A Derivative of the D5 Monoclonal Antibody That Targets the gp41 N-Heptad Repeat of HIV-1 with Broad Tier-2-Neutralizing Activity.
A Derivative of the D5 Monoclonal Antibody That Targets the gp41 N-Heptad Repeat of HIV-1 with Broad Tier-2-Neutralizing Activity.
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DOI：
10.1128/jvi.02350-20
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发表时间：
2021-07-12
影响因子：
5.4
通讯作者：
Kim PS
中科院分区：
文献类型：
--
作者：
Rubio AA;Filsinger Interrante MV;Bell BN;Brown CL;Bruun TUJ;LaBranche CC;Montefiori DC;Kim PS
HIV-1感染由病毒糖蛋白Env启动，其在与细胞辅助受体相互作用后，采用称为前发夹中间体（PHI）的瞬时构象。N-七肽重复序列（NHR）是暴露在PHI中的gp 41的高度保守区域;它是FDA批准的药物恩夫韦肽和中和单克隆抗体（mAb）的靶标。然而，迄今为止，这些单克隆抗体对1级HIV-1毒株仅具有微弱的有效性，1级HIV-1毒株对中和抗体最敏感。在这里，我们通过重组先前描述的D5的六个抗体互补决定区中的四个中的突变，设计并测试了D5的11种IgG变体，D5是一种抗NHR mAb。一种变体D5_AR表现出对用HXB 2 Env假型化的慢病毒的50%抑制剂量（ID 50）的6倍增强。D5_AR对一组不同的2级HIV-1病毒表现出弱的交叉进化枝中和活性，2级HIV-1病毒对中和抗体的敏感性低于1级病毒，并且是目前基于抗体的疫苗工作的目标。此外，在表达FcγRI的靶细胞中，D5_AR IgG的中和效力大大增强，ID 50值<0.1 μg/ml;该免疫球蛋白受体在巨噬细胞和树突状细胞上表达，与粘膜表面HIV-1感染的早期阶段有关。D5和D5_AR在IgG、Fab和单链可变片段（scFv）形式中具有等同的中和效力，表明中和不受空间位阻的影响。总而言之，这些结果为通过引发针对gp 41 NHR的抗体来靶向PHI的疫苗策略提供了支持，并支持在非人灵长类动物被动免疫研究中对抗NHR mAb的研究。尽管抗逆转录病毒疗法取得了进展，但艾滋病毒仍然是一种全球流行病，已夺去3200多万人的生命。因此，开发有效的艾滋病毒疫苗仍然是一项紧迫的公共卫生需求。HIV-1前发夹中间体（PHI）的gp 41 N-七肽重复序列（NHR）高度保守（>90%），并被FDA批准的药物恩夫韦肽抑制，使其成为有吸引力的疫苗靶点。然而，迄今为止，抗NHR抗体还不是有效的。在这里，我们设计了D5_AR，一种抗NHR抗体D5的更有效的变体，并建立了其抑制HIV-1菌株的能力，这些菌株更难以中和，更能代表循环菌株（2级菌株）。在表达FcγRI的细胞中，D5_AR的中和活性大大增强; FcγRI在涉及HIV-1性传播最早阶段的细胞上表达。总之，这些结果支持了靶向gp 41 NHR和PHI用于疫苗开发的努力。
HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the prehairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date, these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5’s six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in the 50% inhibitory dose (ID50) against lentivirus pseudotyped with HXB2 Env. D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI, with ID50 values of <0.1 μg/ml; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and single-chain variable-fragment (scFv) formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR and support investigation of anti-NHR mAbs in nonhuman primate passive immunization studies. IMPORTANCE Despite advances in antiretroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective HIV vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 prehairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date, anti-NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.
靶向gp41的HIV-1融合抑制剂的合理改进：创新设计的具有替代构象的Ile-Asp-Leu尾
影响因子：
4.6
作者：
Zhu Y;Su S;Qin L;Wang Q;Shi L;Ma Z;Tang J;Jiang S;Lu L;Ye S;Zhang R
通讯作者：
Zhang R