# Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $467,077

## Abstract

ABSTRACT
Our ultimate goal to define the molecular mechanisms for EBV latency establishment and reactivation in the oral
cavity. In this proposal, we aim to characterize how EBV usurps B-cell maturation programs for cell survival and
the establishment of a continuum of cell states balancing latency-driven proliferation, differentiation, and lytic
reactivation. It is our central hypothesis that EBV establishes B-cell latent infection through mimicry of the
germinal center (GC) reaction and subsequently promotes a continuum of activation and differentiation that is
balanced to enable access to a cell state supporting lytic reactivation. We have formulated our central hypothesis
based on preliminary data including single-cell gene expression, chromatin conformation of tonsillar B cells and
EBV-immortalized cells as well as characterization of new spontaneously lytic strains of EBV. We found that
EBV latent infection promotes GC mimicry through temporal regulation of anti-apoptotic MCL-1 and BFL-1. Using
scRNA-seq of LCLs, we discovered a continuum of gene expression where NFB signaling/activation (e.g.
NFKB2, MYC, IRF8) is strongly anti-correlated with plasmablast differentiation (e.g. CD38, PRDM1, XBP1).
Furthermore, EBV lytic genes were expressed in cells most similar to the high differentiation state suggesting a
model whereby EBV-infected cells constantly sample this differentiated state to enable a switch to lytic
reactivation. Finally, using new strains of EBV we describe a paradigm of a persistent, spontaneous switch to
productive infection that is transient and reversible. Therefore, the rationale for this proposed research is that
understanding how EBV establishes latency and reactivates to productive infection provides insight into
therapeutic modalities to eliminate EBV-infected cells from the oral cavity. The underlying molecular circuitry
controlling these cell fate decisions may also provide important new information regarding the plasticity of B-cell
maturation states. We plan to test our central hypothesis and complete the objectives in this proposal through
the following three specific aims: i) to determine the molecular mechanisms by which EBV promotes B-cell
survival mimicking tonsillar B-cell maturation, ii) to define the underlying molecular circuitry supporting a novel
activation/differentiation continuum within individual EBV-immortalized B cells, and iii) to define the biochemical
and cell biological features of a newly described EBV recurrence phenotype in which latently infected cells
produce virions and return to their basal latent state.

## Key facts

- **NIH application ID:** 10235702
- **Project number:** 2R01DE025994-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Micah Alan Luftig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,077
- **Award type:** 2
- **Project period:** 2016-03-04 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235702

## Citation

> US National Institutes of Health, RePORTER application 10235702, Defining the Mechanisms of Epstein-Barr Virus Persistence and Recurrence (2R01DE025994-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10235702. Licensed CC0.

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