# Pathogenesis and Novel Therapeutics to Reverse T Cell Exhaustion in Persistent Viral Infections

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $241,875

## Abstract

Project Summary/Abstract
 T cells are essential for immune surveillance since they recognize, attack and remove virus-infected
and cancer-transformed cells. Inhibitory receptors (IR) temper inflammatory responses to microbial infections
by regulating T cell effector activity. In humans, persistent viruses such as HIV, HCV and HBV as well as
several types of cancer have adapted to exploit IR signaling by upregulating IR ligands, resulting in the
suppression of T cell function (exhaustion) and escape from immune control. T cell exhaustion and the
resurrection of T cell function, by neutralizing IR signaling, was first delineated in C57BL/6 mice following
infection with the Clone 13 variant of lymphocytic choriomeningitis virus (LCMV). Infection with Clone 13
results in suboptimal CD4 and CD8 T cell effector function, ranging from reduced to absent cytotoxic capacity
of CD8 T cells to decreased production of anti-viral cytokines such as IFN-γ and TNF-α. Chronicling the
resurrection of anti-viral T cell activity using antibodies that target IRs suggests that an in vitro phenotypic
assay using the LCMV system could be an effective screening platform to identify novel small pharmacologic
and beneficial molecule(s) that disrupt pathways regulating T cell dysfunction. To this end, we developed a
screening strategy that utilizes transgenic mice (IFN-γ-YFP) combined with high-throughput (HTS) flow
cytometry to examine compounds that potentiate IFN-γ expression in exhausted T cells isolated from LCMV
infected animals. Using this approach, we propose to screen a best-in-class drug repurposing collection of
12,000 compounds (ReFrame) developed by TSRI’s non-profit affiliate, Calibr. The ReFrame library’s scale
and comprehensiveness will allow us to explore complex biological processes in T cells and identify novel
therapeutic agents that can reverse T cell exhaustion in the context of persistent viral infections and cancer.

## Key facts

- **NIH application ID:** 9823854
- **Project number:** 5R21AI141842-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Luke Lee Lairson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,875
- **Award type:** 5
- **Project period:** 2018-11-15 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823854

## Citation

> US National Institutes of Health, RePORTER application 9823854, Pathogenesis and Novel Therapeutics to Reverse T Cell Exhaustion in Persistent Viral Infections (5R21AI141842-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9823854. Licensed CC0.

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