Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding
Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding
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DOI：
10.1073/pnas.1217609110
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发表时间：
2013-01-02
影响因子：
11.1
通讯作者：
Lewis, George K.
中科院分区：
文献类型：
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作者：
Guan, Yongjun;Pazgier, Marzena;Lewis, George K.
HIV-1包膜糖蛋白（Env）在病毒进入过程中经历了CD 4结合和辅助受体接合的构象转变。这一过程中的物理步骤正在被定义，但对它们作为潜在保护HIV-1感染的抗体靶点的重要性知之甚少。在这里，我们通过表征41种对CD 4接合后三聚体Env上暴露的表位具有特异性的人mAb来探测过渡表位暴露的功能意义。这些mAb识别三个表位簇：簇A，在三聚体Env中被gp 41封闭的gp 120面;簇B，邻近辅助受体结合位点（CoRBS）并涉及V1/V2结构域的区域;和簇C，辅助受体结合位点。通过抗体依赖性细胞介导的细胞毒性（ADCC）以及1级和2级假病毒的中和作用，对mAb进行功能评价。所有三个簇都包括介导ADCC的mAb。然而，对于簇A存在强烈的效力偏倚，簇A具有至少三个有效的ADCC表位，其同源mAb具有正电性互补位。在使用病毒致敏靶细胞的测定形式中，簇A表位是病毒进入期间的功能性ADCC靶标。相比之下，只有簇C含有被中和mAb识别的表位。在与表位精细特异性相关的宽度和效力上存在显著差异。相反，ADCC效力与任何表位簇的中和效力或宽度无关。因此，Fc介导的效应子功能和中和作用与抗Env抗体应答中的特异性共选择，但选择的性质对于这两种抗病毒活性是不同的。
The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virionsensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. Thus, Fcmediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.