Rates of adverse fetal outcomes vary between regions, and not every pregnancy exposed to ZIKV results in birth defects. ZIKV infection during pregnancy is associated with adverse fetal outcomes including birth defects, microcephaly, neurological complications, and even spontaneous abortion.

Zika virus (ZIKV) transmission has been reported in 87 countries and territories around the globe. With ZIKV now endemic in the Americas, greater emphasis needs to be placed on elucidating and understanding the underlying mechanisms that contribute to fetal outcome. Our results, in concert with those from other studies, suggest that subtle differences in ZIKV strains may have important phenotypic impacts. Rates of fetal demise broadly correlated with maternal viremia but were independent of fetus and placenta virus titer, indicating that additional underlying factors contribute to fetus outcome. Here, we show significant differences in the rate of fetal demise following maternal inoculation with ZIKV strains from Puerto Rico, Panama, Mexico, Brazil, and Cambodia. Therefore, we sought to characterize and compare the pathogenic potential of multiple Asian/American-lineage ZIKV strains in an established Ifnar1 -/- pregnant mouse model. The underlying mechanisms responsible for this heterogeneity in outcomes have not been well defined. During the 2015-2016 American outbreak of ZIKV, CZS rates varied by geographic location. However, not all pregnancies exposed to ZIKV result in an infant with apparent defects. Zika virus (ZIKV) is a flavivirus that causes a constellation of adverse fetal outcomes collectively termed Congenital Zika Syndrome (CZS). These results illustrate the potential impact of individual mutations in viral phenotype. Three other mutants that had mutations in a genome region associated with replication resulted in changes in in vitro and in vivo replication rates.

Three of the mutants caused catastrophic embryo effects including increased embryonic death or significant decrease in head diameter. We assayed each mutant for changes in growth rate, and for virulence in adult mice and pregnant mice. The six mutants we generated represent mutations that differentiated the early epidemic genotype from genotypes that were either ancestral or that occurred later in the epidemic. Using this clone, six mutants were created by changing nucleotides in the genome to cause one to two amino acid substitutions in the encoded proteins. To determine if naturally occurring individual mutations in the Zika virus epidemic genotype affect viral virulence or replication rate in vitro or in vivo, we generated an infectious clone representing the epidemic genotype of stain Puerto Rico, 2015. This analytical pathway, integrating both bioinformatic and wet lab experiments, provides a foundation for understanding how naturally occurring single mutations affect disease outcome and can be used to predict the of severity of future ZIKV outbreaks. Additionally, mutants with changes in the region of NS3 that interfaces with NS5 during replication displayed reduced replication in the blood of adult mice. In particular, a NS2B mutant previously detected during in vivo studies in rhesus macaques was found to cause lethal infections in adult mice, abortions in pregnant females, and increased viral genome copies in both brain tissue and blood of female mice. Mutants had distinct phenotypes, including changes in replication rate, embryo death, and decreased head size. The phenotypes of these naturally occurring variants were examined using both cell culture and murine model systems. Using this criteria, six mutants (representing naturally occurring mutations) were generated as synthetic infectious clones using a 2015 Puerto Rican epidemic strain PRVABC59 as the parental backbone. Information on transmission dynamics, prevalence, and persistence of intra-host mutants, and the position of a mutation on a protein were then used to prioritize 544 reported mutations based on their ability to impact ZIKV phenotype. This resource was mined to identify emerging mutations and trends in mutations as the outbreak progressed over time. The 2014–2016 Zika virus (ZIKV) epidemic in the Americas resulted in large deposits of next-generation sequencing data from clinical samples.

Side effect of zika virus