@article{5e24422acb874b7fa4a411736d5da386,
title = "An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity",
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 antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 + T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection. HIV-1 envelope glycoproteins (Env) are very flexible and exist in at least three different conformational states. Alsahafi et al. characterize a fourth Env state that is efficiently recognized by antibodies capable of mediating potent antibody-dependent cellular toxicity.",
keywords = "17b, A32, ADCC, CD4i Abs, HIV-1, State 2A, cryo-EM, envelope glycoproteins, smFRET",
author = "Nirmin Alsahafi and Nordine Bakouche and Mohsen Kazemi and Jonathan Richard and Shilei Ding and Sudipta Bhattacharyya and Durba Das and Anand, {Sai Priya} and J{\'e}r{\'e}mie Pr{\'e}vost and Tolbert, {William D.} and Hong Lu and Halima Medjahed and Gabrielle Gendron-Lepage and {Ortega Delgado}, {Gloria Gabrielle} and Sharon Kirk and Bruno Melillo and Walther Mothes and Joseph Sodroski and Smith, {Amos B.} and Kaufmann, {Daniel E.} and Xueling Wu and Marzena Pazgier and Isabelle Rouiller and Andr{\'e}s Finzi and Munro, {James B.}",
note = "Funding Information: 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. Funding Information: 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. A.F. and J.B.M. conceived the study. A.F. I.R. N.A. N.B. and J.B.M. designed experimental approaches. A.F. and J.B.M. wrote the paper. A.F. I.R. N.A. N.B. M.K. S.B. D.D. J.R. S.D. S.P.A. H.L. H.M. S.K. X.W. W.M. and J.B.M. performed, analyzed, and interpreted the experiments. W.D.T. A.B.S. M.P. and D.E.K. supplied novel reagents. All authors have read, edited, and approved the final manuscript. The authors declare no competing interests. J.B.M. and W.M. are inventors on a patent related to the application of smFRET imaging to HIV-1 Env (US patent number US9938324B2). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = apr,
day = "10",
doi = "10.1016/j.chom.2019.03.002",
language = "English",
volume = "25",
pages = "578--587.e5",
journal = "Cell Host and Microbe",
issn = "1931-3128",
number = "4",
}