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

• Published in: Structure (London) Vol. 25; no. 11; pp. 1719 - 1731.e4
• Main Authors: Tolbert, William D., Gohain, Neelakshi, Alsahafi, Nirmin, Van, Verna, Orlandi, Chiara, Ding, Shilei, Martin, Loïc, Finzi, Andrés, Lewis, George K., Ray, Krishanu, Pazgier, Marzena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 07.11.2017; Elsevier (Cell Press); Elsevier
• Subjects: Amino Acid Sequence; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Viral - chemistry; Antibodies, Viral - immunology; Antibodies, Viral - pharmacology; Antibody-Dependent Cell Cytotoxicity; antibody-dependent cellular cytotoxicity (ADCC); Binding Sites; Biochemistry; Biochemistry, Molecular Biology; C11 epitope region; C11-like antibody; CD4 Antigens - chemistry; CD4 Antigens - immunology; Cell Line; Chemical Sciences; cluster A epitopes; Cristallography; crystal structure; Crystallography, X-Ray; Epitopes - chemistry; Epitopes - immunology; HIV Antibodies - chemistry; HIV Antibodies - immunology; HIV Antibodies - pharmacology; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - immunology; HIV-1 - genetics; HIV-1 - immunology; HIV-1 entry; Humans; Immunity, Innate; Immunology; Immunotherapy; Life Sciences; Medicinal Chemistry; Microbiology and Parasitology; Models, Molecular; Molecular Mimicry; N12-i3 antibody; Peptides - chemical synthesis; Peptides - immunology; Protein Binding; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Sequence Alignment; Sequence Homology, Amino Acid; Structural Biology; T-Lymphocytes - immunology; T-Lymphocytes - virology; Virology; Virus Internalization - drug effects; cluster A epitopes; antibody-dependent cellular cytotoxicity (ADCC); C11-like antibody; crystal structure; C11 epitope region; HIV-1 entry; N12-i3 antibody
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2017.09.009

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.