Nef and Vpu protect infected cells from ADCP mediated by plasma from people with HIV-1

The HIV-1 envelope glycoprotein (Env) represents the only viral antigen at the surface of infected cells, making it an ideal target for antibody-based therapies. Most antibodies elicited in people with HIV (PWH) do not recognize Env in its native “closed” conformation but readily bind to Env when it samples the CD4-bound “open” conformation. Downregulation of CD4 at the surface of infected cells by the viral accessory proteins Nef and Vpu prevents the premature opening of Env and has been shown to protect infected cells from antibody-dependent cellular cytotoxicity (ADCC) mediated by PWH plasma. Here, we report that deletion of Nef and Vpu from primary infectious molecular clones renders infected cells vulnerable to antibody-dependent cellular phagocytosis (ADCP) mediated by PWH plasma. This is in part linked to the premature engagement of Env with CD4. In agreement with an “open” Env being vulnerable to ADCP, small CD4-mimetic compounds (CD4mc) sensitize in vitro-infected cells and ex vivo-expanded CD4 T cells to ADCP mediated by autologous monocytes in the presence of PWH plasma. This effect was further improved by increasing cell surface Env through IFN-induced BST-2 upregulation.