During natural infection by HIV-1, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves extensive neutralization of diverse viral strains. To understand the structural basis for its neutralization breadth and potency, we determined the crystal structure of VRC01 in complex with an HIV-1 gp120 core. The heavy chain of VRC01 interacts with gp120 in a manner similar to CD4. A 43° rotation coupled with a 6-Å shift from the CD4-defined orientation focuses VRC01 onto the conformationally invariant site of initial CD4 attachment, allowing it to overcome the masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this mode of recognition, VRC01 contacts gp120 mainly through V-gene-derived regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate effective neutralization of HIV-1 by natural human antibodies.

Anti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest in other protective mechanisms involving antibodies, such as antibody-dependent cellmediated cytotoxicity (ADCC). Env epitopes targeted by many antibodies effective at mediating ADCC are poorly exposed on the unliganded Env trimer. Here we investigated the mechanism of exposure of ADCC epitopes on Env and showed that binding of Env and CD4 within the same HIV-1-infected cell effectively exposes these epitopes. Env capacity to transit to the CD4-bound conformation is required for ADCC epitope exposure. Importantly, cell surface CD4 downregulation by Nef and Vpu accessory proteins and Vpu-mediated BST-2 antagonism modulate exposure of ADCC-mediating epitopes and reduce the susceptibility of infected cells to this effector function in vitro. Significantly, Env conformational changes induced by cell surface CD4 are conserved among Env from HIV-1 and HIV-2/SIVmac lineages. Altogether, our observations describe a highly conserved mechanism required to expose ADCC epitopes that might help explain the evolutionary advantage of downregulation of cell surface CD4 by the HIV-1 Vpu and Nef proteins. IMPORTANCEHIV-1 envelope epitopes targeted by many antibodies effective at mediating antibody-dependent cell-mediated cytotoxicity (ADCC) are poorly exposed on the unliganded envelope trimer. Here we investigated the mechanism of exposure of these epitopes and found that envelope interaction with the HIV-1 CD4 receptor is required to expose some of these epitopes. Moreover, our results suggest that HIV-1 CD4 downregulation might help avoid the killing of HIV-1-infected cells by this immune mechanism.