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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
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Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.

机译：持久性细胞内人类免疫缺陷病毒1型整合酶链转移抑制剂活性的鉴定和表征。

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摘要

Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleosideucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG approximately AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
机译：药代动力学和药效学方面的考虑因素显着影响传染病的治疗选择。药效学的一个方面是抗生素后作用，传统上定义为抗生素去除后细菌生长延迟。相同的原理可以适用于抗病毒药物。例如，从培养基中除去核苷/核苷酸逆转录酶抑制剂（N / NtRTI）后，可以观察到人类免疫缺陷病毒1型（HIV-1）复制的明显延迟，因为一旦将这些前药内化，它们必须被代谢成活性的磷酸化形式进入细胞。相对较新的一类抗HIV-1药物是整合酶链转移抑制剂（INSTIs），此处对INSTIs raltegravir（RAL）和elvitegravir（EVG）进行了测试，同时检测了N / NtRTI阳性对照富马酸替诺福韦二甲酚（TDF）和叠氮胸苷（AZT）以及非核苷类逆转录酶抑制剂阴性对照奈韦拉平（NVP），以评估潜在的抗病毒后作用。用INSTIs预处理的转化的CD4阳性原代细胞显着抵抗随后的HIV-1攻击，揭示出以下持久的细胞内药物强度层次：TDF> EVG大约AZT> RAL> NVP。此外，开发了改进的添加时间测定法以评估残留药物活性水平。在HIV-1感染的急性期，大约0.8％的RAL和2％的初始EVG和TDF 1-h脉冲药物水平持续存在。 EVG还显示出显着的杀病毒活性。尽管没有理由怀疑专一的细胞内修饰，但该研究仍定义了原型INSTI的显着细胞内持久性。因此，正在进行的第二代制剂应考虑在此类药物中产生重大抗病毒作用的潜力。结合的细胞内持久性和杀病毒活性表明对EVG的潜在的暴露前预防应用。

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