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Basic Characteristics of Mutations
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Mutation Site
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F412L |
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Mutation Site Sentence
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Notably, all mutants (D301N, N408K, F412C/L and K513R) showing a greater than 10-fold increased CDV EC50 also had an ACV EC50 that was <20% of wild type (significant at p<10−37), ranging from 6.0 μM for N408K to 10.8 μM for F412L. |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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UL54 |
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Standardized Encoding Gene
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UL54
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Genotype/Subtype
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- |
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Viral Reference
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-
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Functional Impact and Mechanisms
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Disease
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Cell line
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Immune
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- |
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Target Gene
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-
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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CDV;ACV |
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Location
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- |
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Literature Information
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PMID
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34560144
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Title
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Opposite effects of cytomegalovirus UL54 exonuclease domain mutations on acyclovir and cidofovir susceptibility
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Author
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Chou S
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Journal
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Antiviral research
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Journal Info
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2021 Nov;195:105181
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Abstract
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Acyclovir has weak activity against human cytomegalovirus (CMV). Despite some efficacy as prophylaxis, more potent anti-CMV drugs are preferred. Acyclovir resistance of CMV has been little studied. The viral UL97 kinase phosphorylates acyclovir, and cross-resistance of ganciclovir-resistant mutants is documented. However, UL54 exonuclease domain mutants may confer ganciclovir and cidofovir resistance by a mechanism that does not apply to acyclovir as an obligate chain terminator. To test for differential susceptibilities, 11 exonuclease domain mutants were tested for their 50% inhibitory concentrations (EC50s) of acyclovir in comparison with cidofovir. The 5 mutants with the highest cidofovir EC50s (>10-fold increased over wild type) all had acyclovir EC50s less than 20% of wild type. The relatively common N408K mutant had an acyclovir EC50 of 6 muM, comparable to that reported for wild type varicella-zoster virus. Several foscarnet-resistant UL54 mutants outside the exonuclease domains, some with low-grade ganciclovir/cidofovir cross-resistance, showed various degrees of acyclovir resistance. Based on these in vitro data, acyclovir may become a therapeutic option when a highly cidofovir-resistant exonuclease mutation is present without a simultaneous mutation in UL97.
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Sequence Data
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-
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