Variation in virion phosphatidylserine content drives differential GAS6 binding among closely related flaviviruses

Many enveloped viruses engage phosphatidylserine (PS) receptors to enter cells, a phenomenon known as 'apoptotic mimicry'. We previously reported that Zika virus (ZIKV), but not closely-related West Nile virus (WNV) or dengue virus (DENV), utilized AXL to infect cells because only ZIKV could bind the AXL ligand GAS6, a PS-binding protein. In this study, we investigated the mechanisms underlying the differential ability of these viruses to bind GAS6. Although immature virions expose larger patches of the viral membrane than do mature ones, our data show that virion maturity levels did not contribute to GAS6 binding. Surprisingly, while ZIKV contains PS comparable to cellular membranes, PS on WNV and DENV is markedly reduced. These findings explain why only ZIKV can bind GAS6 and provide insights into a novel mechanism by which closely-related flaviviruses differentially utilize cellular entry factors.