Targeting the late stage of HIV-1 entry for antibody-dependent cellular cytotoxicity: structural basis for Env epitopes in the C11 region

William Tolbert (1, 2) , Neelakshi Gohain (1, 2) , Nirmin Alsahafi (3, 4) , Verna Van (1, 2) , Chiara Orlandi (1) , Shilei Ding (3) , Loïc M Martin (5, 6) , Andrés Finzi (3) , George Lewis (1) , Krishanu Ray (2) , Marzena Pazgier (3, 2)

1 IHV - Institute of Human Virology
2 University of Maryland School of Medicine
3 CHUM - Centre Hospitalier de l'Université de Montréal
4 Service d’Ingénierie Moléculaire des Protéines
5 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
6 MTS - Médicaments et Technologies pour la Santé

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.

Domaines: Chimie thérapeutique; Cristallographie; Biochimie [q-bio.BM]; Biologie structurale [q-bio.BM]; Immunothérapie; Virologie

William Tolbert, Neelakshi Gohain, Nirmin Alsahafi, Verna Van, Chiara Orlandi, et al.. Targeting the late stage of HIV-1 entry for antibody-dependent cellular cytotoxicity: structural basis for Env epitopes in the C11 region. Structure, 2017, 25 (11), pp.1719-1731.e4. ⟨10.1016/j.str.2017.09.009⟩. ⟨hal-02531052⟩