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首页> 外文学位 >The effects of nonnucleoside reverse transcriptase inhibitor resistance mutations on human immunodeficiency virus type 1 replication and reverse transcriptase function.
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The effects of nonnucleoside reverse transcriptase inhibitor resistance mutations on human immunodeficiency virus type 1 replication and reverse transcriptase function.

机译：非核苷类逆转录酶抑制剂耐药性突变对人免疫缺陷病毒1型复制和逆转录酶功能的影响。

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摘要

The development of drug resistant Human Immunodeficiency Virus type 1 (HIV-1) variants limits the clinical efficacy of antiretroviral therapies. This work summarizes studies of the effects of nonnucleoside reverse transcriptase inhibitor (NNRTI) -resistance mutations on HIV-1 replication and reverse transcriptase (RT) function.; The replication capacities of HIVNL4-3 derivatives containing NNRTI-resistance mutations were initially evaluated in both a T cell-lymphoma line and in primary human PBMCs. A hierarchy of replication fitness was determined: wt ≅ V179D > K103N ≅ Y181C > V106A ≅ P236L. The least fit variants V106A and P236L are also uncommon in clinical isolates, suggesting that HIV-1 replication fitness can influence the frequency with which viral variants emerge during therapy.; The underlying biochemical mechanisms for these observed reductions in viral fitness were investigated. No significant differences between mutant and wild-type RTs were found in assays of DNA polymerization. NNRTI-resistant mutants did have specific effects on DNA 3′-end and RNA 5′-end-directed RNase H activities using non-viral RNA:DNA hybrids. K103N demonstrated a 1.6-fold reduction in the former activity only, whereas V179D had little effect on RNase H cleavage. V106A and P236L RTs were approximately 4 fold slower in substrate degradation during both modes of cleavage. Y181C catalyzed secondary RNase H cleavages more rapidly during both modes of cleavage.; Analyses of polypurine tract (PPT) primer processing were also conducted. K103N was similar to wild-type in PPT processing. However, V106A and P236L were slowed in PPT formation only. Y181C was enhanced in the primary cleavages associated with PPT formation and removal. These mutants had no effect on the initiation of DNA synthesis from the PPT.; Collectively, these studies demonstrate that NNRTI-resistance mutations have characteristic effects on RNase H cleavage by HIV-1 RT. These RNase H abnormalities affect processing of the PPT primer and likely result in a slowing of the initiation of plus-strand synthesis. Greater reductions in RNase H cleavage correlate with greater reductions in HIV-1 replication fitness and a lesser likelihood of developing during clinical failure of an NNRTI. These studies suggest that the selection for NNRTI-resistant variants will result in characteristic effects on reverse transcription that may influence viral pathogenicity.
机译：抗药性人类免疫缺陷病毒1型（HIV-1）变异体的发展限制了抗逆转录病毒疗法的临床疗效。这项工作总结了非核苷类逆转录酶抑制剂（NNRTI）耐药突变对HIV-1复制和逆转录酶（RT）功能的影响的研究。最初在T细胞淋巴瘤细胞系和原代人PBMC中评估了含有NNRTI抗性突变的HIVNL4-3衍生物的复制能力。确定复制适应性的等级：wt≅V179D> K103N≅Y181C> V106A≅P236L。最不适合的变异体V106A和P236L在临床分离株中也很少见，这表明HIV-1复制适应性会影响治疗期间病毒变异体出现的频率。研究了这些观察到的病毒适应性降低的潜在生化机制。在DNA聚合分析中未发现突变型和野生型RT之间的显着差异。使用非病毒RNA：DNA杂种，耐NNRTI的突变体确实对DNA 3 '-末端和RNA 5 '末端定向的RNase H活性具有特异性作用。 K103N仅显示前者活性降低1.6倍，而V179D对RNase H裂解几乎没有影响。在两种切割模式下，V106A和P236L RT的底物降解速度均慢约4倍。在两种切割模式下，Y181C催化的二次RNase H切割均更快。还进行了多嘌呤束（PPT）引物处理的分析。 K103N与PPT处理中的野生型相似。但是，V106A和P236L仅在PPT形成中减慢了速度。 Y181C在与PPT形成和去除相关的初级切割中得到增强。这些突变体对从PPT开始DNA合成的启动没有影响。总体而言，这些研究表明，NNRTI抗性突变对HIV-1 RT对RNase H的切割具有特征性影响。这些RNase H异常影响PPT引物的加工，并可能导致正链合成的启动减慢。 RNase H裂解的更大减少与HIV-1复制适应性的更大减少以及在NNRTI临床失败期间发展的可能性较小有关。这些研究表明，对NNRTI抗性变体的选择将对逆转录产生特征性影响，从而可能影响病毒的致病性。

著录项

  • 作者

    Gerondelis, Peter.;

  • 作者单位

    The University of Rochester.;

  • 授予单位 The University of Rochester.;
  • 学科 Biology Microbiology.; Health Sciences Pathology.; Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 229 p.
  • 总页数 229
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 微生物学;病理学;
  • 关键词

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