title: Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike.
abstract: The extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160)3, cleaved to (gp120/gp41)3] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easy-to-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120.6. Sequence variation at neutralizing epitopes does not fully account for its exceptional resistance to antibodies. The full-length, membrane-bound CH120.6 Env is indeed stable and conformationally homogeneous. Its antigenicity correlates closely with its neutralization sensitivity, and major changes in antigenicity upon CD4 engagement appear to be restricted to the coreceptor site. The CH120.6 gp140 trimer, the soluble and uncleaved ectodomain of (gp160)3, retains many antigenic properties of the intact Env, consistent with a conformation close to that of Env spikes on a virion, whereas its monomeric gp120 exposes many nonneutralizing or strain-specific epitopes. Thus, trimer organization and stability are important determinants not only for occluding many epitopes but also for conferring resistance to neutralization by all but a small set of antibodies. Env preparations derived from neutralization-resistant viruses may induce irrelevant antibody responses less frequently than do other Envs and may be excellent templates for developing soluble immunogens.
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Cai
authors.affiliation: GlaxoSmithKline Vaccines, Rockville, MD 20850.
authors.forename: Selen
authors.initials: S
authors.lastname: Karaca-Griffin
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.affiliation: GlaxoSmithKline Vaccines, Rockville, MD 20850.
authors.forename: Sai
authors.initials: S
authors.lastname: Tian
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fredette
authors.affiliation: GlaxoSmithKline Vaccines, Rockville, MD 20850.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Linton
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Sophia
authors.initials: S
authors.lastname: Rits-Volloch
authors.affiliation: Codex BioSolutions, Inc., Gaithersburg, MD 20879.
authors.forename: Jianming
authors.initials: J
authors.lastname: Lu
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Wagh
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545.
authors.forename: James
authors.initials: J
authors.lastname: Theiler
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545.
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; bchen@crystal.harvard.edu harrison@crystal.harvard.edu.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 20115.|Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 20115.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
authors.affiliation: GlaxoSmithKline Vaccines, Rockville, MD 20850.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfi
authors.affiliation: Laboratory of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; bchen@crystal.harvard.edu harrison@crystal.harvard.edu.|Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
mesh_terms: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000941:Antigens / Q000737:chemistry / Q000378:metabolism*; D000939:Epitopes; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D019302:HIV Envelope Protein gp160 / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000941:Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160
keywords: HIV-1 gp160; neutralizing antibodies; vaccine design