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Structural studies of human picornaviruses

Final Report Summary - PICOSTRUCTURE (Structural studies of human picornaviruses)

The project “PicoStructure” was focused on determining molecular mechanisms necessary for replication of small non-enveloped viruses from the order Picornavirales. These viruses cause diseases in humans and animals. Currently there are no anti-viral drugs approved against picornavirus infections and the available treatments are only symptomatic. Our results provide structural information for development of anti-viral drugs and vaccines.
Among the most important results of the project are:

(1) Structural characterization of ubiquitous Aichi virus
Aichi virus 1 (AiV-1) causes diarrhea, abdominal pain, nausea, vomiting, and fever. AiV-1 is identified in environmental screening studies with higher frequency and greater abundance than other human enteric viruses. Accordingly, 80-95% of adults worldwide have suffered from AiV-1 infections. Based on the AiV-1 virion structure, we show that antiviral compounds that were developed against related enteroviruses are unlikely to be effective against AiV-1. We also determined that AiV-1 genome release requires large and reversible reorganization of the capsid.

(2) Structure of deformed wing virus, a major honeybee pathogen.
Deformed wing virus (DWV) from the family Iflaviridae, together with its vector, the mite Varroa destructor, is the major threat to the world's honeybees. However, lack of knowledge of the atomic structures of iflaviruses has hindered the development of effective treatments against them. We determined the virion structures of DWV to a resolution of 3.1 Å using cryo-electron microscopy and 3.8 Å by X-ray crystallography. The C-terminal extension of capsid protein VP3 folds into a globular protruding (P) domain, exposed on the virion surface. The P domain contains an Asp-His-Ser catalytic triad that is, together with five residues that are spatially close, conserved among iflaviruses. These residues may participate in receptor binding or provide the protease, lipase, or esterase activity required for entry of the virus into a host cell. Identifying the putative catalytic site within the DWV virion structure enables future analyses of how DWV and other iflaviruses infect insect cells and also opens up possibilities for the development of antiviral treatments.

(3) Determination of genome release mechanism of enteroviruses
Viruses from the genus Enterovirus are important human pathogens. Receptor binding or exposure to acidic pH in endosomes converts enterovirus particles to an activated state that is required for genome release. However, the mechanism of enterovirus uncoating is not well understood. We used cryo-electron microscopy to visualize virions of human echovirus 18 in the process of genome release. We discovered that the exit of the RNA from the particle of echovirus 18 results in a loss of one, two, or three adjacent capsid-protein pentamers. The opening in the capsid, which is more than 120 Å in diameter, enables the release of the genome without the need to unwind its putative double-stranded RNA segments. We also detect capsids lacking pentamers during genome release from echovirus 30. Thus, our findings uncover a mechanism of enterovirus genome release that could become target for antiviral drugs.