Sensitivity of arabinosyladenine-resistant mutants of herpes simplex virus to other antiviral drugs and mapping of drug hypersensitivity mutations to the DNA polymerase locus

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Abstract
Seven herpes simplex virus mutants which have been previously shown to be resistant to arabinosyladenine were examined for their sensitivities to 4 types of antiviral drugs. These drugs were a pyrophosphate analog, 4 nucleoside analogs altered in their sugar moieties, 2 nucleoside analogs altered in their base moieties and 1 altered in both. The 7 mutants exhibited 5 distinct phenotypes based on their sensitivities to the drugs relative to wild-type strain KOS. All mutants exhibited resistance to acyclovir and arabinosylthymine, as well as marginal resistance to iododeoxyuridine; all but one exhibited resistance to phosphonoformic acid. The mutants exhibited either sensitivity or hypersensitivity to the other drugs tested, 2''-nordeoxyguanosine, 5-methyl-2''-fluoroarauracil, 5-iodo-2''-fluoroauracil and bromovinyldeoxyuridine, some of which differed only slightly from drugs to which the mutants were resistant. These results suggest ways to detect and treat arabinosyladenine-resistant isolates in the clinic. Antiviral hypersensitivity was a common phenotype. Mutations conferring hypersensitivity to 2''-nor-deoxyguanosine in mutant PAAr5 and to bromovinyldeoxyuridine in mutant tsD9 were mapped to nonoverlapping regions of 1.1 and 0.8 kilobase pairs, respectively, within the herpes simplex virus DNA polymerase locus. Thus, viral DNA polymerase mediates sensitivity to these 2 drugs. It was not possible to confirm reports of mutations in the DNA polymerase locus conferring resistance to these 2 drugs. All of the mutants exhibited altered sensitivity to 2 or more types of drugs, suggesting that single mutations affect recognition of the base, sugar and triphosphate moieties of nucleoside triphosphates by viral polymerase.

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