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Nature. 2017 May 25;545(7655):482-486. doi: 10.1038/nature22365. Epub 2017 May 17.

Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes.

Liu Y1,2,3, Liu J1,3, Du S1, Shan C4, Nie K1, Zhang R1,2, Li XF5, Zhang R3, Wang T3,6, Qin CF5, Wang P7, Shi PY4, Cheng G1,3.

Author information

Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
School of Life Science, Tsinghua University, Beijing 100084, China.
SZCDC-SUSTech Joint Key Laboratory for Tropical Diseases, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, China.
Department of Biochemistry &Molecular Biology, Department of Pharmacology &Toxicology, and Sealy Center for Structural Biology &Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Department of Biology, Southern University of Science and Technology, Nanshan, Shenzhen, Guangdong 518055, China.
Department of Microbiology and Immunology, School of Medicine, New York Medical College, Valhalla, New York 10595, USA.


Zika virus (ZIKV) remained obscure until the recent explosive outbreaks in French Polynesia (2013-2014) and South America (2015-2016). Phylogenetic studies have shown that ZIKV has evolved into African and Asian lineages. The Asian lineage of ZIKV was responsible for the recent epidemics in the Americas. However, the underlying mechanisms through which ZIKV rapidly and explosively spread from Asia to the Americas are unclear. Non-structural protein 1 (NS1) facilitates flavivirus acquisition by mosquitoes from an infected mammalian host and subsequently enhances viral prevalence in mosquitoes. Here we show that NS1 antigenaemia determines ZIKV infectivity in its mosquito vector Aedes aegypti, which acquires ZIKV via a blood meal. Clinical isolates from the most recent outbreak in the Americas were much more infectious in mosquitoes than the FSS13025 strain, which was isolated in Cambodia in 2010. Further analyses showed that these epidemic strains have higher NS1 antigenaemia than the FSS13025 strain because of an alanine-to-valine amino acid substitution at residue 188 in NS1. ZIKV infectivity was enhanced by this amino acid substitution in the ZIKV FSS13025 strain in mosquitoes that acquired ZIKV from a viraemic C57BL/6 mouse deficient in type I and II interferon (IFN) receptors (AG6 mouse). Our results reveal that ZIKV evolved to acquire a spontaneous mutation in its NS1 protein, resulting in increased NS1 antigenaemia. Enhancement of NS1 antigenaemia in infected hosts promotes ZIKV infectivity and prevalence in mosquitoes, which could have facilitated transmission during recent ZIKV epidemics.

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