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    Focused evolution of HIV-1 neutralizing antibodies revealed by crystal structures and deep sequencing
    1.
    发明授权
    Focused evolution of HIV-1 neutralizing antibodies revealed by crystal structures and deep sequencing 有权

    公开(公告)号：US10273291B2

    公开(公告)日：2019-04-30

    申请号：US14116710

    申请日：2012-03-23

    申请人： John R. Mascola ,  Gary Nabel ,  Barton F. Haynes ,  Xueling Wu ,  Thomas B. Kepler ,  Peter Kwong

    发明人： John R. Mascola ,  Gary Nabel ,  Barton F. Haynes ,  Xueling Wu ,  Thomas B. Kepler ,  Peter Kwong

    IPC分类号： C07K16/10 ,  A61K39/42 ,  G01N33/569

    摘要： Antibody VRC01 represents a human immunoglobulin that neutralizes—˜90% of diverse HIV-1 isolates. To understand how such broadly neutralizing HIV-1 antibodies develop and recognize the viral envelope, we used X-ray crystallography and 454 pyrosequencing to characterize additional antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding of different antibodies to the same CD4-binding-site epitope. Antibody recognition was achieved through the evolution of complementary contact domains that were generated in diverse ways. Phylogenetic analysis of expressed heavy and light chains determined by deep sequencing revealed a common pathway of antibody heavy chain maturation confined to IGHV1-2*02 lineage that could pair with different light chains. The maturation pathway inferred by antibodyomics reveals that diverse antibodies evolve to a highly affinity-matured state to recognize an invariant viral structure, providing insight into the development and evolution of broadly neutralizing HIV-1 immunity.

    FOCUSED EVOLUTION OF HIV-1 NEUTRALIZING ANTIBODIES REVEALED BY CRYSTAL STRUCTURES AND DEEP SEQUENCING
    2.
    发明申请
    FOCUSED EVOLUTION OF HIV-1 NEUTRALIZING ANTIBODIES REVEALED BY CRYSTAL STRUCTURES AND DEEP SEQUENCING 审中-公开
    HIV-1中和化学反应的结晶和深度排列反应的聚焦演变

    公开(公告)号：US20140205607A1

    公开(公告)日：2014-07-24

    申请号：US14116710

    申请日：2012-03-23

    申请人： John R. Mascola ,  Gary Nabel ,  Barton F. Haynes ,  Xueling Wu ,  Thomas B. Kepler ,  Peter Kwong

    发明人： John R. Mascola ,  Gary Nabel ,  Barton F. Haynes ,  Xueling Wu ,  Thomas B. Kepler ,  Peter Kwong

    IPC分类号： C07K16/10 ,  G01N33/569

    CPC分类号： C07K16/1063 ,  A61K39/42 ,  C07K2317/21 ,  C07K2317/565 ,  C07K2317/76 ,  G01N33/56988

    摘要： Antibody VRC01 represents a human immunoglobulin that neutralizes—˜90% of diverse HIV-1 isolates. To understand how such broadly neutralizing HIV-1 antibodies develop and recognize the viral envelope, we used X-ray crystallography and 454 pyrosequencing to characterize additional antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding of different antibodies to the same CD4-binding-site epitope. Antibody recognition was achieved through the evolution of complementary contact domains that were generated in diverse ways. Phylogenetic analysis of expressed heavy and light chains determined by deep sequencing revealed a common pathway of antibody heavy chain maturation confined to IGHV1-2*02 lineage that could pair with different light chains. The maturation pathway inferred by antibodyomics reveals that diverse antibodies evolve to a highly affinity-matured state to recognize an invariant viral structure, providing insight into the development and evolution of broadly neutralizing HIV-1 immunity.

    摘要翻译： 抗体VRC01代表一种人类免疫球蛋白，可中和〜90％的不同HIV-1分离株。 为了了解这种广泛中和的HIV-1抗体如何发展和识别病毒包膜，我们使用X射线晶体学和454焦磷酸测序来鉴定HIV-1感染个体的其他抗体。 晶体结构揭示了不同抗体与相同CD4结合位点表位结合的收敛模式。 通过以不同方式产生的互补接触域的发展，实现了抗体识别。 通过深度测序确定的表达重链和轻链的系统发育分析揭示了限制在可与不同轻链配对的IGHV1-2 * 02谱系的抗体重链成熟的共同途径。 通过抗体学推断的成熟途径揭示了多种抗体进化到高度亲和力成熟的状态，以识别不变的病毒结构，提供对广泛中和HIV-1免疫的发展和进化的洞察。