Cytoskeletal Vimentin Directs Cell-Cell Transmission of Hepatitis C Virus

Area of Science:

• Virology
• Cell Biology
• Immunology

Background:

• Hepatitis C virus (HCV) causes significant liver disease globally.
• While direct-acting antivirals are effective, HCV cell-cell transmission persists in vivo.
• Mechanisms of intercellular HCV spread remain largely unknown.

Purpose of the Study:

• To elucidate the role of vimentin in Hepatitis C virus (HCV) infection and cell-cell transmission.
• To identify the specific viral and host factors involved in HCV intercellular spread.
• To explore vimentin as a potential therapeutic target for HCV.

Main Methods:

• Utilized cell culture models and differentiated hepatocytes.
• Employed genetic knockout of vimentin.
• Performed mutual co-immunoprecipitation screening.
• Investigated the function of vimentin domains and plasma membrane localization.
• Tested the efficacy of vimentin antibodies in blocking HCV transmission.

Main Results:

• Vimentin is dispensable for HCV infection but essential for cell-cell transmission in hepatocytes.
• Vimentin knockout specifically disrupts HCV intercellular spread without affecting cell-free infection.
• Vimentin's N-terminal region (1-95 amino acids) interacts with HCV E1 envelope protein.
• Vimentin on recipient cell plasma membranes mediates HCV cell-cell transmission.
• Vimentin antibodies significantly inhibit HCV cell-cell transmission, alone or with neutralizing antibodies.

Conclusions:

• Vimentin plays a critical, previously unrecognized role in Hepatitis C virus (HCV) cell-cell transmission.
• The interaction between vimentin and HCV E1 is key for intercellular viral spread.
• Targeting vimentin presents a promising new therapeutic avenue for controlling HCV persistence and infection.