Counteraction of APOBEC3 Proteins by Herpesvirus Ribonucleotide Reductases

Abstract

The APOBEC3 family of DNA cytosine deaminases plays an important role in antiviral innate immunity. In this thesis, we describe the novel function of APOBEC3B as a physiologic restriction factor against herpesviruses such as Epstein-Barr virus and herpes simplex virus type 1. We additionally define the counteraction mechanism imparted by herpesviruses using the virus-encoded ribonucleotide reductase large subunit. These viral proteins directly bind A3B to inhibit enzymatic activity, relocalize it away from replicating viral DNA, and protect the virus from A3B-mediated hypermutation for preservation of the viral genome. These results have the potential to reveal new modes of antiviral therapy and have implications in the treatment of A3B-driven cancers.