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 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.
Alam
S Munir
SM
Department of Medicine, Duke Human Vaccine Institute, Duke University School of Medicine, RP1 Circuit Drive, Durham, NC 27710, USA. alam0004@mc.duke.edu
McAdams
Mildred
M
Boren
David
D
Rak
Michael
M
Scearce
Richard M
RM
Gao
Feng
F
Camacho
Zenaido T
ZT
Gewirth
Daniel
D
Kelsoe
Garnett
G
Chen
Pojen
P
Haynes
Barton F
BF
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D000918:Antibody Specificity; D016736:Antiphospholipid Syndrome / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D002308:Cardiolipins / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008055:Lipids / Q000276:immunology; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D002308:Cardiolipins; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D008055:Lipids; D008081:Liposomes