Revealing the hidden roles of ssRNA genomes regulating viral infectivity

We discovered a molecular mechanism that regulates virus assembly in different families of positive-sense, single-stranded RNA viruses and the para-retrovirus Hepatitis B Virus. These viruses encompass multiple dispersed sequences/secondary motifs termed Packaging Signals (PSs) in their genomes (gRNAs) that have distinct affinities for their cognate coat protein (CP). This hierarchy of CP affinities defines a preferred assembly pathway, simplifying assembly in complex molecular environments and ensuring genetic robustness to mutation. In this research programme we will investigate a further major gRNA-encoded principle of viral infectivity. Virions are transport vehicles between host cells, that cannot afford to become too stable, or they would lose the ability to deliver their cargoes. It appears that PS-gRNA contacts rearrange in the fully assembled virion, preparing it for gRNA release in response to defined cues from the host cell. We will explore the role(s) of this “molecular frustration” in clinically-important viral lifecycles using a unique interdisciplinary combination of tools we have created. As PSs motifs are evolutionarily conserved across viral families, their interactions with CP lend themselves as targets for broad-spectrum anti-viral therapy, including an emerging Virus X. Insights into cargo encapsidation and release can also be exploited in vaccination and gene therapy.