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

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.
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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
Publication Date:
OSTI Identifier:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 514; Journal Issue: 7523; Journal ID: ISSN 0028-0836
Nature Publishing Group
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; HIV infections; X-ray crystallography; Protein vaccines; Protein function predictions