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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.

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  • Authors

    Patel MR, Loo YM, Horner SM, Gale M, Malik HS

    Institution

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    Source

    PLoS biology 10:3 2012 pg e1001282

    MeSH

    Adaptor Proteins, Signal Transducing
    Amino Acid Sequence
    Animals
    Evolution, Molecular
    Genes, Viral
    Hepacivirus
    Hepatitis C
    Host-Pathogen Interactions
    Humans
    Models, Molecular
    Molecular Sequence Data
    Phylogeny
    Primates
    Proteolysis
    Selection, Genetic
    Sequence Alignment
    Viral Nonstructural Proteins
    Virus Replication

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, Non-P.H.S.

    Language

    eng

    PubMed ID

    22427742