PLOS Pathogens: Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

Enteroviruses (family of the Picornaviridae) cover a large
group of medically important human pathogens for which no antiviral
treatment is approved. Although these viruses have been extensively
studied, some aspects of the viral life cycle, in particular
morphogenesis, are yet poorly understood. We report the discovery of
TP219 as a novel inhibitor of the replication of several enteroviruses,
including coxsackievirus and poliovirus. We show that TP219 binds
directly glutathione (GSH), thereby rapidly depleting intracellular GSH
levels and that this interferes with virus morphogenesis without
affecting viral RNA replication. The inhibitory effect on assembly was
shown not to depend on an altered reducing environment. Using TP219, we
show that GSH is an essential stabilizing cofactor during the transition
of protomeric particles into pentameric particles. Sequential passaging
of coxsackievirus B3 in the presence of low GSH-levels selected for
GSH-independent mutants that harbored a surface-exposed methionine in
VP1 at the interface between two protomers. In line with this
observation, enteroviruses that already contained this surface-exposed
methionine, such as EV71, did not rely on GSH for virus morphogenesis.
Biochemical and microscopical analysis provided strong evidence for a
direct interaction between GSH and wildtype VP1 and a role for this
interaction in localizing assembly intermediates to replication sites.
Consistently, the interaction between GSH and mutant VP1 was abolished
resulting in a relocalization of the assembly intermediates to
replication sites independent from GSH. This study thus reveals GSH as a
novel stabilizing host factor essential for the production of
infectious enterovirus progeny and provides new insights into the poorly
understood process of morphogenesis.

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