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Although interferon (IFN) signaling induces genes that limit viral infection, many pathogenic viruses overcome this host response. As an example, 2'-O methylation of the 5′ cap of viral RNA subverts mammalian antiviral responses by evading restriction of Ifit1, an IFN-stimulated gene that regulates protein synthesis. However, alphaviruses replicate efficiently in cells expressing Ifit1 even though their genomic RNA has a 5′ cap lacking 2'-O methylation. We show that pathogenic alphaviruses use secondary structural motifs within the 5′ untranslated region (UTR) of their RNA to alter Ifit1 binding and function. Mutations within the 5′-UTR affecting RNA structural elements enabled restriction by or antagonism of Ifit1 in vitro and in vivo. These results identify an evasion mechanism by which viruses use RNA structural motifs to avoid immune restriction.
Keeping Alphaviruses Under Wraps
Viruses mutate to avoid detection, and the host responds in kind. For example, 2′-O methylation of the 5′ cap of viral RNA allows viruses to escape detection by the interferon-stimulated host defense protein, IFIT1. Alphaviruses, however, lack this modification but are able to remain undetected in the presence of IFIT1. How? Using a combination of viral mutants and biochemical analysis, Hyde et al. (p. 783, published online 30 January) found that alphaviruses contain secondary structural motifs in the 5′ untranslated region of their genomic RNA that allow them to avoid detection by IFIT1. When these regions were rendered nonfunctional, IFIT1 was able to keep the virus under control.