The replication properties of a contemporary Zika virus from West Africa depends on NS1/NS4B proteins

Zika virus (ZIKV) have become a global health problem over the past decade due to the extension of the geographic distribution of ZIKV of Asian genotype. Epidemics of Asian ZIKV have been associated with developmental disorders in humans. ZIKV of African lineage would have an epidemic potential associated to fetal pathogenicity requiring a greater attention towards the most recently isolated viral strains from West Africa. In the present study, an infectious molecular clone GUINEA-18 has been obtained from viral strain ZIKV-15555 that had been sequenced from an individual infected by ZIKV in Guinea in 2018. A molecular clone-based comparative study between GUINEA-18 and viral clone MR766MC from historical African ZIKV strain MR766 revealed a lower replication rate for GUINEA-18 associated to a weaker cytotoxicity and reduced innate immune system activation in Vero E6, A549 and HCM3 cell lines. Analysis of chimeric viruses between MR766MC and GUINEA-18 stressed the importance NS1/NS4B proteins with a particular focus for NS4B on GUINEA-18 replication properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. Study of G3BP protein showed that GUINEA-18 but not MR766MC was efficient to inhibit stress granule assembly in A549 cells subjected to a physiological stressor. GUINEA-18 depends on NS1/NS4B proteins for suppressing stress granule response to environmental stress. The involvement of GUINEA-18 NS1/NS4B proteins on virus replication capability and host-cell responses to ZIKV infection raises the question of the importance of nonstructural proteins in the pathogenicity of contemporary viral strains from West Africa. AUTHOR SUMMARYMost of studies having for objectives to understand the biology of Zika virus (ZIKV) were carried out using epidemic viral strains of Asian lineage. It is now admitted that ZIKV of African genotype would have also a great epidemic potential associated a high risk of fetal pathogenicity. Today, it is urgent to improve our knowledge on recently isolated ZIKV strains in West Africa. In our study, we used the sequence of viral strain from an individual infected by ZIKV in Guinea in 2018 to generate an infectious molecular clone. Analysis of viral clone highlighted the preponderant role of NS1/NS4B proteins in virus replication strategy and cell interactions with a particular focus on ZIKV-specific stress granule formation blockade. We believe that our data will improve our knowledge on the biology of contemporary West Africa ZIKV opening perspectives towards a better understanding on the pathogenicity of African viral strains.