Department of Microbiology, Virology Unit, Institute of Tropical Medicine, Nationalestraat 155, B-2000 Antwerp, Belgium.
Antimicrob Agents Chemother. 2011 Apr;55(4):1403-13. doi: 10.1128/AAC.01426-10. Epub 2011 Jan 31.
Microbicides based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect women from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when these microbicides are used by undiagnosed HIV-positive women, they could potentially select for viral resistance, which may compromise subsequent therapeutic options. Second, NNRTI-based microbicides that are inactive against NNRTI-resistant strains might promote the selective transmission of these viruses. In order to address these concerns, drug resistance was selected in vitro by the serial passage of three viral isolates from subtypes B and C and CRF02_AG (a circulating recombinant form) in activated peripheral blood mononuclear cells (PBMCs) under conditions of increasing concentrations of three NNRTIs (i.e., TMC120, UC781, and MIV-160) that are currently being developed as candidate microbicides. TMC120 and MIV-160 displayed a high genetic barrier to resistance development, whereas resistance to UC781 emerged rapidly, similarly to efavirenz and nevirapine. Phenotypically, the selected viruses appeared to be highly cross-resistant to current first-line therapeutic NNRTIs (i.e., delavirdine, nevirapine, and efavirenz), although they retained some susceptibility to the more recently developed NNRTIs lersivirine and etravirine. The ability of UC781, TMC120, and MIV-160 to inhibit the in vitro-selected NNRTI-resistant viruses was also limited, although residual activity could be observed for the candidate microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT recombinant NNRTI-resistant viruses (i.e., TMC120-resistant VI829, EFV-resistant VI829, MIV-160-resistant VI829, and EFV-resistant MP568) showed impairments in replicative fitness. Overall, these in vitro analyses demonstrate that due to potential cross-resistance, the large-scale introduction of single-NNRTI-based microbicides should be considered with caution.
基于非核苷类逆转录酶抑制剂（NNRTIs）的杀微生物剂目前正在被开发，以通过性接触保护女性免受 HIV 感染。然而，这些产品的大规模引入引起了两个主要关注。首先，当未被诊断出 HIV 阳性的女性使用这些杀微生物剂时，它们可能会选择病毒耐药性，从而可能影响后续的治疗选择。其次，针对 NNRTI 耐药株无效的基于 NNRTI 的杀微生物剂可能会促进这些病毒的选择性传播。为了解决这些问题，在含有三种正在开发中的候选杀微生物剂（TMC120、UC781 和 MIV-160）的浓度逐渐增加的条件下，通过在激活的外周血单核细胞（PBMC）中对三种 HIV 分离株（来自亚型 B 和 C 以及 CRF02_AG（一种循环重组形式））进行连续传代，在体外选择了耐药性。TMC120 和 MIV-160 对耐药性的发展显示出很高的遗传屏障，而对 UC781 的耐药性则迅速出现，类似于依非韦伦和奈韦拉平。表型上，选择的病毒对当前一线治疗性 NNRTIs（即依法韦仑、奈韦拉平、和依非韦伦）表现出高度交叉耐药性，尽管它们对最近开发的 NNRTIs（即拉替拉韦和依曲韦林）仍保持一定的敏感性。UC781、TMC120 和 MIV-160 抑制体外选择的 NNRTI 耐药病毒的能力也受到限制，尽管候选杀微生物剂 NNRTI MIV-170 仍具有残留活性。有趣的是，只有四种 p2/p7/p1/p6/PR/RT/INT 重组 NNRTI 耐药病毒（即 TMC120 耐药 VI829、EFV 耐药 VI829、MIV-160 耐药 VI829 和 EFV 耐药 MP568）显示复制适应性受损。总的来说，这些体外分析表明，由于潜在的交叉耐药性，应谨慎考虑大规模引入基于单一 NNRTI 的杀微生物剂。
