title: HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane.
abstract: Although rarely elicited during natural human infection, the most broadly neutralizing antibodies (BNAbs) against diverse human immunodeficiency virus (HIV)-1 strains target the membrane-proximal ectodomain region (MPER) of viral gp41. To gain insight into MPER antigenicity, immunogenicity, and viral function, we studied its structure in the lipid environment by a combination of nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and surface plasmon resonance (SPR) techniques. The analyses revealed a tilted N-terminal alpha helix (aa 664-672) connected via a short hinge to a flat C-terminal helical segment (675-683). This metastable L-shaped structure is immersed in viral membrane and, therefore, less accessible to immune attack. Nonetheless, the 4E10 BNAb extracts buried W672 and F673 after initial encounter with the surface-embedded MPER. The data suggest how BNAbs may perturb tryptophan residue-associated viral fusion involving the mobile N-terminal MPER segment and, given conservation of MPER sequences in HIV-1, HIV-2, and SIV, have important implications for structure-guided vaccine design.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhen-Yu J
authors.initials: ZY
authors.lastname: Sun
authors.forename: Kyoung Joon
authors.initials: KJ
authors.lastname: Oh
authors.forename: Mikyung
authors.initials: M
authors.lastname: Kim
authors.forename: Jessica
authors.initials: J
authors.lastname: Yu
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
authors.forename: Likai
authors.initials: L
authors.lastname: Song
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Qiao
authors.forename: Jia-huai
authors.initials: JH
authors.lastname: Wang
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D000956:Antigens, Viral / Q000737:chemistry* / Q000276:immunology; D004578:Electron Spin Resonance Spectroscopy; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D017433:Protein Structure, Secondary; D020349:Surface Plasmon Resonance
chemical_list: D000956:Antigens, Viral; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41