Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier.,Immunity

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Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier.
Immunity ( IF 25.5 ) Pub Date : 2018-12-11 , DOI: 10.1016/j.immuni.2018.10.015
Mattia Bonsignori ₁ , Eric Scott ₂ , Kevin Wiehe ₁ , David Easterhoff ₁ , S Munir Alam ₁ , Kwan-Ki Hwang ₂ , Melissa Cooper ₂ , Shi-Mao Xia ₂ , Ruijun Zhang ₂ , David C Montefiori ₃ , Rory Henderson ₂ , Xiaoyan Nie ₄ , Garnett Kelsoe ₅ , M Anthony Moody ₆ , Xuejun Chen ₇ , M Gordon Joyce ₇ , Peter D Kwong ₇ , Mark Connors ₈ , John R Mascola ₇ , Andrew T McGuire ₉ , Leonidas Stamatatos ₉ , Max Medina-Ramírez ₁₀ , Rogier W Sanders ₁₁ , Kevin O Saunders ₃ , Thomas B Kepler ₁₂ , Barton F Haynes ₁₃

Affiliation

Duke Human Vaccine Institute, Duke University, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA.
Duke Human Vaccine Institute, Duke University, Durham, NC, USA.
Duke Human Vaccine Institute, Duke University, Durham, NC, USA; Department of Surgery, Duke University, Durham, NC, USA.
Department of Immunology, Duke University, Durham, NC, USA.
Duke Human Vaccine Institute, Duke University, Durham, NC, USA; Department of Immunology, Duke University, Durham, NC, USA.
Duke Human Vaccine Institute, Duke University, Durham, NC, USA; Department of Pediatrics, Duke University, Durham, NC, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA.
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA.
Department of Microbiology, Boston University School of Medicine, Boston, MA, USA.
Duke Human Vaccine Institute, Duke University, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA; Department of Immunology, Duke University, Durham, NC, USA.

Elicitation of VRC01-class broadly neutralizing antibodies (bnAbs) is an appealing approach for a preventative HIV-1 vaccine. Despite extensive investigations, strategies to induce VRC01-class bnAbs and overcome the barrier posed by the envelope N276 glycan have not been successful. Here, we inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation. Env immunogens designed on reverted VRC01-class bnAbs bound to VRC01 UCA with affinity sufficient to activate naive B cells. Early mutations defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B cell maturation toward the development of neutralization breadth. Finally, VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan.

中文翻译：

HIV-1 VRC01 抗体谱系未突变共同祖先的推断揭示了克服关键聚糖屏障的替代途径。

诱导 VRC01 类广泛中和抗体 (bnAbs) 是预防性 HIV-1 疫苗的一种有吸引力的方法。尽管进行了广泛的研究，但诱导 VRC01 类 bnAbs 并克服由包膜 N276 聚糖构成的屏障的策略尚未成功。在这里，我们推断了 VRC01 谱系的高概率未突变共同祖先 (UCA)，并重建了谱系成熟的阶段。在还原的 VRC01 类 bnAb 上设计的 Env 免疫原与 VRC01 UCA 结合，具有足以激活幼稚 B 细胞的亲和力。早期突变定义了朝向有限或广泛中和的成熟途径，这表明可能需要集中免疫反应来引导 B 细胞成熟朝向中和宽度的发展。最后，

更新日期：2018-12-11

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