Rational Design of a Flavivirus Vaccine by Abolishing Viral RNA 2′- O Methylation

• DOI: 10.1128/jvi.02806-12
• Publication Date: 2013-03-14T04:25:54Z
• Authors: 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
• Keywords: Flavivirus; RNA virus; RNA methylation

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