Journal Article

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

Zhang, Baoshan, Soto, Cinque, Connors, Mark, Morris, Lynn, Louder, Mark K., Mothes, Walther, Munro, James B., Tumba, Nancy, Yang, Yongping, Kwong, Peter D., Pancera, Marie, Huang, Jinghe, Blanchard, Scott C., Cohen, Myron S., Stuckey, Jonathan, Druz, Aliaksandr, Georgiev, Ivelin S., Gorman, Jason, Acharya, Priyamvada, Joyce, M. Gordon, Stewart-Jones, Guillaume B. E., Ofek, Gilad, Mascola, John R., Chuang, Gwo-Yu, Zhou, Tongqing, Bailer, Robert T., Haynes, Barton F.

2014

Overview

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. A crystal structure of the human immunodeficiency virus Env trimer, used by the virus to infect cells, is determined here; the new structure, which shows the pre-fusion form of Env, increases our understanding of the fusion mechanism and of how the conformation of Env allows the virus to evade the immune response. Structural basis for HIV-1 immune evasion Peter Kwong and colleagues provide a new crystal structure of the human immunodeficiency virus type 1 (HIV-1) Env trimer, part of the type I fusion machine that facilitates virus entry into cells by interacting with host cellular receptors and fusing membranes of virus and host cell. The Env trimer consists of three gp120 and three gp41 subunits. The structure, at 3.5 Å resolution, shows the pre-fusion form of Env and allows the conformation of the gp41 subunits to be resolved, thereby increasing our understanding of how the trimer functions to enable fusion and how it evades recognition by the immune response. This evasion is, to a large degree, responsible for the difficulty in developing an effective HIV-1 vaccine.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/1 / 38/109 / 38/35 / 60 APPLIED LIFE SCIENCES / 631/114/2410 / 631/250/255/1901 / 631/250/590/2294 / 631/535/1266 / 82/80 / AIDS Vaccines - chemistry / AIDS Vaccines - immunology / Amino Acid Sequence / Antibodies, Neutralizing - immunology / BASIC BIOLOGICAL SCIENCES / Cohort Studies / Crystallography, X-Ray / Crystals / Genetic Variation / Glycosylation / Health aspects / HIV / HIV antibodies / HIV Antibodies - immunology / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - genetics / HIV Envelope Protein gp120 - immunology / HIV Envelope Protein gp41 - chemistry / HIV Envelope Protein gp41 - genetics / HIV Envelope Protein gp41 - immunology / HIV infections / HIV Infections - immunology / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immune Evasion / Immunology / Infections / Membrane Fusion / Models, Molecular / Molecular Sequence Data / multidisciplinary / Peptides / Physiological aspects / Polysaccharides - chemistry / Polysaccharides - immunology / Protein function predictions / Protein Multimerization / Protein Structure, Quaternary / Protein Subunits - chemistry / Protein Subunits - genetics / Protein Subunits - immunology / Protein vaccines / Science / Structural Homology, Protein / Structure / Viral proteins / Virus Internalization / X-ray crystallography