Convergent Evolution of Escape from Hepaciviral Antagonism in Primates

Abstract

The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS—a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV). We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that “escape” mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV. Hepatitis C virus (HCV) causes chronic liver disease and is estimated to infect 170 million people worldwide. HCV is able to establish a persistent infection in part by inhibiting the innate immune response. It does so by using its protease, NS3, to cleave the host's antiviral factor MAVS, which normally activates the interferon response. Using an assay that measures MAVS activity, we found that multiple primate species contain a version of MAVS that is resistant to HCV antagonism. Surprisingly, most of these primates have independently converged on changes in the same amino acid residue of MAVS to escape cleavage by the HCV protease. We found that the HCV protease has lower binding affinity for these resistant MAVS variants, which consequently are more effective at restricting HCV infection. Using a combination of phylogenetic and functional analyses of proteases from other HCV-related viruses, we infer that ancestral primates were likely exposed to and adapted to HCV-like viruses. One consequence of this adaptation is that changes that have given rise to extant MAVS variants may now provide protection from modern-day viruses.