Immunogenicity of a Prefusion HIV-1 Envelope Trimer in Complex with a Quaternary-Structure-Specific Antibody
Immunogenicity of a Prefusion HIV-1 Envelope Trimer in Complex with a Quaternary-Structure-Specific Antibody
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DOI：
10.1128/jvi.02380-15
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发表时间：
2016-03-01
影响因子：
5.4
通讯作者：
Mascola, John R.
中科院分区：
文献类型：
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作者：
Cheng, Cheng;Pancera, Marie;Mascola, John R.
HIV-1包膜三聚体（Env）是广泛中和抗体的靶点，目前正在探索作为引发保护性抗体的候选疫苗。HIV-1 Env最有前途的抗原和结构模拟物之一是SOSIP。664-来自进化枝A菌株BG 505的稳定可溶性三聚体，优先被广泛中和抗体识别。三聚体免疫增强了自体2级BG 505菌株的高滴度中和;然而，广度是有限的，并且大量兴趣集中在理解和改善三聚体免疫原性上。我们试图提高BG 505 SOSIP的抗原特异性。664通过减少可变环3（V3）区的识别，其仅产生弱中和抗体。为了将三聚体稳定在其融合前闭合构象，我们将三聚体BG 505 SOSIP复合。664与PGT 145的抗原结合片段（Fab），PGT 145是一种广泛中和的四级结构特异性抗体。与无配体的三聚体相比，PGT 145 Fab-BG 505 SOSIP. 664复合物显示增加的解链温度稳定性和减少的V3识别。在豚鼠中，用PGT 145 Fab-BG 505 SOSIP免疫。664复合物引起的V3定向结合和中和滴度比用无配体BG 505 SOSIP获得的那些低100倍。664.复合和无配体的BG 505 SOSIP。664引起自体BG 505病毒的相当中和，并且在两种情况下，BG 505中和定位于一些豚鼠的gp 120的外部结构域。我们的研究结果表明，它是可能的，以减少免疫识别的V3区的三聚体，同时保持所需的抗原性，以诱导自体中和抗体。这些数据表明，三聚体免疫原的适当修饰可以进一步将免疫应答集中在关键中和表位上。
The HIV-1 envelope trimer (Env) is the target of broadly neutralizing antibodies and is being explored as a vaccine candidate to elicit protective antibodies. One of the most promising antigenic and structural mimics of HIV-1 Env is the SOSIP. 664-stabilized soluble trimer from the clade A strain BG505, which is preferentially recognized by broadly neutralizing antibodies. Trimer immunization elicits high-titer neutralization of the autologous tier 2 BG505 strain; however, breadth is limited, and substantial interest has focused on understanding and improving trimer immunogenicity. We sought to improve the antigenic specificity of BG505 SOSIP. 664 by reducing recognition of the variable loop 3 (V3) region, which elicits only weakly neutralizing antibodies. To stabilize the trimer in its prefusion closed conformation, we complexed trimeric BG505 SOSIP. 664 with the antigen-binding fragment (Fab) of PGT145, a broadly neutralizing quaternary-structure-specific antibody. Compared to the ligand-free trimer, the PGT145 Fab-BG505 SOSIP. 664 complex displayed increased melting temperature stability and reduced V3 recognition. In guinea pigs, immunization with the PGT145 Fab-BG505 SOSIP. 664 complex elicited similar to 100-fold lower V3-directed binding and neutralization titers than those obtained with ligand-free BG505 SOSIP. 664. Both complexed and ligand-free BG505 SOSIP. 664 elicited comparable neutralization of the autologous BG505 virus, and in both cases, BG505 neutralization mapped to the outer domain of gp120 for some guinea pigs. Our results indicate that it is possible to reduce immune recognition of the V3 region of the trimer while maintaining the antigenic profile needed to induce autologous neutralizing antibodies. These data suggest that appropriate modifications of trimer immunogens could further focus the immune response on key neutralization epitopes.