Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region

Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 Å resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal “eighth strand” of a critical β sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment. In prior entry states, this sandwich comprises only seven strands, with the eighth strand instead pairing with a portion of the gp120 C terminus. The conformational gymnastics of HIV-1 gp120 thus includes altered β-strand pairing, possibly to reduce immunogenicity, although nevertheless still recognized by the human immune system. [Display omitted] •The C11-like ADCC epitope footprint is defined at the molecular level•The C11 subregion maps to a newly formed gp120 8-stranded β sandwich•The C11 and A32 epitope subregions are adjacent and non-overlapping•The C11 epitope is formed upon release of the gp120 N terminus from the Env trimer Tolbert at al. describe a crystal structure of Fabs of A32- and C11-like antibody bound to a single gp120 subunit. The C11-like antibody, N12-i3, recognizes a new eight-stranded β sandwich structure of gp120 that is formed at the late stage of HIV-1 entry.