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

Josephine M. Reynaud, Dal Young Kim, Svetlana Atasheva, Aliaksandra Rasalouskaya, James P. White, Michael S. Diamond, Scott Weaver, Elena I. Frolova, Ilya Frolov

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1004863
JournalPLoS Pathogens
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2015

Fingerprint

Alphavirus
Interferon Type I
Genome
Virion
Interferons
Venezuelan Equine Encephalitis Viruses
Chikungunya virus
Nucleocapsid
RNA Viruses
Viral RNA
Antiviral Agents
Vaccines
Mutation
Genes

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Reynaud, J. M., Kim, D. Y., Atasheva, S., Rasalouskaya, A., White, J. P., Diamond, M. S., ... Frolov, I. (2015). IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. PLoS Pathogens, 11(4), [e1004863]. https://doi.org/10.1371/journal.ppat.1004863

IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. / Reynaud, Josephine M.; Kim, Dal Young; Atasheva, Svetlana; Rasalouskaya, Aliaksandra; White, James P.; Diamond, Michael S.; Weaver, Scott; Frolova, Elena I.; Frolov, Ilya.

In: PLoS Pathogens, Vol. 11, No. 4, e1004863, 01.04.2015.

Research output: Contribution to journalArticle

Reynaud, JM, Kim, DY, Atasheva, S, Rasalouskaya, A, White, JP, Diamond, MS, Weaver, S, Frolova, EI & Frolov, I 2015, 'IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon', PLoS Pathogens, vol. 11, no. 4, e1004863. https://doi.org/10.1371/journal.ppat.1004863
Reynaud, Josephine M. ; Kim, Dal Young ; Atasheva, Svetlana ; Rasalouskaya, Aliaksandra ; White, James P. ; Diamond, Michael S. ; Weaver, Scott ; Frolova, Elena I. ; Frolov, Ilya. / IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. In: PLoS Pathogens. 2015 ; Vol. 11, No. 4.
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