Genetic and antigenic structural characterization for resistance of echovirus 11 to pleconaril in an immunocompromised patient

• DOI: 10.1099/vir.0.069773-0
• Publication Date: 2014-11-13T23:14:39Z
• Authors: K. S. M. Benschop; J. G. Wildenbeest; G. Koen; R. P. Minnaar; F. J. van Hemert; B. M. Westerhuis; D. Pajkrt; P. J. van den Broek; A. C. T. M. Vossen; K. C. Wolthers
• Keywords: Gene Expression Regulation, Viral; Oxadiazoles; 0303 health sciences; Molecular Sequence Data; Immunoglobulins, Intravenous; Echovirus Infections; Antiviral Agents; Enterovirus B, Human; 3. Good health; 03 medical and health sciences; Drug Resistance, Viral; Mutagenesis, Site-Directed; Humans; Antigens, Viral; Oxazoles

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