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* Department of Medicine, Duke University School of Medicine, Durham, NC 27710; and
Department of Medicine, University of California, Los Angeles, CA 90095
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 Kd 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health Center for HIV/AIDS Vaccine Immunology Grant, AI0678501, by National Institute of Allergy and Infectious Diseases P01 AI52816, AI51445, and a Collaboration for AIDS Vaccine Discovery grant from the Bill and Melinda Gates Foundation.
2 Address correspondence and reprint requests to Dr. Barton F. Haynes, Duke Human Vaccine Institute, Box 3258, Duke University, RP1 Circuit Drive, Room 107, Durham, NC 27710; E-mail address: hayne002{at}mc.duke.edu or Dr. S. Munir Alam, Duke Human Vaccine Institute, Box 3258, Duke University, RP1 Circuit Drive, Room 107, Durham, NC 27710; E-mail address: alam0004{at}mc.duke.edu
3 Current address: Hauptman-Woodward Medical Research Institute, Buffalo, NY 14203.
4 Abbreviations used in this paper: MPER, membrane proximal external region; Env, envelope; APS, antiphospholipid syndrome; SPR, surface plasmon resonance; RU, response unit; SA, streptavidin; HR, heptad repeat.
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