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Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo

Laboratoire de Virologie, UPRES EA 2387, CERVI¹, Laboratoire de Génétique Moléculaire, Service de Biochimie Médicale² and Service des Maladies Infectieuses et Tropicales³, Groupe Hospitalier Pitié-Salpêtrière, 83 Bld de l’Hôpital, 75651 Paris Cedex 13, France

Author for correspondence: Henri Agut. Fax +33 1 42 17 74 11. e-mail henri.agut{at}psl.ap-hop-paris.fr

After serial passage in the presence of increasing concentrations of ganciclovir (GCV) in vitro, a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC₅₀ of this mutant was 24-, 52- and 3-fold higher than that of the wild-type (wt) IC₅₀ in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type: an AG substitution of the U69 protein kinase (PK) gene resulted in an M³¹⁸V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A⁹⁶¹V amino acid substitution within the DNA polymerase. The M³¹⁸V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M⁴⁶⁰V and M⁴⁶⁰I changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The M³¹⁸V change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCV-resistant HCMV infection. These findings provide strong circumstantial evidence that the M³¹⁸V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.

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