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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Human immunodeficiency virus type 1 resistance or cross-resistance to nonnucleoside reverse transcriptase inhibitors currently under development as microbicides.
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Human immunodeficiency virus type 1 resistance or cross-resistance to nonnucleoside reverse transcriptase inhibitors currently under development as microbicides.

机译：人类免疫缺陷病毒对非核苷类逆转录酶抑制剂的1型抗性或交叉抗性目前正在发展为杀菌剂。

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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.
机译：目前正在开发基于非核苷类逆转录酶抑制剂（NNRTIs）的杀微生物剂，以保护妇女免于通过性接触感染HIV。但是，这些产品的大规模引入引起两个主要问题。首先，当未确诊的HIV阳性女性使用这些杀菌剂时，他们可能会选择病毒抵抗力，这可能会损害随后的治疗选择。第二，对NNRTI耐药菌株没有活性的基于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，在三种浓度增加的条件下，通过在活化的外周血单核细胞（PBMC）中连续筛选三种来自B和C型亚型的病毒分离株和CRF02_AG（循环重组体）的体外耐药性目前正在开发作为候选杀微生物剂的NNRTI（即TMC120，UC781和MIV-160）。 TMC120和MIV-160对耐药性发展表现出高度的遗传障碍，而对UC781的耐药性迅速出现，类似于依非韦伦和奈韦拉平。从表型上看，尽管对新开发的NNRTIs lersivirine和etravirine保留了一定的敏感性，但所选病毒似乎对当前的一线治疗性NNRTIs（即地拉韦定，奈韦拉平和依非韦伦）具有高度的交叉抗性。 UC781，TMC120和MIV-160抑制体外选择的NNRTI抗病毒的能力也受到限制，尽管可以观察到候选杀微生物剂NNRTI MIV-170的残留活性。有趣的是，只有四种p2 / p7 / p1 / p6 / PR / RT / INT重组NNRTI抗性病毒（即，TMC120抗性VI829，EFV抗性VI829，MIV-160抗性VI829和EFV抗性MP568）显示出损伤在复制健身中。总体而言，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单种基于NNRTI的杀菌剂。

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