Nonneutralizing HIV-1 gp41 Envelope Cluster II Human Monoclonal Antibodies Show Polyreactivity for Binding to Phospholipids and Protein Autoantigens
Nonneutralizing HIV-1 gp41 Envelope Cluster II Human Monoclonal Antibodies Show Polyreactivity for Binding to Phospholipids and Protein Autoantigens
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DOI：
10.1128/jvi.01680-10
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发表时间：
2011-02-01
影响因子：
5.4
通讯作者：
Alam, S. Munir
中科院分区：
文献类型：
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作者：
Dennison, S. Moses;Anasti, Kara;Alam, S. Munir
HIV-1 gp 41包膜抗体，这是经常诱导的HIV-1感染者，主要是非中和性。靶向gp 41近膜表位（MPER）的罕见且难以诱导的中和抗体（2F 5和4 E10）是多特异性的，需要脂质结合才能中和HIV-1。这些结果提出了如何普遍的多反应性是gp 41抗体和gp 41非中和抗体的结合特性如何不同于那些广泛中和的抗体之间的问题。在这项研究中，我们已经确定了一组人gp 41抗体与免疫显性簇I（gp 41氨基酸[aa] 579至613）或簇II（gp 41 aa 644至667）内的结合特异性，用于与自身抗原、gp 140蛋白和MPER肽-脂质缀合物反应。我们报告说，虽然没有研究的gp 41簇I抗体是多特异性的，所有三个gp 41簇II抗体结合的脂质或自身抗原，从而显示簇II抗体表现出多反应性的倾向。所有簇II gp 41单克隆抗体（MAb），包括脂质反应性的那些，未能结合gp 41 MPER肽-脂质复合物。簇II抗体以纳摩尔结合亲和力（解离常数[K-d]）与寡聚gp 140蛋白强烈结合，因此，它们识别gp 41上不同于中和gp 41抗体的构象表位。这些结果表明，脂质反应性gp 41簇II抗体是非中和性的，因为它们不能结合gp 41上的相关中和表位。
HIV-1 gp41 envelope antibodies, which are frequently induced in HIV-1-infected individuals, are predominantly nonneutralizing. The rare and difficult-to-induce neutralizing antibodies (2F5 and 4E10) that target gp41 membrane-proximal epitopes (MPER) are polyspecific and require lipid binding for HIV-1 neutralization. These results raise the questions of how prevalent polyreactivity is among gp41 antibodies and how the binding properties of gp41-nonneutralizing antibodies differ from those of antibodies that are broadly neutralizing. In this study, we have characterized a panel of human gp41 antibodies with binding specificities within the immunodominant cluster I (gp41 amino acids [aa] 579 to 613) or cluster II (gp41 aa 644 to 667) for reactivity to autoantigens, to the gp140 protein, and with MPER peptide-lipid conjugates. We report that while none of the gp41 cluster I antibodies studied were polyspecific, all three gp41 cluster II antibodies bound either to lipids or autoantigens, thus showing the propensity of cluster II antibodies to manifest polyreactivity. All cluster II gp41 monoclonal antibodies (MAbs), including those that were lipid reactive, failed to bind to gp41 MPER peptide-lipid complexes. Cluster II antibodies bound strongly with nanomolar binding affinity (dissociation constant [K-d]) to oligomeric gp140 proteins, and thus, they recognize conformational epitopes on gp41 that are distinct from those of neutralizing gp41 antibodies. These results demonstrate that lipid-reactive gp41 cluster II antibodies are nonneutralizing due to their inability to bind to the relevant neutralizing epitopes on gp41.