Structure and immune recognition of trimeric pre-fusion HIV-1 Env

Marie Pancera, Tongqing Zhou, Aliaksandr Druz, Ivelin S. Georgiev, Cinque Soto, Jason Gorman, Jinghe Huang, Priyamvada Acharya, Gwo-Yu Chuang, Gilad Ofek, Guillaume B. E. Stewart-Jones, Jonathan Stuckey, Robert T. Bailer, M. Gordon Joyce, Mark K. Louder, Nancy Tumba, Yongping Yang, Baoshan Zhang, Myron S. Cohen, Barton F. Haynes, John R. Mascola, Lynn Morris, James B. Munro, Scott C. Blanchard, Walther Mothes, Mark Connors and Peter D. Kwong ()
Additional contact information
Marie Pancera: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Tongqing Zhou: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Aliaksandr Druz: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Ivelin S. Georgiev: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Cinque Soto: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jason Gorman: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jinghe Huang: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Priyamvada Acharya: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Gwo-Yu Chuang: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Gilad Ofek: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Guillaume B. E. Stewart-Jones: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jonathan Stuckey: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Robert T. Bailer: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
M. Gordon Joyce: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Mark K. Louder: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Nancy Tumba: Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa
Yongping Yang: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Baoshan Zhang: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Myron S. Cohen: Epidemiology, Microbiology and Immunology, University of North Carolina at Chapel Hill
Barton F. Haynes: Duke University Human Vaccine Institute, Surgery, Pediatrics and Immunology, Duke University School of Medicine, and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University
John R. Mascola: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Lynn Morris: Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa
James B. Munro: Yale University School of Medicine
Scott C. Blanchard: Weill Cornell Medical College of Cornell University
Walther Mothes: Yale University School of Medicine
Mark Connors: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Peter D. Kwong: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature, 2014, vol. 514, issue 7523, 455-461

Abstract: Abstract The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.

Date: 2014
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DOI: 10.1038/nature13808

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