Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation

被引：343

作者：

Mouquet, Hugo ^{[1
]}

Scheid, Johannes F. ^{[1
,2
]}

Zoller, Markus J. ^{[3
]}

Krogsgaard, Michelle ^{[4
,5
]}

Ott, Rene G. ^{[6
]}

Shukair, Shetha ^{[7
]}

Artyomov, Maxim N. ^{[8
,9
,10
,11
,12
]}

Pietzsch, John ^{[1
,13
]}

Connors, Mark ^{[14
,15
]}

Pereyra, Florencia ^{[16
,17
]}

Walker, Bruce D. ^{[16
,17
]}

Ho, David D. ^{[18
]}

Wilson, Patrick C. ^{[19
]}

Seaman, Michael S. ^{[20
]}

Eisen, Herman N. ^{[8
,9
,10
,11
,12
]}

Chakraborty, Arup K. ^{[8
,9
,10
,11
,12
]}

Hope, Thomas J. ^{[7
]}

Ravetch, Jeffrey V. ^{[6
]}

Wardemann, Hedda ^{[3
]}

Nussenzweig, Michel C. ^{[1
,21
]}

机构：

[1] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA

[2] Charite, D-10117 Berlin, Germany

[3] Max Planck Inst Infect Biol, D-10117 Berlin, Germany

[4] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[5] NYU, Sch Med, Inst Canc, New York, NY 10016 USA

[6] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10065 USA

[7] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA

[8] MIT, Dept Chem, Cambridge, MA 02139 USA

[9] MIT, Dept Chem Engn, Cambridge, MA 02139 USA

[10] MIT, Dept Biol, Cambridge, MA 02139 USA

[11] MIT, Dept Biol Engn, Cambridge, MA 02139 USA

[12] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[13] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany

[14] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA

[15] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA

[16] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA

[17] Harvard Univ, Sch Med, Boston, MA 02114 USA

[18] Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA

[19] Univ Chicago, Dept Med, Rheumatol Sect, Chicago, IL 60637 USA

[20] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[21] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA

来源：

NATURE | 2010年 / 467卷 / 7315期

基金：

美国国家卫生研究院;

关键词：

HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; MEMORY B-CELLS; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; TYPE-1; AUTOREACTIVITY; INDIVIDUALS; MODULATION; GENERATION;

D O I：

10.1038/nature09385

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding(1-3). Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development(4), it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients(5) with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV.

引用

页码：591 / U117

页数：6

共 31 条

[1] Molecular structure of eight human autoreactive monoclonal antibodies [J].