Single mutations at many sites within the DNA polymerase locus of herpes simplex viruses can confer hypersensitivity to aphidicolin and resistance to phosphonoacetic acid.
Single mutations at many sites within the DNA polymerase locus of herpes simplex viruses can confer hypersensitivity to aphidicolin and resistance to phosphonoacetic acid.
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单纯疱疹病毒 DNA 聚合酶位点内许多位点的单一突变可导致对阿非迪霉素过敏和对膦酰乙酸产生抗性。
DOI：
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发表时间：
1984
影响因子：
3.8
通讯作者：
P. O’Hare
中科院分区：
文献类型：
--
作者：
R. Honess;D. Purifoy;D. Young;R. Gopal;N. Cammack;P. O’Hare
Aphidicolin是一种四环二萜类化合物，可抑制许多真核细胞的DNA聚合酶-α活性，可抑制感染培养物中单纯疱疹病毒的生长和DNA合成以及体外病毒DNA聚合酶的活性。一个广泛的稳定的阿非迪霉素敏感性之间的病毒株的集合，没有预先暴露于这种药物，但选择耐膦酰乙酸（PAA）或无环鸟苷的聚合酶突变的病毒通常表现出增加的敏感性阿非迪霉素。在16个无关的PAA耐药变异体中，7个对阿非迪霉素过敏。在聚合酶基因中具有温度敏感性（ts）病变的许多突变体也显示出蚜虫霉素敏感性（例如HSV-1[mP 17]tsH）或蚜虫霉素超敏性（例如HSV-1[科斯] tsD 9、tsC 4）增加。体内病毒生长和DNA合成的抗性或超敏性与体外病毒DNA聚合酶反应的抗性或超敏性相关。抗性表型与聚合酶基因在与外部标记重组过程中紧密连锁。此外，从具有独立PAA抗性或聚合酶基因中的ts突变的超敏变体中选择阿非迪霉素抗性突变体可导致PAA敏感和ts+表型的共选择。通过研究独立的过敏变体之间的重组，证实了多个独立的突变可以决定aphidicolin超敏反应。形成了抗蚜虫菌素的重组后代，其重组频率（0.4至2.6%）与基因内事件相容。与亲本过敏的变体，这是有限的PAA选择的产品，或与ts聚合酶突变，aphidicolin抗性重组是PAA敏感和/或ts+。重组后代之间的其他标志物（TS，斑块形态）的分离允许PAA抗性和aphidicolin超敏反应的多个决定因素相对于聚合酶基因和其他基因中的其他标志物的取向。在聚合酶基因座内的一系列单独位点中的任何一个处确定的残基的性质可以确定对抗病毒药物的抗性或敏感性，并且与聚合酶基因座处的变化相关的阿非迪霉素超敏性促进该基因座的高分辨率遗传分析。
Aphidicolin, a tetracyclic diterpenoid which inhibits the DNA polymerase-alpha activities of many eukaryotic cells, inhibited herpes simplex virus growth and DNA synthesis in infected cultures and the activity of the virus DNA polymerase in vitro. A wide range of stable aphidicolin sensitivities was represented amongst a collection of virus strains with no prior exposure to this drug, but viruses with polymerase mutations selected for resistance to phosphonoacetic acid (PAA) or to acycloguanosine typically showed increased sensitivity to aphidicolin. Of 16 unrelated PAA-resistant variants, 7 were hypersensitive to aphidicolin. A number of mutants with temperature-sensitive (ts) lesions in the polymerase gene also showed increased aphidicolin sensitivity (e.g. HSV-1[mP17]tsH) or aphidicolin hypersensitivity (e.g. HSV-1[KOS]tsD9, tsC4). Resistance or hypersensitivity of virus growth and DNA synthesis in vivo were correlated with resistance or hypersensitivity of virus DNA polymerase reactions in vitro. Resistance phenotypes were closely linked to the polymerase gene during recombination with outside markers. Moreover, the selection of aphidicolin-resistant mutants from hypersensitive variants with independent PAA resistance or ts mutations in the polymerase gene could result in co-selection for PAA-sensitive and ts+ phenotypes. Confirmation that multiple independent mutations could determine aphidicolin hypersensitivity was obtained by studies of recombination between independent hypersensitive variants. Aphidicolin-resistant recombinant progeny were formed with recombination frequencies (0.4 to 2.6%) compatible with intragenic events. With parental hypersensitive variants which were products of limited PAA selection, or with the ts polymerase mutations, aphidicolin-resistant recombinants were PAA-sensitive and/or ts+. The segregation of other markers (ts, plaque morphology) amongst recombinant progeny permitted the orientation of multiple determinants of PAA resistance and aphidicolin hypersensitivity with respect to other markers in the polymerase gene and in other genes. The nature of residues determined at any one of a constellation of separate sites within the polymerase locus can determine resistance or sensitivity to antiviral drugs and aphidicolin hypersensitivity associated with changes at the polymerase locus facilitates high resolution genetic analysis of this locus.
单纯疱疹病毒 DNA 聚合酶基因突变导致对 aphidicolin 过敏。
影响因子：
14.9
作者：
Coen,DM;Furman,PA;Aschman,DP;Schaffer,PA
通讯作者：
Schaffer,PA
1型单纯疱疹病毒胸苷激酶基因的核苷酸序列。
DOI：
10.1073/pnas.78.3.1441
发表时间：
1981
影响因子：
11.1
作者：
Wagner,MJ;Sharp,JA;Summers,WC
通讯作者：
Summers,WC