title: Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface.
abstract: A vaccine capable of stimulating protective antiviral antibody responses is needed to curtail the global AIDS epidemic caused by HIV-1. Although rarely elicited during the course of natural infection or upon conventional vaccination, the membrane-proximal ectodomain region (MPER) of the HIV-1 glycoprotein of M(r) 41,000 (gp41) envelope protein subunit is the target of 3 such human broadly neutralizing antibodies (BNAbs): 4E10, 2F5, and Z13e1. How these BNAbs bind to their lipid-embedded epitopes and mediate antiviral activity is unclear, but such information might offer important insight into a worldwide health imperative. Here, EPR and NMR techniques were used to define the manner in which these BNAbs differentially recognize viral membrane-encrypted residues configured within the L-shaped helix-hinge-helix MPER segment. Two distinct modes of antibody-mediated interference of viral infection were identified. 2F5, like 4E10, induces large conformational changes in the MPER relative to the membrane. However, although 4E10 straddles the hinge and extracts residues W672 and F673, 2F5 lifts up residues N-terminal to the hinge region, exposing L669 and W670. In contrast, Z13e1 effects little change in membrane orientation or conformation, but rather immobilizes the MPER hinge through extensive rigidifying surface contacts. Thus, BNAbs disrupt HIV-1 MPER fusogenic functions critical for virus entry into human CD4 T cells and macrophages either by preventing hinge motion or by perturbing MPER orientation. HIV-1 MPER features important for targeted vaccine design have been revealed, the implications of which extend to BNAb targets on other viral fusion proteins.
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Likai
authors.initials: L
authors.lastname: Song
authors.forename: Zhen-Yu J
authors.initials: ZY
authors.lastname: Sun
authors.forename: Kate E
authors.initials: KE
authors.lastname: Coleman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zwick
authors.forename: Johannes S
authors.initials: JS
authors.lastname: Gach
authors.forename: Jia-huai
authors.initials: JH
authors.lastname: Wang
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Mikyung
authors.initials: M
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000276:immunology / Q000821:virology; D004578:Electron Spin Resonance Spectroscopy; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008561:Membrane Fusion / Q000276:immunology; D009500:Neutralization Tests; D019906:Nuclear Magnetic Resonance, Biomolecular; D053586:Virus Internalization
chemical_list: D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41