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Article Dans Une Revue EBioMedicine Année : 2016

Co-receptor binding site antibodies enable CD4-mimetics to expose conserved anti-cluster A ADCC epitopes on HIV-1 envelope glycoproteins

Beatrice H. Hahn
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Résumé

Human immunodeficiency virus type 1 (HIV-1) has evolved a sophisticated strategy to conceal conserved epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies, which are present in the sera of most HIV-1-infected individuals, preferentially recognize Env in its CD4-bound conformation. Accordingly, recent studies showed that small CD4-mimetics (CD4mc) able to “push” Env into this conformation sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. Here we test whether CD4mc also expose epitopes recognized by anti-cluster A monoclonal antibodies such as A32, thought to be responsible for the majority of ADCC activity present in HIV+ sera and linked to decreased HIV-1 transmission in the RV144 trial. We made the surprising observation that CD4mc are unable to enhance recognition of HIV-1-infected cells by this family of antibodies in the absence of antibodies such as 17b, which binds a highly conserved CD4-induced epitope overlapping the co-receptor binding site (CoRBS). Our results indicate that CD4mc initially open the trimeric Env enough to allow the binding of CoRBS antibodies but not anti-cluster A antibodies. CoRBS antibody binding further opens the trimeric Env, allowing anti-cluster A antibody interaction and sensitization of infected cells to ADCC. Therefore, ADCC responses mediated by cluster A antibodies in HIV-positive sera involve a sequential opening of the Env trimer on the surface of HIV-1-infected cells. The understanding of the conformational changes required to expose these vulnerable Env epitopes might be important in the design of new strategies aimed at fighting HIV-1
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Dates et versions

hal-02530909 , version 1 (14-12-2023)

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Paternité - Pas de modifications

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Jonathan Richard, Beatriz Pacheco, Neelakshi Gohain, Maxime Veillette, Shilei Ding, et al.. Co-receptor binding site antibodies enable CD4-mimetics to expose conserved anti-cluster A ADCC epitopes on HIV-1 envelope glycoproteins. EBioMedicine, 2016, 12, pp.208-218. ⟨10.1016/j.ebiom.2016.09.004⟩. ⟨hal-02530909⟩
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