Characterization of a cidofovir-resistant HHV-6 mutant obtained by in vitro selection.
Cidofovir (CDV) was used for in vitro selection of a human herpesvirus 6 (HHV-6) mutant with decreased susceptibility to this drug. The resulting mutant was highly resistant to CDV as compared to its sensitive counterpart (inhibitory concentration 50% (IC50): 213 microM versus 1.8 microM). Its replication fitness was not impaired. Genotypic characterization of the resistant virus revealed a mutation in the U38 gene encoding the viral DNA polymerase. The resulting R798I amino acid change was located in the conserved domain VII close to the highly conserved motif KKRY interacting with the DNA primer-template duplex, and is likely responsible for the high-level resistance to CDV, even though a definite virological and/or biochemical confirmation is required. The possible emergence of such changes in HHV-6 DNA polymerase in patients receiving CDV therapy should be taken into account in the treatment of HHV-6 infections.
Bonnafous
Pascale
P
Université Pierre et Marie Curie-Paris 6, EA2387, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'Hôpital, F-75013 Paris, France. pascale.bonnafous@psl.aphp.fr
Boutolleau
David
D
Naesens
Lieve
L
Deback
Claire
C
Gautheret-Dejean
Agnès
A
Agut
Henri
H
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D024882:Drug Resistance, Viral; D015654:Herpesvirus 6, Human / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D063065:Organophosphonates / Q000494:pharmacology*; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication
D000998:Antiviral Agents; D063065:Organophosphonates; D014764:Viral Proteins; D003596:Cytosine; D004259:DNA-Directed DNA Polymerase; D000077404:Cidofovir