Journal article
An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity
N Alsahafi, N Bakouche, M Kazemi, J Richard, S Ding, S Bhattacharyya, D Das, SP Anand, J Prévost, WD Tolbert, H Lu, H Medjahed, G Gendron-Lepage, GG Ortega Delgado, S Kirk, B Melillo, W Mothes, J Sodroski, AB Smith, DE Kaufmann Show all
Cell Host and Microbe | CELL PRESS | Published : 2019
Abstract
The HIV-1 envelope glycoprotein (Env) (gp120-gp41) 3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by anti..
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Awarded by Stichting A.F. Deutman Oogheelkunde Researchfonds
Funding Acknowledgements
The authors thank Maolin Lu and Xiaochu Ma for helpful discussions and critical reading of the manuscript, the CRCHUM Flow Cytometry Platform, the FRQS AIDS and Infectious Diseases network, Mario Legault for cohort coordination and clinical samples, and Dennis Burton for the infectious molecular clone JRFL. We would like to thank Andrew Leis from the Bio21 Advanced Microscopy Facility (University of Melbourne). This work was supported by a CIHR foundation grant #352417 to A. F. Support for this work was also provided by NIH R01 to A. F. and M. P. (AI129769), A. F. and X. W. (AI122953), J. S. (AI124982), and NIAID R01 to M. P. (AI116274). This study was also supported by NIH AI100663 Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID) (D. E. K.; PI: Dennis Burton) and by R01-GM56550 to A.B.S. Work by J.B.M. was supported by the NIH (1K22AI116262), the Gilead Sciences Research Scholars Program in HIV, and the Campbell Foundation for AIDS Research. A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235. N.A. is the recipient of a King Abdullah scholarship for higher education from the Saudi Government. J.R. is the recipient of a Mathilde Krim Fellowships in Basic Biomedical Research from AmfAR. S.D. is the recipient of an FRSQ postdoctoral fellowship award. D.E.K. is supported by an FRQS Senior Research Scholar Award. I.R. is supported by the STEM-M Stimulus Fund (University of Melbourne). We thank Jeffrey Lifson and Julian Bess for providing the AT-2 inactivated viral particles from the AIDS and Cancer Virus Program, and Leidos Biomedical Research, Inc./Frederick National Laboratory for Cancer Research supported with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, US Army, the Department of Defense, or the US Government.