Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cell Rep. 2021 May 25;35(8):109167. doi: 10.1016/j.celrep.2021.109167.
HIV monoclonal antibodies for viral reservoir eradication strategies will likely need to recognize reactivated infected cells and potently drive Fc-mediated innate effector cell activity. We systematically characterize a library of 185 HIV-envelope-specific antibodies derived from 15 spontaneous HIV controllers (HCs) that selectively exhibit robust serum Fc functionality and compared them to broadly neutralizing antibodies (bNAbs) in clinical development. Within the 10 antibodies with the broadest cell-recognition capability, seven originated from HCs and three were bNAbs. V3-loop-targeting antibodies are enriched among the top cell binders, suggesting the V3-loop may be selectively exposed and accessible on the cell surface. Fc functionality is more variable across antibodies, which is likely influenced by distinct binding topology and corresponding Fc accessibility, highlighting not only the importance of target-cell recognition but also the need to optimize for Fc-mediated elimination. Ultimately, our results demonstrate that this comprehensive selection process can identify monoclonal antibodies poised to eliminate infected cells.
用于病毒储存库清除策略的 HIV 单克隆抗体可能需要识别被激活的感染细胞，并有效地驱动 Fc 介导的先天效应细胞活性。我们系统地表征了来自 15 名自发性 HIV 控制器 (HC) 的 185 种 HIV 包膜特异性抗体的文库，这些抗体选择性地表现出强大的血清 Fc 功能，并将其与临床开发中的广泛中和抗体 (bNAb) 进行了比较。在具有最广泛细胞识别能力的 10 种抗体中，有 7 种来自 HC，有 3 种是 bNAb。V3 环靶向抗体在顶级细胞结合物中更为丰富，这表明 V3 环可能在细胞表面选择性地暴露和可及。Fc 功能在抗体之间变化更大，这可能受到不同的结合拓扑和相应的 Fc 可及性的影响，这不仅突出了靶细胞识别的重要性，也突出了需要优化 Fc 介导的消除作用。最终，我们的结果表明，这种全面的选择过程可以识别出有望消除感染细胞的单克隆抗体。
