Isotype modulates epitope specificity, affinity, and antiviral activities of anti–HIV-1 human broadly neutralizing 2F5 antibody
Isotype modulates epitope specificity, affinity, and antiviral activities of anti–HIV-1 human broadly neutralizing 2F5 antibody
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同型调节抗 HIV-1 人类广泛中和 2F5 抗体的表位特异性、亲和力和抗病毒活性
DOI：
10.1073/pnas.1200024109
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
M. Bomsel
中科院分区：
文献类型：
--
作者：
D. Tudor;Huifeng Yu;Julien Maupetit;A. Drillet;Tahar Bouceba;I. Schwartz;L. Lopalco;P. Tufféry;M. Bomsel
恒定重链（CH 1）结构域影响抗体亲和力和精细特异性，挑战只有可变区有助于抗原结合的范式。为了研究CH 1结构域的作用，我们从广泛中和的抗HIV-1 2F 5 IgG 1构建了IgA 2，并比较了2F 5 IgA 2和IgG的结合亲和力和功能活性。我们发现，2F 5的IgA 2结合到gp 41膜近端的外部区域具有比IgG 1更高的亲和力。在功能上，与IgG 1相比，2F 5 IgA 2更有效地阻断HIV-1跨上皮细胞的转胞吞作用和R5 HIV-1对CD 4+细胞的感染。2F 5 IgG 1和IgA 2协同作用，完全阻断HIV-1从Langerhans转移到自体CD 4 + T细胞，并抑制CD 4 + T细胞感染。通过筛选随机肽文库和计算机对接建模进行的表位作图表明，沿着gp 41上的2F 5 IgG典型ELDKWA表位，IgG 1识别gp 41 C-螺旋上的额外3D构象表位。相反，IgA 2表位包括gp 41 N-螺旋上的独特构象基序。总体而言，2F 5的CH 1区域有助于形成其表位特异性、抗体亲和力和功能活性。在HIV-1/AIDS等性传播感染的情况下，提高粘膜IgA疫苗应答应补充IgG疫苗应答，阻断HIV-1传播。
The constant heavy chain (CH1) domain affects antibody affinity and fine specificity, challenging the paradigm that only variable regions contribute to antigen binding. To investigate the role of the CH1 domain, we constructed IgA2 from the broadly neutralizing anti–HIV-1 2F5 IgG1, and compared 2F5 IgA2 and IgG binding affinity and functional activities. We found that 2F5 IgA2 bound to the gp41 membrane proximal external region with higher affinity than IgG1. Functionally, compared with IgG1, 2F5 IgA2 more efficiently blocked HIV-1 transcytosis across epithelial cells and CD4+ cell infection by R5 HIV-1. The 2F5 IgG1 and IgA2 acted synergistically to fully block HIV-1 transfer from Langerhans to autologous CD4+ T cells and to inhibit CD4+ T-cell infection. Epitope mapping performed by screening a random peptide library and in silico docking modeling suggested that along with the 2F5 IgG canonical ELDKWA epitope on gp41, the IgG1 recognized an additional 3D-conformational epitope on the gp41 C-helix. In contrast, the IgA2 epitope included a unique conformational motif on the gp41 N-helix. Overall, the CH1 region of 2F5 contributes to shape its epitope specificity, antibody affinity, and functional activities. In the context of sexually transmitted infections such as HIV-1/AIDS, raising a mucosal IgA-based vaccine response should complement an IgG-based vaccine response in blocking HIV-1 transmission.
影响因子：
6.8
作者：
Roux, Kenneth H.;Taylor, Kenneth A.
通讯作者：
Taylor, Kenneth A.