title: MPER-specific antibodies induce gp120 shedding and irreversibly neutralize HIV-1.
abstract: Interference with virus entry is known to be the principle mechanism of HIV neutralization by antibodies, including 2F5 and 4E10, which bind to the membrane-proximal external region (MPER) of the gp41 envelope protein. However, to date, the precise molecular events underlying neutralization by MPER-specific antibodies remain incompletely understood. In this study, we investigated the capacity of these antibodies to irrevocably sterilize HIV virions. Long-term effects of antibodies on virions can differ, rendering neutralization either reversible or irreversible. MPER-specific antibodies irreversibly neutralize virions, and this capacity is associated with induction of gp120 shedding. Both processes have similar thermodynamic properties and slow kinetics requiring several hours. Antibodies directed to the CD4 binding site, V3 loop, and the MPER can induce gp120 shedding, and shedding activity is detected with high frequency in plasma from patients infected with divergent genetic HIV-1 subtypes. Importantly, as we show in this study, induction of gp120 shedding is closely associated with MPER antibody inhibition, constituting either a primary event leading to virion neutralization or representing an immediate consequence thereof, and thus needs to be factored into the mechanistic processes underlying their activity.
authors.affiliation: Institute of Medical Virology, University Hospital Zurich, Switzerland.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Ruprecht
authors.forename: Anders
authors.initials: A
authors.lastname: Krarup
authors.forename: Lucy
authors.initials: L
authors.lastname: Reynell
authors.forename: Axel M
authors.initials: AM
authors.lastname: Mann
authors.forename: Oliver F
authors.initials: OF
authors.lastname: Brandenberg
authors.forename: Livia
authors.initials: L
authors.lastname: Berlinger
authors.forename: Irene A
authors.initials: IA
authors.lastname: Abela
authors.forename: Roland R
authors.initials: RR
authors.lastname: Regoes
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Peter
authors.initials: P
authors.lastname: Rusert
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology* / Q000502:physiology; D015153:Blotting, Western; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000502:physiology; D015700:HIV Envelope Protein gp41 / Q000276:immunology* / Q000502:physiology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D009500:Neutralization Tests; D014771:Virion / Q000276:immunology; D017201:Virus Shedding / Q000276:immunology* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C514793:gp120 protein, Human immunodeficiency virus 1