An arthropod-borne virus, Zika virus (ZIKV), has recently emerged as a major human pathogen. Associated with
complications during perinatal development and Guillain-Barré syndrome in adults, ZIKV raises new challenges for understanding
the molecular determinants of flavivirus pathogenesis. This underscores the necessity for the development of a reverse
genetic system based on an epidemic ZIKV strain. Here, we describe the generation and characterization in cell cultures of an
infectious cDNA clone of ZIKV isolated from the 2015 epidemic in Brazil. The cDNA-derived ZIKV replicated efficiently in a
variety of cell lines, including those of both neuronal and placental origin. We observed that the growth of cDNA-derived virus
was attenuated compared to the growth of the parental isolate in most cell lines, which correlates with substantial differences in
sequence heterogeneity between these viruses that were determined by deep-sequencing analysis. Our findings support the role
of genetic diversity in maintaining the replicative fitness of viral populations under changing conditions. Moreover, these results
indicate that caution should be exercised when interpreting the results of reverse-genetics experiments in attempts to accurately
predict the biology of natural viruses. Finally, a Vero cell-adapted cDNA clone of ZIKV was generated that can be used as a convenient
platform for studies aimed at the development of ZIKV vaccines and therapeutics