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...
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Published in | Structure (London) Vol. 25; no. 11; pp. 1719 - 1731.e4 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Ltd
07.11.2017
Elsevier (Cell Press) Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC5677539 USDOE Office of Science (SC), Biological and Environmental Research (BER) Lead contact |
ISSN: | 0969-2126 1878-4186 |
DOI: | 10.1016/j.str.2017.09.009 |