Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan.,Immunity

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Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan.
Immunity ( IF 25.5 ) Pub Date : 2019-07-16 , DOI: 10.1016/j.immuni.2019.06.004
Jeffrey Umotoy ₁ , Bernard S Bagaya ₂ , Collin Joyce ₃ , Torben Schiffner ₄ , Sergey Menis ₁ , Karen L Saye-Francisco ₃ , Trevor Biddle ₃ , Sanjay Mohan ₅ , Thomas Vollbrecht ₅ , Oleksander Kalyuzhniy ₁ , Sharon Madzorera ₆ , Dale Kitchin ₆ , Bronwen Lambson ₆ , Molati Nonyane ₆ , William Kilembe ₇ , , , Pascal Poignard ₈ , William R Schief ₉ , Dennis R Burton ₁₀ , Ben Murrell ₁₁ , Penny L Moore ₁₂ , Bryan Briney ₄ , Devin Sok ₁₃ , Elise Landais ₁₄

Affiliation

International AIDS Vaccine Initiative Neutralizing Antibody Center, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA.
UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda; Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala-Uganda.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Medicine, University of California San Diego, San Diego, CA 92103, USA.
Centre for HIV and STIs, National Institute for Communicable Diseases, of the National Health Laboratory Service (NHLS), Johannesburg 2131, South Africa.
Rwanda-Zambia HIV Research Group, Lusaka & Ndola, Zambia.
International AIDS Vaccine Initiative Neutralizing Antibody Center, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Institut de Biologie Structurale, Université Grenoble Alpes, Commissariat a l'Energie Atomique, Centre National de Recherche Scientifique and Centre Hospitalier Universitaire Grenoble Alpes, 38044 Grenoble, France.
International AIDS Vaccine Initiative Neutralizing Antibody Center, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) The Scripps Research Institute, La Jolla, CA 92037, USA.
International AIDS Vaccine Initiative Neutralizing Antibody Center, La Jolla, CA 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02114, USA.
Department of Medicine, University of California San Diego, San Diego, CA 92103, USA; Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
Centre for HIV and STIs, National Institute for Communicable Diseases, of the National Health Laboratory Service (NHLS), Johannesburg 2131, South Africa; School of Pathology Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of Kwa-Zulu Natal, Durban 4013, South Africa.
International AIDS Vaccine Initiative Neutralizing Antibody Center, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) The Scripps Research Institute, La Jolla, CA 92037, USA.
International AIDS Vaccine Initiative Neutralizing Antibody Center, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, New York, NY 10004, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.

The VH1-2 restricted VRC01-class of antibodies targeting the HIV envelope CD4 binding site are a major focus of HIV vaccine strategies. However, a detailed analysis of VRC01-class antibody development has been limited by the rare nature of these responses during natural infection and the lack of longitudinal sampling of such responses. To inform vaccine strategies, we mapped the development of a VRC01-class antibody lineage (PCIN63) in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies had the hallmark VRC01-class features and demonstrated neutralization breadth similar to the prototype VRC01 antibody, but were 2- to 3-fold less mutated. Maturation occurred rapidly within ∼24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.

中文翻译：

VRC01 类 HIV 广泛中和抗体谱系的快速集中成熟涉及 N276-聚糖的结合和调节。

针对 HIV 包膜 CD4 结合位点的 VH1-2 限制性 VRC01 类抗体是 HIV 疫苗策略的主要焦点。然而，由于自然感染期间这些反应的罕见性质以及缺乏对此类反应的纵向采样，对 VRC01 类抗体发展的详细分析受到限制。为了为疫苗策略提供信息，我们绘制了 C 亚型感染的 IAVI Protocol C 中和剂 PC063 中 VRC01 类抗体谱系 (PCIN63) 的发展情况。 PCIN63 单克隆抗体具有 VRC01 类标志性特征，并表现出与原型 VRC01 抗体相似的中和广度，但突变程度低 2 至 3 倍。谱系出现后约 24 个月内迅速成熟，并且在关键接触残基处积累了体细胞超突变。这项广泛中和 VRC01 类抗体谱系的纵向研究揭示了在亲和力成熟过程中与 N276 聚糖的早期结合，这可能对疫苗设计有影响。

更新日期：2019-07-17

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