Unleashing natural immunity against epstein-barr virus project summary epstein-barr virus (EBV) is a near-ubiquitous herpesvirus that contributes significantly to global health burdens

The National Institute of Allergy and Infectious Diseases awarded the University of Texas Health Science Center at San Antonio $153,560 on October 8, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate disruption of the Epstein-Barr virus ribonucleotide reductase and APOBEC3B interaction as a therapeutic approach to restore natural antiviral immunity against EBV.

The research addresses the absence of FDA-approved antivirals for EBV infection and the rising incidence of infectious mononucleosis in high-income countries, which carries elevated risk of multiple sclerosis and EBV-associated cancers. The recipient's laboratory has identified a direct interaction between EBV's ribonucleotide reductase (RNR) and the cellular antiviral enzyme APOBEC3B (A3B) that protects the virus from lethal DNA mutagenesis. The project pursues two aims: Aim 1 employs separation-of-function mutants to determine whether EBV RNR's enzymatic activity or A3B-binding capability is more critical for lytic replication, infectivity, and disease progression in vivo, and to elucidate the molecular mechanism by which A3B restricts EBV. Aim 2 pursues pharmacological disruption of the EBV RNR-A3B interaction through protein degradation strategies.

Work is performed in San Antonio, Texas. The period of performance runs from the award date through April 30, 2027.

EBV is the causative agent of infectious mononucleosis (EBV-IM), an acute disease with rising incidence in high- income countries including the united states. EBV-IM also increases the risk of developing multiple sclerosis and EBV-associated cancers. Despite widespread impact, there are currently no FDA-approved antivirals to treat EBV infections. Furthermore, vaccines may inadvertently increase EBV-IM incidence by delaying infection until adolescence, and long-term, chronic complications of this disease underscore an urgent need for new therapeutic approaches. Recent studies from our laboratory have revealed a strong and direct interaction between EBV's ribonucleotide reductase (RNR) and a cellular antiviral enzyme called APOBEC3B (A3B). This interaction is broadly conserved among related herpesviruses, and IT serves to protect the virus from lethal DNA mutagenesis by A3B. When this interaction is disrupted in cell culture models, the virus becomes susceptible to DNA deamination by A3B, leading to a significant loss of infectivity. These results combine to indicate that disrupting this virus-host interaction could restore A3B's natural ability to restrict EBV replication. We hypothesize that genetic and pharmacological disruption of the EBV RNR-A3B interaction will restore A3B's antiviral function, thereby reducing EBV lytic replication and pathogenesis in vivo. Aim 1 employs separation-of-function mutants to ask whether EBV RNR's enzymatic (dntp synthesis) or A3B-binding activity is more critical for lytic replication, infectivity, and disease progression in vivo, as well as elucidating the molecular mechanism by which A3B restricts EBV. Aim 2 pursues pharmacological disruption of the EBV RNR-A3B interaction by degrading the viral RNR (e.g., using protacs) to unleash A3B's antiviral activity against EBV and exploiting this conserved mechanism for broad-spectrum therapy against related herpesviruses. The overall impact of these studies will be a deeper mechanistic understanding of EBV lytic replication and pathogenesis, with the potential to transform EBV treatment by leveraging the host's natural immunity and laying the foundation for the development of targeted antivirals against EBV. Training will take place at the university of texas health SAN antonio, an institution with a world-class community of virology, immunology, biochemistry, and drug development researchers and robust core facilities. The primary goal of the training is to acquire skill sets that will facilitate my development into an independently funded scientist leading a laboratory investigating antiviral mechanisms and novel antiviral strategies. This includes comprehensive training in all aspects of a humanized mouse model and gaining expertise in drug development through a tailored individual development plan and mentorship from experts in all relevant scientific areas.