eCD4-Ig Variants That More Potently Neutralize HIV-1
eCD4-Ig Variants That More Potently Neutralize HIV-1
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DOI：
10.1128/jvi.02011-17
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发表时间：
2018-06-01
影响因子：
5.4
通讯作者：
Farzan, Michael
中科院分区：
文献类型：
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作者：
Fetzer, Ina;Gardner, Matthew R.;Farzan, Michael
人类免疫缺陷病毒1型（HIV-1）进入抑制剂eCD 4-IG是CD 4-IG和辅助受体模拟肽的融合物。eCD 4-IG的效力明显高于CD 4-IG，中和效率接近HIV-1广泛中和抗体（bNAb）。然而，与bNAb不同，eCD 4-IG中和了所有HIV-1、HIV-2和猴免疫缺陷病毒（SIV）分离株，这表明它可能在抗体逃逸是一个问题的临床环境中有用。在这里，我们描述了三种新的eCD 4-IG变体，每种变体都具有不同的结构，并且每种变体都利用CD 4结构域1的稳定形式D1.22。这些变体的效力是我们最初的eCD 4-IG变体的10- 20倍，其中带有四个D1.22结构域的构建体（eD 1.22-HL-IG）表现出最大效力。然而，该变体介导的抗体依赖性细胞介导的细胞毒性（ADCC）活性低于eCD 4-IG本身或其他几种eCD 4-IG变体，包括最小的变体（eD 1.22-IG）。具有与原始eCD 4-IG相同结构的变体（eD 1.22-D2-IG）显示出适度更高的热稳定性，并且最好地防止了促进CCR 5阳性、CD 4阴性细胞的感染。所有三种变体以及eCD 4-IG本身比CD 4-IG更有效地介导HIV-1包膜糖蛋白gp 120的脱落。最后，我们发现只有三个D1.22突变对eD1.22-D2-IG的效力有贡献，并且将这些变化引入eCD 4-IG导致比eCD 4-IG效力高9倍和比eD1.22-D2-IG效力高2倍的变体。这些研究将有助于开发eCD 4-IG变异体，这些变异体具有针对预防、治疗和治愈应用优化的特性。重要信息HIV-1 bNAb具有不同于抗逆转录病毒化合物的特性。具体来说，抗体可以招募免疫效应细胞来消除受感染的细胞，而抗逆转录病毒化合物只是干扰病毒生命周期中的各个步骤。不幸的是，HIV-1擅长逃避抗体识别，限制了抗体作为HIV-1感染治疗或作为根除潜伏感染细胞努力的一部分的效用。eCD 4-IG是一种抗体样进入抑制剂，与HIV-1的专性受体非常相似。eCD 4-IG似乎与抗体在性质上不同，因为它能中和所有HIV-1、HIV-2和SIV分离株。在这里，我们描述了三种新的结构上不同的eCD 4-IG变体，并表明每种变体在预防、治疗或治愈HIV-1感染的关键特性方面都表现出色。例如，一种变体最有效地中和了HIV-1，而其他变体则最好地利用自然杀伤细胞来消除受感染的细胞。这些观察结果将有助于产生针对不同临床应用优化的eCD 4-IG变体。
The human immunodeficiency virus type 1 (HIV-1) entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralized all HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates that it has been tested against, suggesting that it may be useful in clinical settings, where antibody escape is a concern. Here, we characterize three new eCD4-Ig variants, each with a different architecture and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as the original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented the promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications.IMPORTANCE HIV-1 bNAbs have properties different from those of antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral life cycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the utility of antibodies as a treatment for HIV-1 infection or as part of an effort to eradicate latently infected cells. eCD4-Ig is an antibody-like entry inhibitor that closely mimics HIV-1's obligate receptors. eCD4-Ig appears to be qualitatively different from antibodies, since it neutralizes all HIV-1, HIV-2, and SIV isolates. Here, we characterize three new structurally distinct eCD4-Ig variants and show that each excels in a key property useful to prevent, treat, or cure an HIV-1 infection. For example, one variant neutralized HIV-1 most efficiently, while others best enlisted natural killer cells to eliminate infected cells. These observations will help generate eCD4-Ig variants optimized for different clinical applications.