Differential virulence between Asian and African lineages of Zika virus

Zika virus (ZIKV) is a small enveloped positive-sense single-stranded RNA virus belonging to the genus Flavivirus of the Flaviviridae family that has reemerged in recent years as a human pathogen with epidemic potential.To date, the ongoing epidemic in the Americas has led to tens of thousands of confirmed cases in Brazil alone (Pan American Health Organization Zika-Epidemiological Report, 2 March 2017).More concerning are the reports of severe neurological disorders such as Guillain-Barre ´syndrome and congenital Zika syndrome (microcephaly and other neurodevelopmental defects), which led the World Health Organization to declare the ZIKV epidemic as a Public Health Emergency of International Concern in 2016.Phylogenetic analyses show that ZIKV can be classified into 2 main lineages: the African lineage and the Asian lineage, the latter of which is responsible for the recent epidemics.Because recent ZIKV infections were associated with the development of congenital and neurological disorders, a key question was raised as to whether Asian-lineage ZIKV strains were phenotypically different from the African lineage strains.It is well described that mutations acquired during Flavivirus evolution can alter their virulence and/or tropism [1].ZIKV is primarily transmitted by the mosquito species Aedes aegypti and Aedes albopictus.Several studies show that vector transmission can differ between ZIKV strains, as the overall ZIKV infection prevalence and transmission rates of African strains may be higher in A. aegypti than Asian strains [2], suggesting that viral adaptation may have occurred-similar to a single mutation in the chikungunya virus envelope protein that affected vector specificity and epidemic potential.During the recent outbreak, it became clear that ZIKV is sometimes able to cause a prolonged infection.Numerous studies showed that Asian-lineage strains isolated in South America replicate at low levels in tissues months after the initial infection.For example, viral genome can be found in stillborn babies who were infected early during gestation [3], weeks after initial infection in sperm, and in rhesus monkeys, ZIKV can be found in the cerebral spinal fluid (CSF) 42 days after infection, weeks after the virus was cleared from the blood [4].However, to date, no data are available on the ability of African-lineage strains to cause prolonged infections, but early studies in 2016 suggested that an African ZIKV strain was highly pathogenic and led to cell death; when the first reports on a potential link between microcephaly and ZIKV emerged, laboratories started to study the effect of ZIKV on human neural precursor cells (hNPCs)/human neural stem cells (hNSCs) with MR766, the most available strain at the time (Fig 1 and Table 1).These first studies showed strong tropism and deleterious effects on NSC homeostasis and growth (e.g., [5]).However, some inconsistencies between this rather strong virulence and the long-term developmental effects associated with ZIKV infections led researchers to question the biological validity of this strain, which has been