Abstract 2276 Inter-organelle contacts induced by viral infection redirect the flow of lipids to facilitate genome replication.

Positive-stranded RNA viruses extensively remodel host cell architecture to enable viral replication. We examined the poorly understood formation of specialized membrane compartments which are critical sites for the synthesis of the viral genome. We show that the replication compartments (RCs) of enteroviruses are created through novel membrane contact sites that recruit host lipid droplets (LDs) to the RCs. Highly conserved viral proteins physically tether the RCs to the LDs and interact with the host lipolysis machinery to mediate the transfer of fatty acids from LDs, thereby providing lipids essential for RC biogenesis. Inhibiting the formation of the membrane contact sites between LDs and RCs or inhibition of the lipolysis pathway disrupts RC biogenesis and enterovirus replication. Our data illuminate mechanistic and functional aspects of organelle remodeling in viral infection and establish that pharmacological targeting of contact sites linking viral and host compartments is a potential strategy for antiviral development. This work was supported by NIH (R01 AI40085, P01 AI091575) and DoD-DARPA INTERCEPT to R.A. and by ARRA Award Number 1S10RR026780-01 from the National Center for Research Resources (NCRR) to CSIF.