Codex_V5

Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus.

Abstract: Certain mutations in the viral DNA polymerase (pol) gene are known to confer drug resistance when transferred to susceptible human cytomegalovirus (CMV) strains, whereas other putative resistance mutations remain unproven. A new marker-transfer technique was used to produce recombinant CMV strains, to determine the drug susceptibility phenotypes conferred by 10 pol mutations (9 observed in clinical isolates). Various degrees of resistance to ganciclovir and cidofovir were conferred by mutations D301N, N410K, D413E, T503I, and L516R, which are located within exonuclease functional domains where D301N and D413E affect highly conserved residues. Mutations A692S, E756K, and E756D, which are not located within recognized functional domains, each conferred foscarnet resistance. This study significantly increases the number of confirmed CMV pol resistance mutations, at both conserved and nonconserved loci, with implications for molecular mechanisms and the genotypic diagnosis of antiviral resistance.

Mutant	Gene	Virus	Antiviral	EC50 ratio	Phenotype
D301N	UL54	Human betaherpesvirus 5	Ganciclovir	2.60	Low level resistance
D301N	UL54	Human betaherpesvirus 5	Cidofovir	3.00	Intermediate level resistance
D301N	UL54	Human betaherpesvirus 5	Foscarnet	0.50	No resistance
N410K	UL54	Human betaherpesvirus 5	Ganciclovir	2.90	Low level resistance
N410K	UL54	Human betaherpesvirus 5	Cidofovir	3.00	Intermediate level resistance
N410K	UL54	Human betaherpesvirus 5	Foscarnet	0.80	No resistance
D413E	UL54	Human betaherpesvirus 5	Ganciclovir	4.80	Intermediate level resistance
D413E	UL54	Human betaherpesvirus 5	Cidofovir	4.30	Intermediate level resistance
D413E	UL54	Human betaherpesvirus 5	Foscarnet	0.80	No resistance
T503I	UL54	Human betaherpesvirus 5	Ganciclovir	2.90	Low level resistance
T503I	UL54	Human betaherpesvirus 5	Cidofovir	6.10	High level resistance
T503I	UL54	Human betaherpesvirus 5	Foscarnet	0.50	No resistance
L516R	UL54	Human betaherpesvirus 5	Ganciclovir	2.10	Low level resistance
L516R	UL54	Human betaherpesvirus 5	Cidofovir	5.10	High level resistance
L516R	UL54	Human betaherpesvirus 5	Foscarnet	0.80	No resistance
E756D	UL54	Human betaherpesvirus 5	Ganciclovir	1.20	No resistance
E756D	UL54	Human betaherpesvirus 5	Cidofovir	0.70	No resistance
E756D	UL54	Human betaherpesvirus 5	Foscarnet	3.40	Intermediate level resistance
E756K	UL54	Human betaherpesvirus 5	Ganciclovir	2.50	Low level resistance
E756K	UL54	Human betaherpesvirus 5	Cidofovir	2.20	Low level resistance
E756K	UL54	Human betaherpesvirus 5	Foscarnet	>8.00	At least High level resistance