# Regulation of the Epstein-Barr Virus Lytic Switch

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $507,533

## Abstract

Abstract
 Epstein-Barr virus (EBV) establishes lifelong infection in 95% of adults worldwide. EBV
causes infectious mononucleosis, lymphomas, nasopharyngeal and gastric cancer, and oral
hairy leukoplakia. EBV is transmitted between hosts through saliva, from which it translocates
across the oral cavity and tonsillar epithelium to reach the B-cell compartment. Upon B-cell
infection, the ~170 kilobase linear double-stranded DNA (dsDNA) EBV genome is delivered to
the nucleus. EBV then uses a series of latency programs to navigate the B-cell compartment,
and colonize the memory B-cell compartment. Ultimately, to spread between cells and to the
tonsillar epithelium for transfer to a new host, EBV must undergo lytic replication, in which
nearly 80 viral proteins are expressed and infectious virion are produced. Lytic replication is
increasingly implicated in oncogenesis. Yet, much remains to be learned about how the viral
lytic switch is controlled. We therefore used a human genome-wide CRISPR/Cas9 screen to
identify host factors that control the viral lytic switch. Our analyses a network of host factors that
repress lytic reactivation, centered on the transcription factor MYC, including cohesins, FACT,
STAGA, and Mediator. Depletion of MYC or factors important for MYC expression, reactivated
the lytic cycle, including in Burkitt xenografts. MYC bound the EBV genome origin of lytic
replication and suppressed its looping to the lytic cycle initiator BZLF1 promoter. Our central
hypothesis is that the MYC:MAX control the EBV lytic switch through regulation of viral genome
loop extrusion. Our Aims are to (1) Define key MYC roles in regulation of oriLyt loop extrusion to
control the EBV lytic switch; (2) Define MYC-gated cohesin roles in regulation of oriLyt loop
extrusion in EBV lytic switch control (3) Define MYC-gated CTCF roles in regulation of oriLyt
loop extrusion to control the EBV lytic switch. Collectively, these studies are expected to identify
how EBV subverts host DNA loop extrusion pathways to control the viral lytic switch.
Our studies may therefore support strategies to develop rational lytic induction therapeutic
therapies for EBV-associated diseases.

## Key facts

- **NIH application ID:** 10317642
- **Project number:** 1R01AI164709-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Benjamin Elison Gewurz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,533
- **Award type:** 1
- **Project period:** 2021-07-06 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317642

## Citation

> US National Institutes of Health, RePORTER application 10317642, Regulation of the Epstein-Barr Virus Lytic Switch (1R01AI164709-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10317642. Licensed CC0.

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