Genetic and antigenic structural characterization for resistance of echovirus 11 to pleconaril in an immunocompromised patient.
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.
Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
K S M
KSM
Benschop
Department of Pediatric Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.|Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
J G
JG
Wildenbeest
Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
G
G
Koen
Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
R P
RP
Minnaar
Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
F J
FJ
van Hemert
Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
B M
BM
Westerhuis
Department of Pediatric Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
D
D
Pajkrt
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
P J
PJ
van den Broek
Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.
A C T M
ACTM
Vossen
Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands.
K C
KC
Wolthers
D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004457:Echovirus Infections / Q000821:virology; D029822:Enterovirus B, Human / Q000235:genetics* / Q000276:immunology*; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010069:Oxadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010080:Oxazoles
D000956:Antigens, Viral; D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D010069:Oxadiazoles; D010080:Oxazoles; C115201:pleconaril