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Stabilization of HIV-1 Envelope in the CD4-bound Conformation through Specific Cross-linking of a CD4 Mimetic

CD4 binding on gp120 leads to the exposure of highly conserved regions recognized by the HIV co-receptor CCR5 and by CD4-induced (CD4i) antibodies. A covalent gp120-CD4 complex was shown to elicit CD4i antibody responses in monkeys, which was correlated with control of the HIV virus infection (DeVic...

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Published in:The Journal of biological chemistry 2011-06, Vol.286 (24), p.21706-21716
Main Authors: Martin, Grégoire, Burke, Brian, Thaï, Robert, Dey, Antu K., Combes, Olivier, Heyd, Bernadette, Geonnotti, Anthony R., Montefiori, David C., Kan, Elaine, Lian, Ying, Sun, Yide, Abache, Toufik, Ulmer, Jeffrey B., Madaoui, Hocine, Guérois, Raphaël, Barnett, Susan W., Srivastava, Indresh K., Kessler, Pascal, Martin, Loïc
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cited_by cdi_FETCH-LOGICAL-c476t-bcaf99b391f359ed7542c8e05899889b768020e332c736d2554f9bcf031257ce3
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container_issue 24
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container_title The Journal of biological chemistry
container_volume 286
creator Martin, Grégoire
Burke, Brian
Thaï, Robert
Dey, Antu K.
Combes, Olivier
Heyd, Bernadette
Geonnotti, Anthony R.
Montefiori, David C.
Kan, Elaine
Lian, Ying
Sun, Yide
Abache, Toufik
Ulmer, Jeffrey B.
Madaoui, Hocine
Guérois, Raphaël
Barnett, Susan W.
Srivastava, Indresh K.
Kessler, Pascal
Martin, Loïc
description CD4 binding on gp120 leads to the exposure of highly conserved regions recognized by the HIV co-receptor CCR5 and by CD4-induced (CD4i) antibodies. A covalent gp120-CD4 complex was shown to elicit CD4i antibody responses in monkeys, which was correlated with control of the HIV virus infection (DeVico, A., Fouts, T., Lewis, G. K., Gallo, R. C., Godfrey, K., Charurat, M., Harris, I., Galmin, L., and Pal, R. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 17477–17482). Because the inclusion of CD4 in a vaccine formulation should be avoided, due to potential autoimmune reactions, we engineered small sized CD4 mimetics (miniCD4s) that are poorly immunogenic and do not induce anti-CD4 antibodies. We made covalent complexes between such an engineered miniCD4 and gp120 or gp140, through a site-directed coupling reaction. These complexes were recognized by CD4i antibodies as well as by the HIV co-receptor CCR5. In addition, they elicit CD4i antibody responses in rabbits and therefore represent potential vaccine candidates that mimic an important HIV fusion intermediate, without autoimmune hazard.
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subjects Affinity Labeling
AIDS Vaccine
Analytical chemistry
Animals
Antigen Presentation
Biochemistry, Molecular Biology
Biotechnology
CD4-Positive T-Lymphocytes - virology
Chemical Modification
Chemical Sciences
CHO Cells
Cricetinae
Cricetulus
Cross-Linking Reagents - chemistry
Cysteine - chemistry
Cysteine-mediated Cross-linking
Disulfides
HIV
HIV Envelope Protein gp120 - chemistry
HIV-1 - chemistry
Human health and pathology
Immunology
Infectious diseases
Life Sciences
Medication
Molecular Mimicry
Pharmaceutical sciences
Protein Binding
Protein Conformation
Protein Cross-linking
Receptors, CCR5 - chemistry
Structural Biology
Vaccinology
Viral Envelope Proteins - chemistry
title Stabilization of HIV-1 Envelope in the CD4-bound Conformation through Specific Cross-linking of a CD4 Mimetic
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