The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor...

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Marburgviruses are highly lethal, with no approved vaccines or therapeutics.
• The human antibody MR191 demonstrates complete protection in non-human primates post-Marburg virus infection.
• The precise neutralization mechanism of MR191 has remained unclear.

Purpose of the Study:

• To elucidate the structural mechanism by which the human antibody MR191 neutralizes Marburg virus.
• To understand the interaction between MR191 and the Marburg virus surface glycoprotein (GP).

Main Methods:

• Determined the 3.2 Å crystal structure of the MR191 antibody complexed with the trimeric Marburg virus GP.
• Analyzed the binding site and interactions between MR191 and GP.
• Mapped virus escape mutations onto the determined structure.

Main Results:

• MR191 neutralizes Marburg virus by binding to the conserved receptor-binding site, competing with the host receptor Niemann-Pick C1.
• The crystal structure revealed previously disordered regions of GP, including the stalk, fusion loop, and GP2 N-terminal region.
• Virus escape mutations located outside the MR191 binding footprint suggest broader roles for GP regions in quaternary structure and antibody binding.

Conclusions:

• The MR191 antibody neutralizes Marburg virus by directly blocking host cell entry via the receptor-binding site.
• The structure provides insights into the Marburg virus GP quaternary structure and identifies novel antibody epitopes.
• Understanding these interactions is crucial for developing effective Marburg virus therapeutics and vaccines.