title: Conformational States of a Soluble, Uncleaved HIV-1 Envelope Trimer.
abstract: The HIV-1 envelope spike [Env; trimeric (gp160)3cleaved to (gp120/gp41)3] induces membrane fusion, leading to viral entry. It is also the viral component targeted by neutralizing antibodies. Vaccine development requires production, in quantities suitable for clinical studies, of a recombinant form that resembles functional Env. HIV-1 gp140 trimers-the uncleaved ectodomains of (gp160)3-from a few selected viral isolates adopt a compact conformation with many antigenic properties of native Env spikes. One is currently being evaluated in a clinical trial. We report here low-resolution (20 Å) electron cryomicroscopy (cryoEM) structures of this gp140 trimer, which adopts two principal conformations, one closed and the other slightly open. The former is indistinguishable at this resolution from those adopted by a stabilized, cleaved trimer (SOSIP) or by a membrane-bound Env trimer with a truncated cytoplasmic tail (EnvΔCT). The latter conformation is closer to a partially open Env trimer than to the fully open conformation induced by CD4. These results show that a stable, uncleaved HIV-1 gp140 trimer has a compact structure close to that of native Env.IMPORTANCEDevelopment of any HIV vaccine with a protein component (for either priming or boosting) requires production of a recombinant form to mimic the trimeric, functional HIV-1 envelope spike in quantities suitable for clinical studies. Our understanding of the envelope structure has depended in part on a cleaved, soluble trimer, known as SOSIP.664, stabilized by several modifications, including an engineered disulfide. This construct, which is difficult to produce in large quantities, has yet to induce better antibody responses than those to other envelope-based immunogens, even in animal models. The uncleaved ectodomain of the envelope protein, called gp140, has also been made as a soluble form to mimic the native Env present on the virion surface. Most HIV-1 gp140 preparations are not stable, however, and have an inhomogeneous conformation. The results presented here show that gp140 preparations from suitable isolates can adopt a compact, native-like structure, supporting its use as a vaccine candidate.
authors.affiliation: Division of Molecular Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, USA.
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Molecular Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Junhua
authors.initials: J
authors.lastname: Pan
authors.affiliation: Division of Molecular Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Grigorieff
authors.affiliation: Division of Molecular Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
authors.affiliation: Division of Molecular Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts, USA bchen@crystal.harvard.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D020285:Cryoelectron Microscopy; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology; D008968:Molecular Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012995:Solubility; D014614:Vaccines, Synthetic; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D014614:Vaccines, Synthetic; D054299:env Gene Products, Human Immunodeficiency Virus
keywords: cryoEM; envelope; human immunodeficiency virus; immunogen