Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region
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AbstractAntibodies 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. Copyright 2017 Elsevier Ltd
SponsorsThis work was supported by NIH grants: NIAID R01 AI116274 to M.P., R01AI129769 to M.P. and A.F., NIGMS R01 GM117836 to K.R., NIAID P01 AI120756 , and the Bill and Melinda Gates Foundation : OPP1033109 to G.K.L. This work was partially supported also by a CIHR foundation grant 352417 to A.F. who is supported by the Canada Research Chairs program .
Keywordantibody-dependent cellular cytotoxicity (ADCC)
C11 epitope region
cluster A epitopes
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85031804948&doi=10.1016%2fj.str.2017.09.009&partnerID=40&md5=15a525461688a21e2095988403823741; http://hdl.handle.net/10713/10001