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

William D. Tolbert, Neelakshi Gohain, Nirmin Alsahafi, Verna Van, Chiara Orlandi, Shilei Ding, Loïc Martin, Andrés Finzi, George K. Lewis, Krishanu Ray, Marzena Pazgier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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. 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.

Original languageEnglish
Pages (from-to)1719-1731.e4
JournalStructure
Volume25
Issue number11
DOIs
StatePublished - 7 Nov 2017
Externally publishedYes

Keywords

  • C11 epitope region
  • C11-like antibody
  • HIV-1 entry
  • N12-i3 antibody
  • antibody-dependent cellular cytotoxicity (ADCC)
  • cluster A epitopes
  • crystal structure

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