Richard, JonathanPacheco, BeatrizGohain, NeelakshiVeillette, MaximeDing, ShileiAlsahafi, NirminTolbert, William D.Prévost, JérémieChapleau, Jean-PhilippeCoutu, MathieuJia, ManxueBrassard, NathaliePark, JongwooCourter, Joel R.Melillo, BrunoMartin, LoïcTremblay, CécileHahn, Beatrice H.Kaufmann, Daniel E.Wu, XuelingSmith, Amos B.Sodroski, JosephPazgier, MarzenaFinzi, Andrés2016-12-022016Richard, J., B. Pacheco, N. Gohain, M. Veillette, S. Ding, N. Alsahafi, W. D. Tolbert, et al. 2016. “Co-receptor Binding Site Antibodies Enable CD4-Mimetics to Expose Conserved Anti-cluster A ADCC Epitopes on HIV-1 Envelope Glycoproteins.” EBioMedicine 12 (1): 208-218. doi:10.1016/j.ebiom.2016.09.004. http://dx.doi.org/10.1016/j.ebiom.2016.09.004.2352-3964http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626217Human 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.en-USHIV-1Envelope glycoproteinsCD4Non-neutralizing antibodiesADCCCD4-mimeticsJournal Article2016-12-0210.1016/j.ebiom.2016.09.004