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

Li, Shi-Hua, Dong, Hongping, Li, Xiao-Feng, Xie, Xuping, Zhao, Hui, Deng, Yong-Qiang, Wang, Xiao-Yu, Ye, Qing, Zhu, Shun-Ya, Wang, Hong-Jiang, Zhang, Bo, Qin, E-De, Qin, Cheng-Feng and Shi, Pei-Yong (2013) Rational design of a flavivirus vaccine through abolishing viral RNA 2′-O methylation. Journal of virology, 87 (10). pp. 5812-5819. ISSN 1098-5514; 0022-538X


Viruses that replicate in the cytoplasm cannot access to 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 subsequently eliminated by host immune response. Such mutant virus could be rationally designed as a live attenuated vaccine. Here we use Japanese encephalitis virus (JEV), an important mosquito-borne flavivirus pathogen, to prove this novel vaccine concept. We show that JEV methyltransferase is responsible for both N7 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 continuous passaging for >30 days. The mutant virus was attenuated in mice, and elicited robust humoral and cellular immune response. 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 methylation-defective virus as a vaccine approach; this vaccine approach should be applicable to other flaviviruses and non-flaviviruses that encode their own viral 2’-O methyltransferases.

Item Type: Article
Date Deposited: 22 Nov 2017 00:45
Last Modified: 22 Nov 2017 00:45