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首页> 外文期刊>Antimicrobial agents and chemotherapy. >In vivo patterns of resistance to the HIV attachment inhibitor BMS-488043.
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In vivo patterns of resistance to the HIV attachment inhibitor BMS-488043.

机译：对HIV附着抑制剂BMS-488043的体内抗药性模式。

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Attachment inhibitors (AI) are a novel class of HIV-1 antivirals, with little information available on clinical resistance. BMS-488043 is an orally bioavailable AI that binds to gp120 of HIV-1 and abrogates its binding to CD4(+) lymphocytes. A clinical proof-of-concept study of the AI BMS-488043, administered as monotherapy for 8 days, demonstrated significant viral load reductions. In order to examine the effects of AI monotherapy on HIV-1 sensitivity, phenotypic sensitivity assessment of baseline and postdosing (day 8) samples was performed. These analyses revealed that four subjects had emergent phenotypic resistance (a 50% effective concentration [EC(50)] >10-fold greater than the baseline value) and four had high baseline EC(50)s (>200 nM). Population sequencing and sequence determination of cloned envelope genes uncovered five gp120 mutations at four loci (V68A, L116I, S375I/N, and M426L) associated with BMS-488043 resistance. Substitution at the 375 locus, located near the CD4 binding pocket, was the most common (maintained in 5/8 subjects at day 8). The five substitutions were evaluated for their effects on AI sensitivity through reverse genetics in functional envelopes, confirming their role in decreasing sensitivity to the drug. Additional analyses revealed that these substitutions did not alter sensitivity to other HIV-1 entry inhibitors. Thus, our studies demonstrate that although the majority of the subjects' viruses maintained sensitivity to BMS-488043, substitutions can be selected that decrease HIV-1 susceptibility to the AI. Most importantly, the substitutions described here are not associated with resistance to other approved antiretrovirals, and therefore, attachment inhibitors could complement the current arsenal of anti-HIV agents.
机译：附着抑制剂（AI）是一类新的HIV-1抗病毒药物，关于临床耐药性的信息很少。 BMS-488043是一种口服生物可利用的AI，可与HIV-1的gp120结合并消除其与CD4（+）淋巴细胞的结合。 AI BMS-488043的临床概念验证研究（单药治疗8天）显示病毒载量显着降低。为了检查AI单一疗法对HIV-1敏感性的影响，对基线和给药后（第8天）样本进行了表型敏感性评估。这些分析表明，四名受试者出现了表型抵抗（50％有效浓度[EC（50）]>高于基线值的10倍），四名受试者的基线EC（50）s高（> 200 nM）。克隆的包膜基因的群体测序和序列测定在与BMS-488043抗性相关的四个位点（V68A，L116I，S375I / N和M426L）发现了五个gp120突变。位于CD4结合袋附近的375个位点的取代是最常见的（在第8天维持在5/8位受试者中）。通过功能包膜中的反向遗传学评估了这五个替代品对AI敏感性的影响，证实了它们在降低对药物敏感性方面的作用。进一步的分析表明，这些取代不会改变对其他HIV-1进入抑制剂的敏感性。因此，我们的研究表明，尽管大多数受试者的病毒对BMS-488043保持敏感性，但可以选择替代品以降低HIV-1对AI的敏感性。最重要的是，此处描述的取代与对其他批准的抗逆转录病毒药物的耐药性无关，因此，附着抑制剂可以补充目前的抗HIV药物库。

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