convergent evolution of escape from hepaciviral antagonism in primates趋同进化逃离hepaciviral对立的灵长类动物.pdfVIP

Convergent Evolution of Escape from Hepaciviral Antagonism in Primates 1 2. 2. 2 1,3 Maulik R. Patel , Yueh-Ming Loo , Stacy M. Horner , Michael Gale Jr. , Harmit S. Malik * 1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 2 Department of Immunology, University of Washington School of Medicine, Seattle, Washington, United States of America, 3 Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America 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 resi