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First posted online 1 August 2001 ARTICLE ABSTRACT
Rec 14 March 2001; Acc 11 July 2001 DOI: 10.1099/vir.0.17734-0

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

Chaysavanh Manichanh,1 Camille Olivier-Aubron,3 Jean-Pierre Lagarde,2 Jean-Thierry Aubin,1 Phillipe Bossi,3 Agnès Gautheret-Dejean,1 Jean-Marie Huraux1 and Henri Agut1

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

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 A to G 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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© 2001 SGM

This article is now available in the November 2001 print issue of JGV (vol. 82, 2767–2776). The complete issue of the journal may be seen in electronic form on JGV Online.