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Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay
Published on: September 14, 2014
MPER-specific antibodies induce gp120 shedding and irreversibly neutralize HIV-1
Claudia R Ruprecht1, Anders Krarup, Lucy Reynell
1Institute of Medical Virology, University Hospital Zurich, Switzerland.
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.
Insights
Antibodies targeting the HIV-1 gp41 membrane-proximal external region (MPER) irreversibly neutralize the virus by inducing gp120 shedding. This shedding is a key event in irreversible HIV neutralization by MPER-specific antibodies.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- Antibodies are crucial for HIV-1 neutralization, primarily by blocking virus entry.
- 2F5 and 4E10 antibodies target the membrane-proximal external region (MPER) of gp41, a key viral envelope protein.
- The exact molecular mechanisms of MPER-specific antibody-mediated neutralization remain unclear.
Purpose of the Study:
- To investigate the irreversible neutralization capacity of MPER-specific antibodies against HIV virions.
- To elucidate the role of gp120 shedding in MPER antibody-mediated HIV neutralization.
- To determine the thermodynamic properties and kinetics of MPER antibody-induced neutralization.
Main Methods:
- Assessing the irreversible neutralization of HIV virions by MPER-specific antibodies.
- Quantifying gp120 shedding induced by MPER antibodies and other HIV-targeting antibodies.
- Analyzing the thermodynamic properties and kinetics of antibody-mediated processes.
Main Results:
- MPER-specific antibodies irreversibly neutralize HIV virions.
- Irreversible neutralization is closely linked to the induction of gp120 shedding.
- gp120 shedding is induced by antibodies targeting various viral sites (CD4 binding site, V3 loop, MPER) and is frequent in diverse HIV-1 subtypes.
- Both gp120 shedding and irreversible neutralization share similar thermodynamic properties and slow kinetics.
Conclusions:
- GP120 shedding is a critical event in, or consequence of, MPER antibody-mediated irreversible HIV neutralization.
- Understanding gp120 shedding is essential for comprehending the mechanisms of MPER antibody activity.
- These findings provide insights into developing more effective antibody-based HIV therapies.
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