IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon

PLoS Pathogens

Michael S. Diamond¹  James P. White¹  Josephine M. Reynaud²  Svetlana Atasheva²  Aliaksandra Rasalouskaya²  Dal Young Kim²  Elena I. Frolova³  Scott C. Weaver⁴  Ilya Frolov⁵ 

[1] Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America;Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America;Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, Missouri, United States of America;Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America

关键词: Viral replication;    5' UTR;    Alphaviruses;    RNA viruses;    Virions;    RNA synthesis;    NIH 3T3 cells;    Protein translation;   

DOI  :  10.1371/journal.ppat.1004863

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Alphaviruses are a group of widely distributed human and animal pathogens. It is well established that their replication is sensitive to type I IFN treatment, but the mechanism of IFN inhibitory function remains poorly understood. Using a new experimental system, we demonstrate that in the presence of IFN-β, activation of interferon-stimulated genes (ISGs) does not interfere with either attachment of alphavirus virions to the cells, or their entry and nucleocapsid disassembly. However, it strongly affects translation of the virion-delivered virus-specific RNAs. One of the ISG products, IFIT1 protein, plays a major role in this translation block, although an IFIT1-independent mechanism is also involved. The 5’UTRs of the alphavirus genomes were found to differ significantly in their ability to drive translation in the presence of increased concentration of IFIT1. Prior studies have shown that adaptation of naturally circulating alphaviruses to replication in tissue culture results in accumulation of mutations in the 5’UTR, which increase the efficiency of the promoter located in the 5’end of the genome. Here, we show that these mutations also decrease resistance of viral RNA to IFIT1-induced translation inhibition. In the presence of higher levels of IFIT1, alphaviruses with wt 5’UTRs became potent inducers of type I IFN, suggesting a new mechanism of type I IFN induction. We applied this knowledge of IFIT1 interaction with alphaviruses to develop new attenuated variants of Venezuelan equine encephalitis and chikungunya viruses that are more sensitive to the antiviral effects of IFIT1, and thus could serve as novel vaccine candidates.

【 授权许可】

CC BY