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

J Gen Virol. 2001 Nov;82(Pt 11):2767-2776. doi: 10.1099/0022-1317-82-11-2767.

Abstract

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 IC(50) of this mutant was 24-, 52- and 3-fold higher than that of the wild-type (wt) IC(50) in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type: an A-->G substitution of the U69 protein kinase (PK) gene resulted in an M(318)V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A(961)V amino acid substitution within the DNA polymerase. The M(318)V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M(460)V and M(460)I 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 M(318)V 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 M(318)V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS-Related Opportunistic Infections / virology
  • Adult
  • Amino Acid Sequence
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Cell Line
  • Cytomegalovirus / drug effects
  • Cytomegalovirus Infections / complications
  • Cytomegalovirus Infections / drug therapy
  • Cytomegalovirus Infections / virology
  • Drug Resistance, Viral / genetics*
  • Exanthema Subitum / drug therapy
  • Exanthema Subitum / virology*
  • Female
  • Ganciclovir / pharmacology*
  • Ganciclovir / therapeutic use
  • Herpesvirus 6, Human / drug effects*
  • Herpesvirus 6, Human / enzymology
  • Herpesvirus 6, Human / genetics
  • Humans
  • Male
  • Microbial Sensitivity Tests / methods
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Protein Kinases / genetics*
  • Sequence Analysis, DNA

Substances

  • Antiviral Agents
  • Protein Kinases
  • Ganciclovir