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首页> 美国卫生研究院文献>Journal of Virology >Isolation and Molecular Characterization of a Nelfinavir (NFV)-Resistant Human Immunodeficiency Virus Type 1 That Exhibits NFV-Dependent Enhancement of Replication
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Isolation and Molecular Characterization of a Nelfinavir (NFV)-Resistant Human Immunodeficiency Virus Type 1 That Exhibits NFV-Dependent Enhancement of Replication

机译：Nelfinavir（NFV）抵抗人类免疫缺陷病毒1型的分离和分子表征其表现出NFV依赖性复制的增强

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During the use of a phenotypic anti-human immunodeficiency virus type 1 (HIV-1) drug resistance assay in a large set of clinical virus isolates, we found a unique variant (CL-4) that exhibited a high level of nelfinavir (NFV) resistance and rather enhanced replication under subinhibitory concentrations of NFV (0.001 to 0.1 μM). Comparison of gag-pol sequences of the CL-4 variant and its predecessor virus isolates showed a stepwise accumulation of a total of 19 amino acid substitutions in protease (PR) and Gag p17 during 32-month NFV-containing antiretroviral therapy, while other Gag regions including the cleavage sites of the p55 precursor remained highly conserved. To understand the relationship between the genetic and phenotypic changes in CL-4, we constructed chimeric viruses using pNL4-3, replacing the PR, p24PR, or p17PR gene segment of CL-4 or its predecessor. A series of tissue culture infections with the chimeras in the absence or presence of increasing concentrations of NFV demonstrated that only the p17PR segment of CL-4 could confer the NFV-dependent replication enhancement phenotype on NL4-3. Our data suggest a novel adaptation mechanism of HIV-1 to NFV, in which coevolution of Gag and PR genes generates a variant that replicates more efficiently in the cellular environment in the presence of NFV than without the drug.
机译：在大量临床病毒分离株中使用表型抗人类免疫缺陷病毒1型（HIV-1）耐药分析时，我们发现了一个独特的变体（CL-4），其表现出高水平的奈非那韦（NFV）在亚抑制浓度的NFV（0.001至0.1μM）下具有耐药性，并且复制增强。比较CL-4变体及其前代病毒分离株的gag-pol序列，发现在32个月含NFV的抗逆转录病毒疗法期间，蛋白酶（PR）和Gag p17中共有19个氨基酸取代的逐步积累，而其他Gag包括p55前体的裂解位点的区域保持高度保守。为了了解CL-4的遗传和表型变化之间的关系，我们使用pNL4-3构建了嵌合病毒，取代了CL-4或其前身的PR，p24PR或p17PR基因片段。在不存在或存在浓度不断升高的NFV的情况下，嵌合体引起的一系列组织培养感染表明，只有CL-4的p17PR片段才能赋予NL4-3依赖NFV的复制增强表型。我们的数据表明了HIV-1对NFV的新型适应机制，其中Gag和PR基因的共同进化产生了一个变异体，该变异体在存在NFV的情况下比不使用药物更能在细胞环境中复制。

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