Liquid-liquid phase separation of nucleocapsid proteins during SARS-CoV-2 and HIV-1 replication

The leap of retroviruses and coronaviruses from animal hosts to humans has led to two ongoing pandemics and tens of millions of deaths worldwide. Retrovirus and coronavirus nucleocapsid proteins have been studied extensively as potential drug targets due to their central roles in virus replication, among which is their capacity to bind their respective genomic RNAs for packaging into nascent virions. This review focuses on fundamental studies of these nucleocapsid proteins and how their intrinsic abilities to condense through liquid-liquid phase separation (LLPS) contribute to viral replication. Therapeutic targeting of these condensates and methodological advances are also described to address future questions on how phase separation contributes to viral replication. Pandemic viruses SARS-CoV-2 and HIV-1 encode nucleocapsid proteins that possess intrinsic disorder that program liquid-liquid phase separation and condensation during viral replication. Chau et al. review recent literature showing that this is critical for virus replication, including gene expression, assembly, and genome packaging, and evading host anti-viral innate responses to infection.