatory wiring within virus-specific exhausted T cells mediate dysfunction? How does
chronic infection exposure impact bystander innate as well as adaptive responses and how durable are these
effects? This is an important knowledge gap preventing the identification of regulatory pathways as well as
relevant cell types that can be targeted to reverse long-lasting immune dysregulation in chronic infection. In
Project 2, we focus on a fundamental, yet understudied aspect of persistent viral infection: the impact
on existing as well as de novo antiviral responses, and we explore new strategies for modulating immune
dysfunction. This problem is ideally studied in human cohorts since animal models cannot mimic the breadth
and timescale of immune exposures in humans. Chronic HCV infection is a unique model system in humans to
study fundamental principles of antiviral immunity – it can cause self-limited acute infection or progress to chronic
disease in healthy adults and remains the only persistent virus that can be fully cured. Therefore, we propose to
use HCV as a pathognomonic disease context to test our overarching hypothesis that chronic infection leads
to broadly dysregulated innate and adaptive responses and that targeted modulation of key molecular
pathways can rescue immune dysfunction. Specifically, we will 1) test whether reversal of known immune
sequelae/”scars” in chronic infection through epigenetic reprogramming can rescue T cell exhaustion, 2) assess
the impact of chronic infection and its cure on bystander T cell differentiation and function, and 3) test how altered
innate myeloid responses following chronic viral infection (HCV) affects inflammatory setpoint and heterologous
vaccine responses. Upon completion of this Project, we will have identified specific mechanistic interventions
that can restore exhausted T cell function by reversing previously defined regulatory “scars”. We will also have
delineated more broadly the immune sequelae of chronic infection on bystander innate and adaptive cells. These
studies are intended to establish new paradigms for antiviral immunity in humans and will ultimately act as proof-
of-concept for new intervention strategies that can enhance or modulate anti-viral immunity with high specificity.
Importantly, this Project will closely interact with Projects 1 and 3, to compare and contrast the immune
pert...

## Key facts

- **NIH application ID:** 10824505
- **Project number:** 2U19AI082630-16
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** GEORG Michael LAUER
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $638,169
- **Award type:** 2
- **Project period:** 2009-06-08 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824505

## Citation

> US National Institutes of Health, RePORTER application 10824505, Project 2: Durable impact of HCV on innate and adaptive immunity (2U19AI082630-16). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10824505. Licensed CC0.

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