Evidence linking APOBEC3B genesis and evolution of innate immune antagonism by gamma-herpesvirus ribonucleotide reductases

Viruses have evolved diverse mechanisms to antagonize host immunity such as direct inhibition and relocalization of cellular APOBEC3B (A3B) by the ribonucleotide reductase (RNR) of Epstein-Barr virus. Here, we investigate the mechanistic conservation and evolutionary origin of this innate immune counteraction strategy. First, we find that human gamma-herpesvirus RNRs engage A3B via largely distinct surfaces. Second, we show that RNR-mediated enzymatic inhibition and relocalization of A3B depend upon binding to different regions of the catalytic domain. Third, we show that the capability of viral RNRs to antagonize A3B is conserved among gamma-herpesviruses that infect humans and Old World monkeys that encode this enzyme but absent in homologous viruses that infect New World monkeys that naturally lack the A3B gene. Finally, we reconstruct the ancestral primate A3B protein and demonstrate that it is active and similarly engaged by the RNRs from viruses that infect humans and Old World monkeys but not by the RNRs from viruses that infect New World monkeys. These results combine to indicate that the birth of A3B at a critical branchpoint in primate evolution may have been a driving force in selecting for an ancestral gamma-herpesvirus with an expanded RNR functionality through counteraction of this antiviral enzyme.

Automated summary

Viruses have evolved mechanisms to counteract host immunity, including inhibiting and relocalizing cellular APOBEC3B (A3B) through the ribonucleotide reductase (RNR) of Epstein-Barr virus. This study investigates the conserved mechanisms and evolutionary origin of this immune counteraction strategy. The results show that human gamma-herpesvirus RNRs interact with A3B through distinct surfaces and their enzymatic inhibition and relocalization of A3B depend on binding to different regions of the catalytic domain. Additionally, the ability of viral RNRs to counteract A3B is conserved in gamma-herpesviruses that infect humans and Old World monkeys but absent in homologous viruses that infect New World monkeys.