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

被引：51

作者：

Bonsignori, Mattia ^{[1
,2
]}

Scott, Eric ^{[1
]}

Wiehe, Kevin ^{[1
,2
]}

Easterhoff, David ^{[1
,2
]}

Alam, S. Munir ^{[1
,2
]}

Hwang, Kwan-Ki ^{[1
]}

Cooper, Melissa ^{[1
]}

Xia, Shi-Mao ^{[1
]}

Zhang, Ruijun ^{[1
,13
]}

Montefiori, David C. ^{[1
,3
]}

Henderson, Rory ^{[1
]}

Nie, Xiaoyan ^{[4
]}

Kelsoe, Garnett ^{[1
]}

Moody, M. Anthony ^{[1
,5
]}

Chen, Xuejun ^{[6
]}

Joyce, M. Gordon ^{[6
,14
,15
]}

Kwong, Peter D. ^{[6
]}

Connors, Mark ^{[7
]}

Mascola, John R. ^{[6
]}

McGuire, Andrew T. ^{[8
,9
]}

Stamatatos, Leonidas ^{[8
,9
]}

Medina-Ramirez, Max ^{[10
]}

Sanders, Rogier W. ^{[10
,11
]}

Saunders, Kevin O. ^{[1
,3
]}

Kepler, Thomas B. ^{[12
]}

Haynes, Barton F. ^{[1
,2
,4
]}

机构：

[1] Duke Univ, Duke Human Vaccine Inst, Durham, NC 27708 USA

[2] Duke Univ, Dept Med, Durham, NC 27708 USA

[3] Duke Univ, Dept Surg, Durham, NC USA

[4] Duke Univ, Dept Immunol, Durham, NC 27708 USA

[5] Duke Univ, Dept Pediat, Durham, NC 27706 USA

[6] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[7] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA

[8] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA

[9] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA

[10] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, Amsterdam, Netherlands

[11] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA

[12] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA

[13] Sanofi, Framingham, MA USA

[14] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA

[15] Henry M Jackson Fdn Adv Mil Med Inc, Bethesda, MD USA

来源：

IMMUNITY | 2018年 / 49卷 / 06期

基金：

美国国家卫生研究院; 比尔及梅琳达.盖茨基金会;

关键词：

BROADLY NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; MOLECULAR-DYNAMICS; SOMATIC HYPERMUTATION; MATURATION PATHWAY; IMMUNOGEN DESIGN; STRUCTURAL BASIS; CELL-LINES; B-CELLS; GERMLINE;

D O I：

10.1016/j.immuni.2018.10.015

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：1162 / +

页数：21

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