# Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas

> **NIH NIH U01** · DUKE UNIVERSITY · 2024 · $746,527

## Abstract

Epstein-Barr virus (EBV) was the first human tumor virus discovered over 50 years ago in the context of
endemic African Burkitt lymphoma. However, we now know it is also a common herpesvirus that persists as a
lifelong latent infection in virtually all adults worldwide. Early work in the field led to a model for EBV infection
promoting B-cell lymphomas as evidenced by the growth transformation, or immortalization, of primary resting
human B cells into lymphoblastoid cell lines (LCLs). In vivo, EBV latent infection is met with a robust cytotoxic
T-cell response keeping most infected individuals protected from the oncogenic potential of the virus. As such,
EBV-associated B-cell lymphomas occur at significantly higher rates in the setting of immune suppression.
Studies of viral and cellular gene expression in EBV-infected cells in vitro and in vivo have led to a model of
lymphomagenesis characterized by the full expression of EBV latency gene products. However, the phenotypes
in bulk culture and tumor tissue lack the nuanced detail of cellular heterogeneity and the consequences of minor
frequency phenotypes on cancer progression. Our recent single cell RNAseq experiments have characterized
gene expression within individual EBV-infected B cells leading to an appreciation of cell fate trajectories and
dynamic gene expression behavior of individual cells that we will integrate with human tumor analysis and mouse
models of lymphomagenesis. It is our ultimate goal to define the importance of specific EBV-infected cell
populations on the progression of B-cell non-Hodgkin lymphomas of the immune suppressed. In this proposal,
we aim to define how EBV-infected cell heterogeneity, including innate antiviral restriction and plasmablast
differentiation, impacts lymphomagenesis and can be exploited for therapy. Our central hypothesis is that EBV-
infected B cells toggle between different states that can restrict or promote lymphomagenesis as well as render
cells susceptible to virus-specific therapeutic intervention. We formulated our central hypothesis based on
preliminary data including single-cell RNA sequencing of EBV-infected primary B cells early after infection and
in LCLs as well as characterization of cell fate dynamics regulating plasmablastic differentiation and lytic
reactivation. We also provide evidence supporting a recent clinical trial using the “kick and kill” strategy of
promoting EBV lytic reactivation with histone deacetylase inhibition coupled with ganciclovir to kill lymphoma
cells that activate viral kinases. Thus, the rationale for the proposed research is that understanding EBV
regulation of infected B-cell fates will dissect mechanisms of pathogenesis and reveal new therapeutic avenues
to target EBV-positive B-cell lymphomas. We plan to test our central hypothesis and complete the objectives in
this proposal through the following three specific aims: i) to define the role of innate immune sensors and
effectors in EBV-mediated immortaliz...

## Key facts

- **NIH application ID:** 10898747
- **Project number:** 5U01CA275306-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Micah Alan Luftig
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $746,527
- **Award type:** 5
- **Project period:** 2022-09-19 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898747

## Citation

> US National Institutes of Health, RePORTER application 10898747, Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas (5U01CA275306-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10898747. Licensed CC0.

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