A Zika virus envelope mutation preceding the 2015 epidemic enhances virulence and fitness for transmission

Chao Shan, Hongjie Xia, Sherry L. Haller, Sasha R. Azar, Yang Liu, Jianying Liu, Antonio E. Muruato, Rubing Chen, Shannan L. Rossi, Maki Wakamiya, Nikos Vasilakis, Rongjuan Pei, Camila R. Fontes-Garfias, Sanjay Kumar Singh, Xuping Xie, Scott C. Weaver, Pei Yong Shi

    Research output: Contribution to journalArticlepeer-review

    44 Scopus citations


    Arboviruses maintain high mutation rates due to lack of proofreading ability of their viral polymerases, in some cases facilitating adaptive evolution and emergence. Here we show that, just before its 2013 spread to the Americas, Zika virus (ZIKV) underwent an envelope protein V473M substitution (E-V473M) that increased neurovirulence, maternal-to-fetal transmission, and viremia to facilitate urban transmission. A preepidemic Asian ZIKV strain (FSS13025 isolated in Cambodia in 2010) engineered with the V473M substitution significantly increased neurovirulence in neonatal mice and produced higher viral loads in the placenta and fetal heads in pregnant mice. Conversely, an epidemic ZIKV strain (PRVABC59 isolated in Puerto Rico in 2015) engineered with the inverse M473V substitution reversed the pathogenic phenotypes. Although E-V473M did not affect oral infection of Aedes aegypti mosquitoes, competition experiments in cynomolgus macaques showed that this mutation increased its fitness for viremia generation, suggesting adaptive evolution for human viremia and hence transmission. Mechanistically, the V473M mutation, located at the second transmembrane helix of the E protein, enhances virion morphogenesis. Overall, our study revealed E-V473M as a critical determinant for enhanced ZIKV virulence, intrauterine transmission during pregnancy, and viremia to facilitate urban transmission.

    Original languageEnglish (US)
    Pages (from-to)20190-20197
    Number of pages8
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number33
    StatePublished - Aug 2020


    • Envelope
    • Evolution
    • Transmission
    • Zika

    ASJC Scopus subject areas

    • General


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