Pleconaril is a capsid inhibitor used previously to treat
enterovirus infections. A
pleconaril-resistant echovirus 11 (E11) strain was identified before
pleconaril treatment was given in an immunocompromised patient. The patient was also treated with
intravenous Ig (
IVIg) for a long period but remained unresponsive. The
pleconaril-resistant strains could not be neutralized in vitro, confirming
IVIg treatment failure. To identify the basis of
pleconaril resistance, genetic and structural analyses were conducted. Analysis of a modelled viral capsid indicated conformational changes in the hydrophobic pocket that could prevent
pleconaril docking. Substitutions (V117I, V119M and I188L) in the
pleconaril-resistant viruses were found in the pocket region of VP1. Modelling suggested that V119M could confer resistance, most probably due to the protruding
sulfate side chain of
methionine. Although
pleconaril resistance induced in vitro in a susceptible E11 clinical isolate was characterized by a different substitution (I183M), resistance was suggested to also result from a similar mechanism, i.e. due to a protruding
sulfate side chain of
methionine. Our results showed that resistant strains that arise in vivo display different markers from those identified in vitro and suggest that multiple factors may play a role in
pleconaril resistance in patient strains. Based on
IVIg treatment failure, we predict that one of these factors could be immune related. Thus, both
IVIg and capsid inhibitors target the viral capsid and can induce mutations that can be cross-reactive, enabling escape from both
IVIg and the
drug. This could limit treatment options and should be investigated further.