The pentameric complex drives immunologically covert cell-cell transmission of wild-type human cytomegalovirus

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Laboratory-adapted human cytomegalovirus (HCMV) strains acquire mutations affecting growth, tropism, and immune cell susceptibility.
• Clinical HCMV strains are unstable in cell culture, hindering research into their properties.

Purpose of the Study:

• To reconstruct a wild-type (WT) HCMV genome to study clinically relevant viral phenotypes.
• To investigate the mechanisms and characteristics of WT HCMV infection, particularly cell-cell transmission.

Main Methods:

• Reconstruction of a WT HCMV genome using bacterial artificial chromosome technology.
• Conditional expression of RL13 and UL128 genes to propagate intact virus.
• Comparison of cell-free versus cell-cell transmission routes for WT HCMV.

Main Results:

• WT HCMV exhibits extremely low cell-free virus titers but efficient cell-cell transmission to fibroblasts, epithelial, and immune cells.
• Cell-cell transfer requires the UL128 locus and is more resistant to IFN, restriction factors, and neutralizing antibodies than cell-free entry.
• Antibody resistance is linked to high-level expression of the pentameric gH/gL/gpUL128-131A complex, characteristic of WT HCMV.

Conclusions:

• WT HCMV primarily utilizes cell-cell transmission for efficient infection, offering advantages over cell-free spread.
• The UL128 locus and pentameric complex are crucial for WT HCMV cell-cell transmission and immune evasion.
• Understanding WT HCMV transmission is vital for developing effective antiviral strategies against clinically relevant strains.