HIV-1 prehairpin intermediate inhibitors show efficacy independent of neutralization tier.
HIV-1 prehairpin intermediate inhibitors show efficacy independent of neutralization tier.
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DOI：
10.1073/pnas.2215792120
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发表时间：
2023-02-21
影响因子：
11.1
通讯作者：
Kim, Peter S.
中科院分区：
文献类型：
--
作者：
Bell, Benjamin N.;Bruun, Theodora U. J.;Friedland, Natalia;Kim, Peter S.
根据HIV-1毒株对患者抗血清中和的敏感性，HIV-1毒株被分为三个级别，但这些级别如何影响针对HIV-1糖蛋白Env的发夹前中间体(PHI)的抑制剂的疗效尚不清楚。在这里，我们发现针对PHI的抗体和蛋白抑制剂在所有三层都具有惊人的一致的中和能力，而目前用于临床试验的四种广谱中和抗体(BNAbs)对这些病毒显示出很大的变异性。尽管到目前为止发现的针对PHI的抗体通常具有适度的中和效力，但我们的结果表明，目前的HIV-1分类系统与PHI靶向HIV-1疫苗的努力无关，并强烈暗示这种策略可以提供特别广泛的保护层。根据艾滋病毒-1感染的捐献者不接受抗逆转录病毒治疗的血浆中和艾滋病毒-1的相对容易程度，将艾滋病毒-1毒株分为三个中和级之一；第一级毒株对中和特别敏感，而第二级和第三级毒株越来越难以中和。以前描述的大多数广谱中和抗体(BNAbs)针对HIV-1包膜(Env)的天然预融合构象，但针对另一种Env构象(前发夹中间体)的抑制剂的分级类别的相关性尚不清楚。在这里，我们证明了两种针对发夹前中间产物不同高度保守区域的抑制剂对所有三个HIV-1中和级别的菌株具有惊人的一致中和效力(对于给定的抑制剂在~100倍以内)；相比之下，针对不同环境表位的同类最佳bNAb对这些菌株的中和效力相差超过10,000倍。我们的结果表明，基于抗血清的HIV-1中和层数与靶向发夹前中间体的抑制剂无关，并突出了针对这一构象的治疗和疫苗努力的潜力。
HIV-1 strains are categorized into three tiers based on their sensitivity to neutralization by patient antisera, but it is poorly understood how these tiers influence the efficacy of inhibitors targeting the prehairpin intermediate (PHI) of HIV-1 glycoprotein Env. Here, we find that a PHI-targeting Ab and protein inhibitor have strikingly consistent neutralization potencies across all three tiers, whereas four broadly neutralizing antibodies (bnAbs) currently used in clinical trials show large variability against these viruses. Although PHI-targeting antibodies identified to date generally have modest neutralization potencies, our results demonstrate that the current system of classifying HIV-1 is not relevant for PHI-targeting HIV-1 vaccine efforts and strongly imply that such strategies can provide an especially broad layer of protection. HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1–infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the prehairpin intermediate, is not well understood. Here, we show that two inhibitors targeting distinct highly conserved regions of the prehairpin intermediate have strikingly consistent neutralization potencies (within ~100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the prehairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation.
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