Rational design of a flavivirus vaccine by abolishing viral RNA 2′-O methylation

Shi Hua Li, Hongping Dong, Xiao Feng Li, Xuping Xie, Hui Zhao, Yong Qiang Deng, Xiao Yu Wang, Qing Ye, Shun Ya Zhu, Hong Jiang Wang, Bo Zhang, Qi Bin Leng, Roland Zuest, E. De Qin, Cheng Feng Qin, Pei Yong Shi

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Viruses that replicate in the cytoplasm cannot access the host nuclear capping machinery. These viruses have evolved viral methyltransferase( s) to methylate N-7 and 2′-O cap of their RNA; alternatively, they "snatch" host mRNA cap to form the 5′ end of viral RNA. The function of 2′-O methylation of viral RNA cap is to mimic cellular mRNA and to evade host innate immune restriction. A cytoplasmic virus defective in 2′-O methylation is replicative, but its viral RNA lacks 2′-O methylation and is recognized and eliminated by the host immune response. Such a mutant virus could be rationally designed as a live attenuated vaccine. Here, we use Japanese encephalitis virus (JEV), an important mosquito-borne flavivirus, to prove this novel vaccine concept. We show that JEV methyltransferase is responsible for both N-7 and 2′-O cap methylations as well as evasion of host innate immune response. Recombinant virus completely defective in 2′-O methylation was stable in cell culture after being passaged for>30 days. The mutant virus was attenuated in mice, elicited robust humoral and cellular immune responses, and retained the engineered mutation in vivo. A single dose of immunization induced full protection against lethal challenge with JEV strains in mice. Mechanistically, the attenuation phenotype was attributed to the enhanced sensitivity of the mutant virus to the antiviral effects of interferon and IFIT proteins. Collectively, the results demonstrate the feasibility of using 2′-O methylationdefective virus as a vaccine approach; this vaccine approach should be applicable to other flaviviruses and nonflaviviruses that encode their own viral 2′-O methyltransferases.

Original languageEnglish (US)
Pages (from-to)5812-5819
Number of pages8
JournalJournal of virology
Volume87
Issue number10
DOIs
StatePublished - May 1 2013

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Li, S. H., Dong, H., Li, X. F., Xie, X., Zhao, H., Deng, Y. Q., Wang, X. Y., Ye, Q., Zhu, S. Y., Wang, H. J., Zhang, B., Leng, Q. B., Zuest, R., Qin, E. D., Qin, C. F., & Shi, P. Y. (2013). Rational design of a flavivirus vaccine by abolishing viral RNA 2′-O methylation. Journal of virology, 87(10), 5812-5819. https://doi.org/10.1128/JVI.02806-12