Molecular differences in APOBEC3 counteraction by primate herpesviruses reveal an evolutionary link between the genesis of APOBEC3B and novel viral ribonucleotide reductase function

Viruses have evolved diverse mechanisms to antagonize host immunity. A recently discovered example is the direct inhibition and relocalization of cellular APOBEC3B (A3B) by the Epstein-Barr virus (EBV) ribonucleotide reductase (RNR) subunit BORF2. Recent reports also indicate interactions between the RNRs of other human herpesviruses and A3B, as well as interactions with the homologous APOBEC3A (A3A) enzyme. Here, we investigate the conservation of this APOBEC3 (A3) counteraction mechanism and reveal novel insights into its evolutionary origin. First, we found that herpesvirus RNRs bind to A3s via partially distinct surfaces. Second, we show that RNR-mediated relocalization and enzymatic inhibition of cellular A3s depend on binding to different regions of the A3 catalytic domain and that the inhibition is specific to A3B. Finally, we show that the ability of viral RNRs to counteract A3s is conserved in herpesviruses that infect humans and Old World monkeys, but absent in viruses infecting New World monkeys that naturally lack A3B. These results combine to indicate that the genesis of A3B at a critical branchpoint in primate evolution may have been a driving force in selecting herpesviruses with an expanded RNR functionality through counteraction of this antiviral enzyme.