Investigation of Key Nicotinamide Adenine Dinucleotide Metabolism Pathway Roles in Support of Epstein-Barr Virus Replication

Epstein-Barr virus (EBV) is spread through the saliva, where it establishes oropharyngeal infection, invades the tonsils and colonizes the B-cell compartment. Orally transmitted EBV is the cause of infectious mononucleosis and of multiple B-cell and epithelial cancers, including Burkitt lymphoma, nasopharyngeal carcinoma and gastric cancer. Though typically maintained in latent status in cancer cells, lytic infection is increasingly implicated in tumorigenesis of EBV+ B and epithelial cells, including through evasion of immune and anti-apoptotic pathways, and by modulating cytokine and chemokine signaling. Consequently, there is increasing interest in defining factors that regulate EBV lytic gene expression, and an unmet need for antiviral agents that block not only late lytic gene expression as presently available, but also immediate early and early gene expression. Key preliminary data includes human genome-wide CRISPR screens to characterize host cell factors important for EBV lytic reactivation and replication, which highlighted unexpected roles for nicotinamide adenine dinucleotide (NAD+) metabolism in support of the EBV lytic cycle. While NAD metabolism was recently found to be essential for EBV-driven B-cell immortalization, its roles in the EBV lytic cycle remain unstudied. The proposal tests the central hypothesis that EBV subverts the salvage NAD+ nucleotide metabolism pathway to support each phase of the viral lytic cycle. Aim 1 characterizes obligatory NAD+ salvage pathway roles in support of the EBV immediate early lytic phase. Aim 2 characterizes obligatory NAD+ salvage pathway roles in support of the EBV early lytic phase. Aim 3 characterizes EBV lytic cycle remodeling of NAD-capped RNA abundances to evade host innate immunity. Collectively, these studies investigate a novel area of cross-talk between host cell nucleotide metabolism and the viral lytic cycle. They promise to lay a foundation for novel therapeutic approaches that potently block EBV lytic gene expression in epithelial and B-cell contexts. The career development plan will prepare the applicant for transition to independence as an investigator with a multi-disciplinary approach to study metabolomic and epigenetic control of EBV/host interactions. Project Number: 1K99DE034830-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Yifei Liao | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $135,000 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 IIDA-J (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11300676