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HIV-1 conceals epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies (Abs), including anti-co-receptor binding site (CoRBS) and anti-cluster A, preferentially recognize Env in its “open” conformation. The binding of anti-CoRBS Abs has been shown to induce conformational changes that further opens Env allowing interaction of anti-cluster A antibodies. We explored the possibility that CoRBS Abs synergize with anti-cluster A Abs to engage Fc-gamma receptors to mediate ADCC. We found that binding of anti-CoRBS and anti-cluster A Abs to the same gp120 is required for interaction with soluble dimeric FcgammaRIIIa in ELISA assays. We also show that Fc regions of both Abs are required to optimally engage FcgammaRIIIa and mediate robust ADCC. Altogether, our results indicate that these two families of Abs act together in a sequential and synergistic fashion to promote FcgammaRIIIa engagement and ADCC.IMPORTANCE The “open” CD4-bound conformation of HIV-1 envelope glycoproteins is the primary target of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies present in HIV+ sera, such as anti-co-receptor binding site and anti-cluster A antibodies. Here we report that the binding of these two families of antibodies is required to engage FcgammaRIIIa and mediate ADCC.