Protein Interactions Group, Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, USA.
Biochem Biophys Res Commun. 2012 Jan 27;417(4):1164-9. doi: 10.1016/j.bbrc.2011.12.089. Epub 2011 Dec 27.
We have previously observed that all known HIV-1 broadly neutralizing antibodies (bnAbs) are highly divergent from germline antibodies in contrast to bnAbs against Hendra virus, Nipah virus and SARS coronavirus (SARS CoV). We have hypothesized that because the germline antibodies are so different from the mature HIV-1-specific bnAbs they may not bind the epitopes of the mature antibodies and provided the first evidence to support this hypothesis by using individual putative germline-like predecessor antibodies. To further validate the hypothesis and understand initial immune responses to different viruses, two phage-displayed human cord blood-derived IgM libraries were constructed which contained mostly germline antibodies or antibodies with very low level of somatic hypermutations. They were panned against different HIV-1 envelope glycoproteins (Envs), SARS CoV protein receptor-binding domain (RBD), and soluble Hendra virus G protein (sG). Despite a high sequence and combinatorial diversity observed in the cord blood-derived IgM antibody repertoire, no enrichment for binders of Envs was observed in contrast to considerable specific enrichments produced with panning against RBD and sG; one of the selected monoclonal antibodies (against the RBD) was of high (nM) affinity with only few somatic mutations. These results further support and expand our initial hypothesis for fundamental differences in immune responses leading to elicitation of bnAbs against HIV-1 compared to SARS CoV and Hendra virus. HIV-1 uses a strategy to minimize or eliminate strong binding of germline antibodies to its Env; in contrast, SARS CoV and Hendra virus, and perhaps other viruses causing acute infections, can bind germline antibody or minimally somatically mutated antibodies with relatively high affinity which could be one of the reasons for the success of sG and RBD as vaccine immunogens.
我们之前观察到，与亨德拉病毒、尼帕病毒和 SARS 冠状病毒（SARS-CoV）的广谱中和抗体（bnAbs）不同，所有已知的 HIV-1 bnAbs 都与种系抗体高度不同。我们假设，由于种系抗体与成熟的 HIV-1 特异性 bnAbs 如此不同，它们可能无法结合成熟抗体的表位，并首次通过使用单个假定的种系样前体抗体提供了支持这一假设的证据。为了进一步验证这一假设并了解对不同病毒的初始免疫反应，构建了两个噬菌体展示的人脐带血衍生 IgM 文库，其中包含大多数种系抗体或体细胞高突变水平非常低的抗体。它们针对不同的 HIV-1 包膜糖蛋白（Env）、SARS-CoV 蛋白受体结合域（RBD）和可溶性亨德拉病毒 G 蛋白（sG）进行了淘选。尽管在脐带血衍生的 IgM 抗体库中观察到了高序列和组合多样性，但与针对 RBD 和 sG 进行淘选所产生的显著特异性富集相比，没有观察到针对 Env 的结合物的富集；从筛选中选择的一种单克隆抗体（针对 RBD）具有高（nM）亲和力，仅发生少数体细胞突变。这些结果进一步支持和扩展了我们最初的假设，即在引发针对 HIV-1 的 bnAbs 的免疫反应方面，与 SARS-CoV 和亨德拉病毒相比存在根本差异。HIV-1 采用了一种策略来最小化或消除种系抗体与其 Env 的强结合；相比之下，SARS-CoV 和亨德拉病毒，也许还有其他引起急性感染的病毒，可以与种系抗体或体细胞突变较少的抗体以相对高的亲和力结合，这可能是 sG 和 RBD 作为疫苗免疫原成功的原因之一。
