Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody.,Cell

当前位置： X-MOL 学术 › Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody.
Cell ( IF 45.5 ) Pub Date : 2020-01-30 , DOI: 10.1016/j.cell.2020.01.010
Philipp Schommers ₁ , Henning Gruell ₂ , Morgan E Abernathy ₃ , My-Kim Tran ₄ , Adam S Dingens ₅ , Harry B Gristick ₃ , Christopher O Barnes ₃ , Till Schoofs ₄ , Maike Schlotz ₄ , Kanika Vanshylla ₄ , Christoph Kreer ₄ , Daniela Weiland ₄ , Udo Holtick ₆ , Christof Scheid ₆ , Markus M Valter ₇ , Marit J van Gils ₈ , Rogier W Sanders ₉ , Jörg J Vehreschild ₁₀ , Oliver A Cornely ₁₁ , Clara Lehmann ₁₂ , Gerd Fätkenheuer ₁₃ , Michael S Seaman ₁₄ , Jesse D Bloom ₁₅ , Pamela J Bjorkman ₃ , Florian Klein ₁₆

Affiliation

Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
Department of Gynecology and Obstetrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Medical Department 2, University Hospital of Frankfurt, 60590 Frankfurt, Germany.
Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Clinical Trials Centre Cologne (ZKS Köln), University of Cologne, 50935 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Seattle, WA 98109, USA.
Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.

Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.

中文翻译：

高度广泛和有效的中和抗体对HIV-1逃逸的限制。

广泛中和抗体（bNAbs）是预防和治疗HIV-1感染的有前途的方法。但是，通过HIV-1包膜糖蛋白（Env）突变引起的病毒逃逸限制了临床应用。在这里，我们描述1-18，一个新的VH1-46-编码的CD4结合位点（CD4bs）bNAb，具有出色的广度（97％）和效价（GeoMean IC50 = 0.048μg/ mL）。值得注意的是，1-18对典型的CD4bs逃脱突变不敏感，可以有效克服HIV-1对其他CD4bs bNAbs的抵抗力。此外，突变的抗原分析揭示了HIV-1逃逸的受限途径。对于治疗用途最有希望的是，即使单独使用1-18，也可以完全抑制HIV-1感染的人源化小鼠的病毒血症，而无需选择耐药的病毒变体。1-18-BG505SOSIP的2.5Å低温EM结构。664 Env复合物表明，重链插入和protomer间接触增加可能促进了这些特征。1-18有效限制HIV-1逃逸途径的能力为成功预防和治疗HIV-1感染提供了新的选择。

更新日期：2020-01-31

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11