Molecular recognition of the native HIV-1 MPER revealed by STED microscopy of single virions

Area of Science:

• Immunology
• Virology
• Biophysics

Background:

• Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 Env gp41 subunit's Membrane-Proximal External Region (MPER) exhibit potent neutralization.
• The native structure and accessibility of the MPER epitope remain poorly understood, leading to various proposed models for antibody recognition.

Purpose of the Study:

• To investigate the accessibility and recognition mechanism of the native Env MPER on single HIV-1 virions using advanced microscopy.
• To elucidate the biophysical interactions governing MPER epitope recognition by bNAbs.

Main Methods:

• Super-resolution microscopy, specifically Stimulated Emission Depletion (STED) microscopy, was employed.
• Fluorescently labeled antibody fragments (Fabs) targeting MPER and gp120 were used to image native Env on single virions.

Main Results:

• STED imaging revealed a common recognition pattern for HIV-1 antibodies targeting either MPER or the surface gp120 subunit on native Env.
• Anti-MPER antibodies demonstrated enhanced binding specificity through additional interactions with the viral lipid membrane.

Conclusions:

• The study provides crucial biophysical insights into how potent and broadly neutralizing anti-MPER antibodies recognize their epitope on HIV virions.
• Understanding these interactions is vital for the rational design of novel therapeutic interventions against HIV-1.