Co-receptor Binding Site Antibodies Enable CD4-Mimetics to Expose Conserved Anti-cluster A ADCC Epitopes on HIV-1 Envelope Glycoproteins

• Published in: EBioMedicine 2016-10, Vol.12 (C), p.208-218
• Main Authors: Richard, Jonathan, Pacheco, Beatriz, Gohain, Neelakshi, Veillette, Maxime, Ding, Shilei, Alsahafi, Nirmin, Tolbert, William D., Prévost, Jérémie, Chapleau, Jean-Philippe, Coutu, Mathieu, Jia, Manxue, Brassard, Nathalie, Park, Jongwoo, Courter, Joel R., Melillo, Bruno, Martin, Loïc, Tremblay, Cécile, Hahn, Beatrice H., Kaufmann, Daniel E., Wu, Xueling, Smith, Amos B., Sodroski, Joseph, Pazgier, Marzena, Finzi, Andrés
• Format: Article
• Language: English
• Subjects: ADCC; Amino Acid Sequence; Antibody-Dependent Cell Cytotoxicity - immunology; Binding Sites; Biochemistry; Biochemistry, Molecular Biology; Biological Mimicry; CD4; CD4 Antigens - chemistry; CD4 Antigens - metabolism; CD4-mimetics; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell Line; Chemical Sciences; Conserved Sequence; Envelope glycoproteins; Epitopes - chemistry; Epitopes - immunology; HIV Antibodies - immunology; HIV Antibodies - metabolism; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - immunology; HIV Envelope Protein gp120 - metabolism; HIV Infections - immunology; HIV Infections - metabolism; HIV Infections - virology; HIV-1; HIV-1 - immunology; Humans; Immunology; Immunotherapy; Life Sciences; Medicinal Chemistry; Non-neutralizing antibodies; Protein Binding - immunology; Receptors, HIV - chemistry; Receptors, HIV - metabolism; Research Paper; Vaccinology
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.09.004

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. •CD4-mimetics fail to enhance recognition of infected cells by anti-cluster A antibodies (Abs).•Co-receptor binding site Abs in conjunction with CD4-mimetics allow binding of Env by anti-cluster A Abs.•Co-receptor binding site Abs help CD4-mimetics sensitize HIV-1-infected cells to ADCC. HIV-1 developed sophisticated strategies to conceal vulnerable epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. CD4-mimetics (CD4mc) were shown to sensitize HIV-1-infected cells to ADCC induced by HIV+ sera. Here we show that this response requires a sequential opening of Env at the surface of HIV-1-infected cells. Co-receptor binding site antibodies, also present in HIV+ sera, are required to expose ADCC-mediating ep