TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1
TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1
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DOI：
10.1128/aac.00986-09
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发表时间：
2010-02-01
影响因子：
4.9
通讯作者：
Rimsky, Laurence T.
中科院分区：
文献类型：
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作者：
Azijn, Hilde;Tirry, Ilse;Rimsky, Laurence T.
非核苷类逆转录酶抑制剂（NNRTI）已被证明对人类免疫缺陷病毒1型（HIV-1）有效。然而，在病毒抑制不完全的情况下，依法韦仑和奈韦拉平选择耐药病毒。二芳基嘧啶依曲韦林已被证明对感染NNRTI耐药HIV-1的患者具有持久疗效。用于检测来自与依曲韦林相同系列的NNRTI候选物的筛选策略鉴定了TMC 278（利匹韦林）。TMC 278是一种NNRTI，对野生型HIV-1 M组分离株显示出亚纳摩尔的50%有效浓度（EC50值）（0.07至1.01 nM），对O组分离株显示出纳摩尔的EC50值（2.88至8.45 nM）。对TMC 278的敏感性不受大多数单一NNRTI耐药相关突变（RAM）的影响，包括位置100、103、106、138、179、188、190、221、230和236的突变。携带Y181C的HIV-1定点突变株对TMC 278敏感，而携带K101P或Y181I/V的HIV-1定点突变株对TMC 278耐药。在体外，观察到TMC 278和依曲韦林之间存在相当大的交叉耐药性。观察到62%的依法韦仑和/或奈韦拉平耐药HIV-1重组临床分离株对TMC 278敏感。在第一代NNRTI无法抑制复制的浓度下，TMC 278可抑制病毒复制。对TMC 278耐药株的选择率在HIV-1 M组亚型之间具有可比性。在TMC 278的选择压力下，HIV-1中出现的NNRTI RAM包括V90 I、L100 I、K101 E、V106 A/I、V108 I、E138 G/K/Q/R、V179 F/I、Y181 C/I、V189 I、G190 E、H221 Y、F227 C和M230 I/L的组合。E138R被确定为新的NNRTI RAM。这些体外分析表明，TMC 278是一种有效的下一代NNRTI，对耐药性发展具有高遗传屏障。
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz-and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.