Theoretical modeling of viral genome encapsidation coupled to liquid-liquid phase separation

To assemble an infectious virion, viral capsid subunits and genomes must colocalize in space and time. This task is particularly challenging because the viral RNA must be selected out of a vast excess of cellular RNA. Recently it has been shown that many viruses construct biomolecular condensates within their host cells, suggesting that viruses can exploit liquid-liquid phase separation (LLPS) to spatially control their assembly. Yet whether and how LLPS affects viral genome packaging remains unclear. We use theoretical modeling to investigate how selective partitioning of capsids subunits and RNA into condensates effects selective genome encapsidation. We find that by locally concentrating viral RNA and capsid subunits while excluding host RNA, condensates can greatly enhance the selective encapsidation of viral RNA. We also identify kinetic traps that prevent encapsidation on biologically relevant time scales, and we discuss potential strategies to overcome them. In addition to regulating virus assembly, our work suggests that LLPS may provide a generic, robust mechanism for the selective encapsulation of microscopic cargo.