# Dissecting immune surveillance to gammaherpesviruses

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $582,013

## Abstract

A primary driver of immune deficiency caused by HIV is the destruction of T cells, which if left untreated results
in AIDS. Depression of cellular immunity results in a failure to control pre-existing virus infections, such as
those by the human gammaherpesviruses: the Epstein-Barr virus and the Kaposi's sarcoma-associated
herpesvirus. In some AIDS patients this results in severe disease, due to a failure to control virus-infected
cells. Disease is a consequence of infection of B cells that harbor latent infection in the absence of virus
replication. Previous work has shown the memory CD8 T cell response is the most important component of
immune surveillance that controls latently infected cells in healthy patients. Therefore deeper understanding of
CD8 T cell-mediated immune surveillance can help us understand how this response fails in AIDS patients,
promoting development of strategies to restore immune surveillance to prevent gammaherpesvirus-associated
diseases. This proposal will build on the novel finding that the BTB-ZF family transcription repressor Zbtb20 is
essential for effective immune surveillance against murine gammaherpesvirus-68 (MHV-68). This rodent virus
has proven to be an excellent model for virus-immune interactions, recapitulating many of the immune
mechanisms used to control AIDS-relevant gammaherpesviruses. Preliminary data show the absence of
Zbtb20 prevents the generation of cells with an effector / effector memory transcriptional signature. In addition
rates of both glycolytic and mitochondrial metabolism were aberrantly elevated in Zbtb20-deficient CD8 T cells,
indicating an important role for Zbtb20 in regulating immunometabolic status appropriate for the differentiation
state of the T cell. This is critical, as it is clear that the metabolic state of the T cell is a critical driver of
differentiation to memory cells, but very little is known about the metabolic state required for long-term
immune surveillance. Our transcriptomic data identify key genes in glycolytic and mitochondrial respiratory
pathways that are elevated in the absence of Ztbtb20. We will test whether dysregulation of these genes leads
to attrition of immune surveillance, and if gene knockdown restores appropriate T cell differentiation and
immunometabolism. Further experiments test the extent to which Zbtb20 is necessary for protection from
disease associated with gammaherpesvirus infection in mice lacking endogenous T cell immunity, to mimic
AIDS-defining immunodeficiency. These parameters are also tested using T cells genetically modified to
restore effector memory differentiation or normalize metabolic rates. In summary, the significance is a
mechanistic understanding of what is required for effective immune surveillance against an important class of
AIDS-associated pathogen. Armed with this knowledge, we can design improved immune-based therapies to
prevent serious disease in AIDS patients.

## Key facts

- **NIH application ID:** 10468133
- **Project number:** 5R01AI155015-03
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Edward J Usherwood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $582,013
- **Award type:** 5
- **Project period:** 2020-09-16 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468133

## Citation

> US National Institutes of Health, RePORTER application 10468133, Dissecting immune surveillance to gammaherpesviruses (5R01AI155015-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468133. Licensed CC0.

---

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