Structural basis for HCMV Pentamer receptor recognition and antibody neutralization

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Human cytomegalovirus (HCMV) is a major cause of congenital birth defects.
• The HCMV Pentamer complex (gH/gL/UL128-130-131A) mediates viral entry into epithelial and endothelial cells.
• The Pentamer elicits potent neutralizing antibody responses, making it a crucial vaccine target, but its structural basis for receptor interaction and neutralization is poorly understood.

Purpose of the Study:

• To elucidate the structural mechanisms of HCMV Pentamer engagement with cellular receptors.
• To understand how neutralizing antibodies interact with the Pentamer complex.
• To identify novel functional receptors for HCMV and characterize their interaction with the Pentamer.

Main Methods:

• X-ray crystallography to determine the structures of the HCMV Pentamer complex.
• Complex formation with cellular receptors Neuropilin 2 (NRP2) and Thrombomodulin (THBD).
• Structural analysis of Pentamer-antibody complexes.

Main Results:

• Determined structures of the HCMV Pentamer bound to NRP2 and neutralizing antibodies.
• Identified Thrombomodulin (THBD) as a functional HCMV receptor and determined the Pentamer-THBD complex structure.
• Observed that both NRP2 and THBD induce dimerization of the Pentamer complex.

Conclusions:

• Provides a structural framework for understanding HCMV receptor recognition and cell entry mechanisms.
• Offers insights into antibody neutralization of HCMV.
• Outlines potential strategies for developing novel antiviral therapies against HCMV infections.