Journal
EBIOMEDICINE
Volume 12, Issue -, Pages 208-218Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2016.09.004
Keywords
HIV-1; Envelope glycoproteins; CD4; Non-neutralizing antibodies; ADCC; CD4-mimetics
Funding
- Canada Foundation for Innovation Program Leader grant [29866]
- CIHR foundation [352417]
- amfAR Innovation Grant [109343-59-RGRL]
- FRQS AIDS and Infectious Diseases Network
- Canada Research Chair on Retroviral Entry
- CIHR Doctoral Research Award [291485]
- CIHR Fellowship Award [135349]
- King Abdullah scholarship for higher education from the Saudi Government
- Research Scholar Career Award of the Quebec Health Research Fund (FRQS)
- CIHR [MOP93770]
- NIH [AI100645, AI100663]
- Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID)
- National Institutes of Health [GM56550]
- late William F. McCarty-Cooper [NIH R01AI116274]
- Bill and Melinda Gates Foundation [OPP1033109]
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Human immunodeficiency virus type 1 (HIV-1) has evolved a sophisticated strategy to conceal conserved epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies, which are present in the sera of most HIV-1-infected individuals, preferentially recognize Env in its CD4-bound conformation. Accordingly, recent studies showed that small CD4-mimetics (CD4mc) able to push Env into this conformation sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. Here we test whether CD4mc also expose epitopes recognized by anti-cluster A monoclonal antibodies such as A32, thought to be responsible for the majority of ADCC activity present in HIV+ sera and linked to decreased HIV-1 transmission in the RV144 trial. We made the surprising observation that CD4mc are unable to enhance recognition of HIV-1-infected cells by this family of antibodies in the absence of antibodies such as 17b, which binds a highly conserved CD4-induced epitope overlapping the co-receptor binding site (CoRBS). Our results indicate that CD4mc initially open the trimeric Env enough to allow the binding of CoRBS antibodies but not anti-cluster A antibodies. CoRBS antibody binding further opens the trimeric Env, allowing anti-cluster A antibody interaction and sensitization of infected cells to ADCC. Therefore, ADCC responses mediated by cluster A antibodies in HIV-positive sera involve a sequential opening of the Env trimer on the surface of HIV-1-infected cells. The understanding of the conformational changes required to expose these vulnerable Env epitopes might be important in the design of new strategies aimed at fighting HIV-1. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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