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

Journal Article · · Nature (London)
DOI:https://doi.org/10.1038/nature13808· OSTI ID:1165315
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  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases, Vaccine Research Center, Lab. of Immunoregulation
  2. National Health Lab. Service (NHLS), Johannesburg (South Africa). National Inst. for Communicable Diseases, Center for HIV and STIs; Univ. of the Witwatersrand, Johannesburg (South Africa); Univ. of KwaZulu-Natal, Durban (South Africa). Centre for the AIDS Programme of Research in South Africa (CAPRISA)
  3. Univ. of North Carolina, Chapel Hill, NC (United States). Dept. of Medicine, Epidemiology, Microbiology and Immunology
  4. Duke Univ., Durham, NC (United States). School of Medicine, Human Vaccine Inst., Dept. of Medicine, Surgery, Pediatrics and Immunology; Duke Univ., Durham, NC (United States). Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery
  5. Yale Univ., New Haven, CT (United States). School of Medicine, Dept. of Microbial Pathogenesis
  6. Cornell Univ., Ithaca, NY (United States). Weill Cornell Medical College, Dept. of Physiology and Biophysics
+ Show Author Affiliations

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. In conclusion, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
W-31-109-Eng-38
OSTI ID:
1165315
Journal Information:
Nature (London), Vol. 514, Issue 7523; ISSN 0028-0836
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 556 works
Citation information provided by
Web of Science

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Human Antibodies that Recognize Novel Immunodominant Quaternary Epitopes on the HIV-1 Env Protein journal July 2016
Antigenic characterization of the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor incorporated into nanodiscs journal February 2017
Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer journal March 2015
Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques journal August 2015
Cryo-electron Microscopy Structure of the Native Prototype Foamy Virus Glycoprotein and Virus Architecture journal July 2016
Thermostability of Well-Ordered HIV Spikes Correlates with the Elicitation of Autologous Tier 2 Neutralizing Antibodies journal August 2016
Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape journal January 2017
Receptor Activation of HIV-1 Env Leads to Asymmetric Exposure of the gp41 Trimer journal December 2016
Lipid interactions and angle of approach to the HIV-1 viral membrane of broadly neutralizing antibody 10E8: Insights for vaccine and therapeutic design journal February 2017
Targeted N-glycan deletion at the receptor-binding site retains HIV Env NFL trimer integrity and accelerates the elicited antibody response journal September 2017
Carbohydrates in Cyberspace journal June 2015
Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer journal August 2017
Structure-Guided Redesign Improves NFL HIV Env Trimer Integrity and Identifies an Inter-Protomer Disulfide Permitting Post-Expression Cleavage journal July 2018
Cross Type Neutralizing Antibodies Detected in a Unique HIV-2 Infected Individual From India journal December 2018
Engineering and Characterization of a Fluorescent Native-Like HIV-1 Envelope Glycoprotein Trimer journal October 2015
Protein Crystallography in Vaccine Research and Development journal June 2015
Structure-Based Reverse Vaccinology Failed in the Case of HIV Because it Disregarded Accepted Immunological Theory journal September 2016
Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies journal November 2016
Structural Basis for Epitopes in the gp120 Cluster A Region that Invokes Potent Effector Cell Activity journal January 2019
Conformational Masking and Receptor-Dependent Unmasking of Highly Conserved Env Epitopes Recognized by Non-Neutralizing Antibodies That Mediate Potent ADCC against HIV-1 journal September 2015
Current Peptide and Protein Candidates Challenging HIV Therapy beyond the Vaccine Era journal September 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
HIV infections
X-ray crystallography
Protein vaccines
Protein function predictions