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

被引:52
作者
Manichanh, C
Olivier-Aubron, C
Lagarde, JP
Aubin, JT
Bossi, P
Gautheret-Dejean, A
Huraux, JM
Agut, H
机构
[1] CERVI, Virol Lab, UPRES, EA 2387, F-75651 Paris 13, France
[2] Grp Hosp Pitie Salpetriere, Mol Genet Lab, Serv Biochim Med, F-75651 Paris, France
[3] Grp Hosp Pitie Salpetriere, Serv Malad Infect & Trop, F-75651 Paris 13, France
关键词
D O I
10.1099/0022-1317-82-11-2767
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 --> G substitution of the U69 protein kinase (PK) gene resulted in an (MV)-V-318 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 (MV)-V-313 change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the (MV)-V-460 and (MI)-I-460 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 (MV)-V-318 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 (MV)-V-318 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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页码:2767 / 2776
页数:10
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