MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Virol. 2020 Jul 16;94(15). doi: 10.1128/JVI.00384-20.
We recently reported a group of lipopeptide-based membrane fusion inhibitors with potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). In this study, the therapeutic efficacy of such a lipopeptide, LP-52, was evaluated in rhesus macaques chronically infected with pathogenic SIVmac239. In a pilot study with one monkey, monotherapy with low-dose LP-52 rapidly reduced the plasma viral loads to below the limit of detection and maintained viral suppression during three rounds of structurally interrupted treatment. The therapeutic efficacy of LP-52 was further verified in four infected monkeys; however, three out of the monkeys had viral rebounds under the LP-52 therapy. We next focused on characterizing SIV mutants responsible for the resistance. Sequence analyses revealed that a V562A or V562M mutation in the N-terminal heptad repeat (NHR) and a E657G mutation in the C-terminal heptad repeat (CHR) of SIV gp41 conferred high resistance to LP-52 and cross-resistance to the peptide drug T20 and two newly designed lipopeptides (LP-80 and LP-83). Moreover, we showed that the resistance mutations greatly reduced the stability of diverse fusion inhibitors with the NHR site, and V562A or V562M in combination with E657G could significantly impair the functionality of viral envelopes (Envs) to mediate SIVmac239 infection and decrease the thermostability of viral six-helical bundle (6-HB) core structure. In conclusion, the present data have not only facilitated the development of novel anti-HIV drugs that target the membrane fusion step, but also help our understanding of the mechanism of viral evolution to develop drug resistance. The anti-HIV peptide drug T20 (enfuvirtide) is the only membrane fusion inhibitor available for treatment of viral infection; however, it exhibits relatively weak antiviral activity, short half-life, and a low genetic barrier to inducing drug resistance. Design of lipopeptide-based fusion inhibitors with extremely potent and broad antiviral activities against divergent HIV-1, HIV-2, and SIV isolates have provided drug candidates for clinical development. Here, we have verified a high therapeutic efficacy for the lipopeptide LP-52 in SIVmac239-infected rhesus monkeys. The resistance mutations selected have also been characterized, providing insights into the mechanism of action of newly designed fusion inhibitors with a membrane-anchoring property. For the first time, the data show that HIV-1 and SIV can share a similar genetic pathway to develop resistance, and that a lipopeptide fusion inhibitor could have a same resistance profile as its template peptide.
我们最近报道了一组基于脂肽的膜融合抑制剂，它们对人类免疫缺陷病毒 1 型（HIV-1）、HIV-2 和猴免疫缺陷病毒（SIV）具有强大的抗病毒活性。在这项研究中，我们评估了这种脂肽 LP-52 在感染致病性 SIVmac239 的恒河猴中的治疗效果。在一项针对一只猴子的初步研究中，低剂量 LP-52 的单一疗法迅速将血浆病毒载量降低到检测限以下，并在三轮结构中断治疗中维持病毒抑制。LP-52 的治疗效果在四只感染的猴子中得到了进一步验证；然而，三只猴子在 LP-52 治疗下出现了病毒反弹。我们接下来专注于表征导致耐药性的 SIV 突变体。序列分析显示，SIV gp41 的 N 端七肽重复（NHR）中的 V562A 或 V562M 突变和 C 端七肽重复（CHR）中的 E657G 突变赋予 LP-52 高耐药性，并与肽类药物 T20 和两种新设计的脂肽（LP-80 和 LP-83）交叉耐药。此外，我们表明，耐药突变大大降低了具有 NHR 位点的多种融合抑制剂的稳定性，并且 V562A 或 V562M 与 E657G 结合可显著损害病毒包膜（Env）的功能，从而介导 SIVmac239 感染并降低病毒六螺旋束（6-HB）核心结构的热稳定性。总之，本研究不仅促进了针对膜融合步骤的新型抗 HIV 药物的开发，而且有助于我们了解病毒进化产生耐药性的机制。抗 HIV 肽类药物 T20（恩夫韦肽）是唯一可用于治疗病毒感染的膜融合抑制剂；然而，它表现出相对较弱的抗病毒活性、半衰期短和诱导耐药性的遗传屏障低。设计具有针对不同 HIV-1、HIV-2 和 SIV 分离株的极强和广谱抗病毒活性的脂肽融合抑制剂为临床开发提供了候选药物。在这里，我们已经验证了 LP-52 在 SIVmac239 感染恒河猴中的高治疗效果。选择的耐药突变也已得到表征，为具有膜锚定特性的新型融合抑制剂的作用机制提供了深入了解。数据首次表明，HIV-1 和 SIV 可以共享类似的遗传途径产生耐药性，并且脂肽融合抑制剂可能具有与其模板肽相同的耐药谱。
