Interplay between flaviviruses and lipids

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Flaviviruses represent serious global health challenges. Research on these viruses, including Zika virus (ZIKV) and Dengue virus (DENV), is crucial to help prevent the spread of their respective epidemics and will ideally result in the availability of therapies. Antiviral development would be aided by a deeper understanding of the mechanisms of viral replication. One stage of the flavivirus life cycle that is particularly poorly understood is the process of host cell entry. For many flaviviruses, including ZIKV and DENV, entry appears to require the presence of phosphatidylserine (PS) receptors on host cells. This finding has led to the model in which these receptors bind to the phospholipids in the membrane envelope of these viruses much in the same way that a cell membrane protein interacts with a viral glycoprotein. This process is termed `apoptotic mimicry', as it resembles the mechanism by which phagocytes use PS receptors to recognize apoptotic cells that display PS on their surface. If this model of host cell entry is correct, it would be critical for the viral particle to incorporate a sufficient concentration of lipids that interact with PS receptor, including PS and/or phosphatidylethanolamine (PE). To date, the lipidome of ZIKV and DENV has not been defined. Furthermore, if PS and/or is required in the lipid envelope of these particles, the mechanism of its acquisition remains to be determined. Since flaviviruses acquire their envelope by budding into the ER, it is conceivable that this occurs by random sampling of ER membranes, which are known to include PS. However, the hepatitis C virus, which also buds into the ER, does not incorporate PS into its particles. Thus, ZIKV either stimulates the production and/or ER concentration of PS, or it actively selects PS during virion envelopment. To address this question, we propose experiments to compare the lipid composition of ZIKV and DENV particles to those of naïve and infected whole cells and ER membranes. The results of this project will provide in-depth insights into flavivirus host cell interactions and replication mechanisms that may aid in the development of therapeutic efforts for ZIKV and could perhaps be further applied in combating other future virus outbreaks.