The role of antibody polyspecificity and lipid reactivity in binding of broadly neutralizing anti-HIV-1 envelope human monoclonal antibodies 2F5 and 4E10 to glycoprotein 41 membrane proximal envelope epitopes

Two neutralizing human mAbs, 2F5 and 4E10, that react with the HIV-1 envelope gp41 membrane proximal region are also polyspecific autoantibodies that bind to anionic phospholipids. To determine the autoantibody nature of these Abs, we have compared their reactivities with human anti-cardiolipin mAbs...

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Published in:Journal of Immunology Vol. 178; no. 7; pp. 4424 - 4435
Main Authors: Alam, S Munir, McAdams, Mildred, Boren, David, Rak, Michael, Scearce, Richard M, Gao, Feng, Camacho, Zenaido T, Gewirth, Daniel, Kelsoe, Garnett, Chen, Pojen, Haynes, Barton F
Format: Journal Article
Language:English
Published: England 01.04.2007
Subjects:
Amino Acid Sequence
Animals
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - immunology
Antibody Specificity
Antiphospholipid Syndrome - immunology
Autoantibodies - immunology
Cardiolipins - immunology
HIV Antibodies - immunology
HIV Envelope Protein gp41 - immunology
HIV-1 - immunology
Human immunodeficiency virus 1
Humans
Lipids - immunology
Liposomes - chemistry
Mice
Molecular Sequence Data
ISSN:0022-1767, 1365-2567
Online Access:Get full text
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Summary:Two neutralizing human mAbs, 2F5 and 4E10, that react with the HIV-1 envelope gp41 membrane proximal region are also polyspecific autoantibodies that bind to anionic phospholipids. To determine the autoantibody nature of these Abs, we have compared their reactivities with human anti-cardiolipin mAbs derived from a primary antiphospholipid syndrome patient. To define the role of lipid polyreactivity in binding of 2F5 and 4E10 mAbs to HIV-1 envelope membrane proximal epitopes, we determined the kinetics of binding of mAbs 2F5 and 4E10 to their nominal gp41 epitopes vs liposome-gp41 peptide conjugates. Both anti-HIV-1 mAbs 2F5 and 4E10 bound to cardiolipin with K(d) values similar to those of autoimmune anti-cardiolipin Abs, IS4 and IS6. Binding kinetics studies revealed that mAb 2F5 and 4E10 binding to their respective gp41 peptide-lipid conjugates could best be defined by a two-step (encounter-docking) conformational change model. In contrast, binding of 2F5 and 4E10 mAbs to linear peptide epitopes followed a simple Langmuir model. A mouse mAb, 13H11, that cross-blocks mAb 2F5 binding to the gp41 epitope did not cross-react with lipids nor did it neutralize HIV-1 viruses. Taken together, these data demonstrate the similarity of 2F5 and 4E10 mAbs to known anti-cardiolipin Abs and support the model that mAb 2F5 and 4E10 binding to HIV-1 involves both viral lipid membrane and gp41 membrane proximal epitopes.
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ISSN:0022-1767
1365-2567
DOI:10.4049/jimmunol.178.7.4424