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首页> 外文学位 >Oxathiolane nucleoside analog resistance in a pathogenic molecular clone of feline immunodeficiency virus and Mapping in vivo replication and pathogenesis determinants of Aleutian mink disease parvovirus.
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Oxathiolane nucleoside analog resistance in a pathogenic molecular clone of feline immunodeficiency virus and Mapping in vivo replication and pathogenesis determinants of Aleutian mink disease parvovirus.

机译：猫免疫缺陷病毒的致病性分子克隆中的氧杂硫杂环戊烷核苷类似物抗性以及阿留申水貂病细小病毒的体内复制和致病因素的作图。

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摘要

Part I. Antiretroviral drug resistance develops during treatment of human immunodeficiency virus type 1 (HIV-I) infection, but the consequences of drug resistance on HIV-I pathogenesis and the clinical relevance of these consequences have not been thoroughly studied. These questions can be addressed in an animal model of natural lentivirus infection. The present study examined site-directed mutants of a pathogenic molecular clone of feline immunodeficiency virus (FIV), FIV-pPPR, as potential models for studying the effects of (--)-beta-L-2 ',3'-dideoxy-3 '-thiacytidine (3TC, lamivudine) resistance on lentiviral pathogenesis. A methionine-to-valine (M183V) mutation at codon 183 of FIV, located in the highly conserve d YMDD motif of the RT-encoding region of the pol gene, conferred high-level phenotypic resistance to 3TC and cross-resistance to the related compound, (--)-beta-L-2',3 '-dideoxy-5-fluoro-3'-thiacytidine [(--FTC]. 3TC resistance was similar in magnitude to HIV-I with a homologous mutation at codon 184 (M184V) that characteristically develops in 3TC-treated HIV-I-infected patients. This FIV-pPPR M183V mutant will be useful in studying the effects of 3TC resistance on lentiviral pathogenesis.; Part II. The ADV-Utah I biological isolate of Aleutian mink disease parvovirus (ADV) replicates efficiently and is highly pathogenic in mink but cannot be propagated in vitro. The ADV-G molecular clone derived from cell culture-adapted ADV-Utah I does not replicate or cause disease in adult mink but can be propagated to high titers in vitro . Recently, the first chimeric viruses of ADV-Utah I and ADV-G that could replicate both in vitro and in vivo and cause pathogenesis in mink were described. ADV-G/U-8 infection was associated with higher antibody titers and more severe histopathological lesions than ADV-G/U-10. These chimeras, however, differed by only one capsid and three nonstructural protein amino acid changes. The purpose of the current studies was to determine whether differences in in vivo replication and pathogenesis between G/U-8 and G/U-10 were attributable to capsid or nonstructural protein changes. In order to answer this question, additional chimeric viruses were constructed, propagated in vitro, and used to infect mink. Antiviral antibody responses, viremia, hypergammaglobulinemia, and histopathological lesions indicated that codon 352 of the capsid protein influenced in vivo replication and pathogenesis, but the effects of the nonstructural protein likely played an interactive role as well.
机译：第一部分：抗逆转录病毒药物耐药性在人类1型免疫缺陷病毒（HIV-1）感染的治疗过程中发展，但是耐药性对HIV-1发病机理的影响以及这些后果的临床相关性尚未得到充分研究。这些问题可以在天然慢病毒感染的动物模型中解决。本研究检查了猫免疫缺陷病毒（FIV）的致病性分子克隆的定点突变体FIV-pPPR，作为研究（-）-beta-L-2'，3'-dideoxy- 3'-硫代胞苷（3TC，拉米夫定）对慢病毒发病机制的抵抗力。位于POL基因RT编码区高度保守的d YMDD基序的FIV密码子183处的甲硫氨酸到缬氨酸（M183V）突变赋予了对3TC的高水平表型抗性以及对相关3TC的交叉抗性化合物（-）-β-L-2'，3'-二脱氧-5-氟-3'-硫代胞苷[（--FTC）。3TC的耐药性与HIV-1相似，密码子有同源突变184（M184V）在3TC治疗的HIV-1感染患者中具有特征性发展，这种FIV-pPPR M183V突变体将有助于研究3TC耐药性对慢病毒发病机理的影响；第二部分ADV-Utah I生物分离株阿留申水貂病细小病毒（ADV）能有效复制并在水貂中具有高致病性，但不能在体外繁殖；源自适应细胞培养的ADV-Utah I的ADV-G分子克隆不会在成年貂中复制或引起疾病，但可以在体外可以高滴度繁殖，最近，第一种嵌合病毒ADV-Utah I和ADV-G描述了可在体外和体内复制并引起水貂致病的方法。与ADV-G / U-10相比，ADV-G / U-8感染具有更高的抗体滴度和更严重的组织病理学损害。但是，这些嵌合体仅在一个衣壳和三个非结构蛋白氨基酸变化上有所不同。当前研究的目的是确定G / U-8和G / U-10之间的体内复制和发病机理的差异是否归因于衣壳蛋白或非结构蛋白的变化。为了回答这个问题，构建了其他嵌合病毒，在体外繁殖，并用于感染水貂。抗病毒抗体反应，病毒血症，高球蛋白血症和组织病理学损害表明衣壳蛋白的352位密码子影响了体内复制和发病机制，但非结构蛋白的作用也可能起到了相互作用的作用。

著录项

  • 作者

    Stevenson, Mary Ann McCrackin.;

  • 作者单位

    University of Montana.;

  • 授予单位 University of Montana.;
  • 学科 Biology Microbiology.; Biology Veterinary Science.; Biology Molecular.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 1999
  • 页码 140 p.
  • 总页数 140
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 微生物学;动物学;分子遗传学;病理学;
  • 关键词

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