Binding Interactions between Soluble HIV Envelope Glycoproteins and Quaternary-Structure-Specific Monoclonal Antibodies PG9 and PG16
Binding Interactions between Soluble HIV Envelope Glycoproteins and Quaternary-Structure-Specific Monoclonal Antibodies PG9 and PG16
复制标题
DOI：
10.1128/jvi.00411-11
复制
发表时间：
2011-07-01
影响因子：
5.4
通讯作者：
Stamatatos, Leonidas
中科院分区：
文献类型：
--
作者：
Davenport, Thaddeus M.;Friend, Della;Stamatatos, Leonidas
PG 9和PG 16是从感染HIV-1的受试者中分离的抗体，并显示出广泛的抗HIV中和活性。它们识别重叠表位，这些表位优先表达在HIV包膜糖蛋白（Env）的膜锚定三聚体形式上。据报道，PG 9和PG 16不与Env的可溶性模拟物结合。PG 9和PG 16表位最佳暴露于其上的可溶性Env蛋白的工程化将支持通过免疫引发广泛的抗HIV中和抗体的努力。在这里，我们确定了几个可溶性的gp 140 Env蛋白的PG 9和PG 16识别，我们研究了这些结合相互作用的分子细节。PG 9和PG 16的IgG版本识别可溶性三聚体gp 140形式的效率低于相应的单体gp 140形式。相比之下，PG 9和PG 16的Fab形式以相同的结合动力学和与抗V3抗体447 D对其表位的高结合亲和力相似的结合亲和力识别单体和三聚体gp 140形式。我们的数据还表明，根据Env骨架，PG 9和PG 16与gp 140的相互作用可能是由gp 41胞外域的存在促进的，并且不依赖于gp 140适当的酶促裂解为gp 120和gp 41。表达PG 9和PG 16表位的可溶性Env蛋白的鉴定以及这两种抗体与其配体之间的分子相互作用的详细表征提供了重要且新颖的信息，其将有助于改进未来Env免疫原的工程化。
PG9 and PG16 are antibodies isolated from a subject infected with HIV-1 and display broad anti-HIV neutralizing activities. They recognize overlapping epitopes, which are preferentially expressed on the membrane-anchored trimeric form of the HIV envelope glycoprotein (Env). PG9 and PG16 were reported not to bind to soluble mimetics of Env. The engineering of soluble Env proteins on which the PG9 and PG16 epitopes are optimally exposed will support efforts to elicit broad anti-HIV neutralizing antibodies by immunization. Here, we identified several soluble gp140 Env proteins that are recognized by PG9 and PG16, and we investigated the molecular details of those binding interactions. The IgG versions of PG9 and PG16 recognize the soluble trimeric gp140 form less efficiently than the corresponding monomeric gp140 form. In contrast, the Fab versions of PG9 and PG16 recognized the monomeric and trimeric gp140 forms with identical binding kinetics and with binding affinities similar to the high binding affinity of the anti-V3 antibody 447D to its epitope. Our data also indicate that, depending on the Env backbone, the interactions of PG9 and PG16 with gp140 may be facilitated by the presence of the gp41 ectodomain and are independent of the proper enzymatic cleavage of gp140 into gp120 and gp41. The identification of soluble Env proteins that express the PG9 and PG16 epitopes and the detailed characterization of the molecular interactions between these two antibodies and their ligands provide important and novel information that will assist in improving the engineering of future Env immunogens.