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

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TitleStructure and immune recognition of trimeric pre-fusion HIV-1 Env.
Publication TypeJournal Article
Year of Publication2014
AuthorsPancera, M, Zhou, T, Druz, A, Georgiev, IS, Soto, C, Gorman, J, Huang, J, Acharya, P, Chuang, G-Y, Ofek, GA, Stewart-Jones, GBE, Stuckey, J, Bailer, RT, M Joyce, G, Louder, MK, Tumba, N, Yang, Y, Zhang, B, Cohen, MS, Haynes, BF, Mascola, JR, Morris, L, Munro, JB, Blanchard, SC, Mothes, W, Connors, M, Kwong, PD
JournalNature
Volume514
Issue7523
Pagination455-61
Date Published2014 Oct 23
ISSN1476-4687
KeywordsAIDS Vaccines, Amino Acid Sequence, Antibodies, Neutralizing, Cohort Studies, Crystallography, X-Ray, Genetic Variation, Glycosylation, HIV Antibodies, HIV Envelope Protein gp120, HIV Envelope Protein gp41, HIV Infections, Humans, Immune Evasion, Membrane Fusion, Models, Molecular, Molecular Sequence Data, Polysaccharides, Protein Multimerization, Protein Structure, Quaternary, Protein Subunits, Structural Homology, Protein, Virus Internalization
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.

DOI10.1038/nature13808
Alternate JournalNature
PubMed ID25296255
PubMed Central IDPMC4348022
Grant ListAI0678501 / AI / NIAID NIH HHS / United States
AI100645 / AI / NIAID NIH HHS / United States
P01 GM056550 / GM / NIGMS NIH HHS / United States
P01-GM56550 / GM / NIGMS NIH HHS / United States
P30 AI050410 / AI / NIAID NIH HHS / United States
R01 GM098859 / GM / NIGMS NIH HHS / United States
R01-GM098859 / GM / NIGMS NIH HHS / United States
R21 AI100696 / AI / NIAID NIH HHS / United States
R21-AI100696 / AI / NIAID NIH HHS / United States
UL1 TR000142 / TR / NCATS NIH HHS / United States
UM1 AI100645 / AI / NIAID NIH HHS / United States
ZIA AI005023-13 / / Intramural NIH HHS / United States
ZIA AI005024-13 / / Intramural NIH HHS / United States