Role of mutational reversions and fitness restoration in Zika virus spread to the Americas

Zika virus (ZIKV) emerged from obscurity in 2013 to spread from Asia to the South Pacific and the Americas, where millions of people were infected, accompanied by severe disease including microcephaly following congenital infections. Phylogenetic studies have shown that ZIKV evolved in Africa and later spread to Asia, and that the Asian lineage is responsible for the recent epidemics in the South Pacific and Americas. However, the reasons for the sudden emergence of ZIKV remain enigmatic. Here we report evolutionary analyses that revealed four mutations, which occurred just before ZIKV introduction to the Americas, represent direct reversions of previous mutations that accompanied earlier spread from Africa to Asia and early circulation there. Our experimental infections of Aedes aegypti mosquitoes, human cells, and mice using ZIKV strains with and without these mutations demonstrate that the original mutations reduced fitness for urban, human-amplifed transmission, while the reversions restored fitness, increasing epidemic risk. These findings include characterization of three transmission-adaptive ZIKV mutations, and demonstration that these and one identified previously restored fitness for epidemic transmission soon before introduction into the Americas. The initial mutations may have followed founder effects and/or drift when the virus was introduced decades ago into Asia. The trajectory of the emergence of Zika virus (ZIKV) into the Americas remains unclear. Here, the authors find that four mutations originated before ZIKV introduction to the Americas are direct reversions of previous mutations that accompanied spread many decades ago from ZIKV's native Africa to Asia, and show in experimental infections of mosquitoes, human cells, and mice that the original mutations reduced fitness for urban transmission, while the reversions restored fitness, likely increasing epidemic risk.

Automated summary

The Zika virus (ZIKV) emerged from Africa and spread to Asia before causing recent epidemics in the South Pacific and the Americas. Evolutionary analyses revealed that four mutations, which occurred just before ZIKV introduction to the Americas, are direct reversions of previous mutations that accompanied earlier spread from Africa to Asia. Experimental infections showed that the original mutations reduced fitness for urban transmission, while the reversions restored fitness, likely increasing epidemic risk.