Motakis Dimitrios, Parniak Michael A
Lady Davis Institute for Medical Research and McGill University AIDS Center, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E8, Canada.
Antimicrob Agents Chemother. 2002 Jun;46(6):1851-6. doi: 10.1128/AAC.46.6.1851-1856.2002.
It was previously found that certain nonnucleoside reverse transcriptase inhibitors (NNRTI) possess virucidal activity against human immunodeficiency virus type 1 (HIV-1), and it was suggested that the tight-binding mode of inhibition of reverse transcriptase might be important for this virucidal activity (Borkow et al., J. Virol. 71:3023-3030, 1997). To test this, we compared six different NNRTI, including three tight-binding NNRTI, namely UC781, efavirenz (EFV) (Sustiva), and 5-chloro-3-phenylsulfonylindole-2-carboxamide (CSIC), and three rapid-equilibrium NNRTI, delavirdine (DLV) (Rescriptor), nevirapine (NVP) (Viramune), and UC84, in a variety of virucidal tests. Incubation of isolated HIV-1 virions with UC781, EFV, or CSIC rapidly inactivated the virus, whereas DLV, NVP, and UC84 were ineffective in this respect. Exposure of H9+ cells chronically infected by HIV-1 to the tight-binding NNRTI abolished the infectivity of nascent virus subsequently produced by these cells following removal of extracellular drug, thereby preventing cell-to-cell virus transmission in the absence of exogenous drug. In contrast, cell-to-cell transmission of HIV was blocked by DLV, NVP, and UC84 only when the drug remained in the extracellular medium. Pretreatment of uninfected lymphocytoid cells with UC781, EFV, or CSIC, but not DLV, NVP, or UC84, protected these cells from subsequent HIV-1 infection in the absence of extracellular drug. The protective effect was dependent on both the dose of NNRTI and the viral load. The overall virucidal efficacy of the tight-binding NNRTI tested was CSIC > UC781 approximately EFV. We conclude that the tight-binding mode of inhibition is an essential characteristic for virucidal NNRTI and that antiviral potency is an insufficient predictor for virucidal utility of NNRTI.
此前发现某些非核苷类逆转录酶抑制剂（NNRTI）对1型人类免疫缺陷病毒（HIV-1）具有杀病毒活性，并且有人提出逆转录酶的紧密结合抑制模式可能对这种杀病毒活性很重要（博尔科夫等人，《病毒学杂志》71:3023 - 3030，1997）。为了验证这一点，我们在各种杀病毒试验中比较了六种不同的NNRTI，包括三种紧密结合的NNRTI，即UC781、依非韦伦（EFV）（施多宁）和5-氯-3-苯基磺酰基吲哚-2-甲酰胺（CSIC），以及三种快速平衡的NNRTI，地拉韦啶（DLV）（雷易得）、奈韦拉平（NVP）（维乐命）和UC84。将分离的HIV-1病毒粒子与UC781、EFV或CSIC一起孵育能迅速使病毒失活，而DLV、NVP和UC84在这方面无效。将长期感染HIV-1的H9 +细胞暴露于紧密结合的NNRTI后，去除细胞外药物后这些细胞随后产生的新生病毒的感染性被消除，从而在没有外源性药物的情况下阻止了细胞间病毒传播。相比之下，只有当药物保留在细胞外培养基中时，HIV的细胞间传播才会被DLV、NVP和UC84阻断。用UC781、EFV或CSIC对未感染的淋巴细胞样细胞进行预处理，但不是用DLV、NVP或UC84，可在没有细胞外药物的情况下保护这些细胞免受随后的HIV-1感染。保护作用取决于NNRTI的剂量和病毒载量。所测试的紧密结合NNRTI的总体杀病毒效力为CSIC > UC781≈EFV。我们得出结论，紧密结合抑制模式是杀病毒NNRTI的一个基本特征，并且抗病毒效力不足以预测NNRTI的杀病毒效用。
