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 epitopes recognized by anti-cluster A antibodies upon CD4mc addition. The understanding of the conformational changes required to expose anti-cluster A epitopes might be important in the design of new strategies aimed at fighting HIV-1.