Emergence of Zika virus: Direct reversion of mutations and fitness restoration prior to spread to the Americas

Summary ParagraphMosquito-borne viruses have recently spread globally, with major impacts on human health. 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. For the first time, severe clinical manifestations, including Guillain Barre syndrome and defects to the fetuses of pregnant women, were detected. 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. However, the reasons for the sudden emergence of ZIKV remain incompletely understood. Accumulating evidence on other arboviruses like chikungunya and West Nile suggest the likelihood that viral mutations could be determinants of change in ZIKV transmission efficiency responsible for efficient spread. Using evolutionary analyses, we determined that four mutations, which occurred just before ZIKV introduction to the Americas, represent direct reversions of previous mutations that accompanied spread many decades ago from ZIKVs native Africa to Asia and early circulation there. Experimental infections of mosquitoes, human cells, and mice using ZIKV strains with and without these mutations demonstrated that the original mutations reduced fitness for urban transmission, while the reversions restored fitness, increasing epidemic risk. Overall, our findings include the three newly identified, transmission-adaptive ZIKV mutations, and demonstration that these and one identified previously restored fitness for epidemic transmission soon before introduction into the America. The initial mutations may have followed founder effects and/or drift when the virus was introduced into Asia, or could be related to changes on host or vector utilization within Asia.