A Zika virus mutation enhances transmission potential and confers escape from protective dengue virus immunity

Zika virus (ZIKV) and dengue virus (DENV) are arthropod-borne pathogenic flaviviruses that co-circulate in many countries. To understand some of the pressures that influence ZIKV evolution, we mimic the natural transmission cycle by repeating serial passaging of ZIKV through cultured mosquito cells and either DENV-naive or DENV-immune mice. Compared with wild-type ZIKV, the strains passaged under both conditions exhibit increased pathogenesis in DENV-immune mice. Application of reverse genetics identifies an isoleucine-to-valine mutation (I39V) in the NS2B proteins of both passaged strains that confers enhanced fitness and escape from pre-existing DENV immunity. Introduction of I39V or I39T, a naturally occurring homologous mutation detected in recent ZIKV isolates, increases the replication of wild-type ZIKV in human neuronal precursor cells and laboratory-raised mosquitoes. Our data indicate that ZIKV strains with enhanced transmissibility and pathogenicity can emerge in DENV-naive or -immune settings, and that NS2B-I39 mutants may represent ZIKV variants of interest. [Display omitted] •ZIKV virus evolution increases pathogenesis in mice•I39V mutation in the NS2B protein confers escape from pre-existing DENV immunity•I39V or I39T mutation increases ZIKV replication in NPCs and mosquitoes Regla-Nava et al. find that serial passaging of ZIKV strain in vitro/in vivo produces a single mutation that is sufficient to enhance ZIKV virulence and escape the protective effects of pre-existing DENV immunity. NS2B I39V/I39T mutation significantly increases infectivity in human fetal NPCs and mosquitoes and enhanced pathogenicity in mice.