TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection.
Human TIM and TAM family proteins were recently found to serve as phosphatidylserine (PS) receptors which promote infections by many different viruses, including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection by hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7.5 cells remarkably lowered HCV cell attachment and subsequent HCV infection. More significantly, the impairment of HCV infection in the TIM-1 knockout cells could be restored completely by ectopic expression of TIM-1 but not TIM-3 or TIM-4. Additionally, HCV infection and cell attachment were inhibited by PS but not by phosphatidylcholine (PC), demonstrating that TIM-1-mediated enhancement of HCV infection is PS dependent. The exposure of PS on the HCV envelope was confirmed by immunoprecipitation of HCV particles with a PS-specific monoclonal antibody. Collectively, these findings demonstrate that TIM-1 promotes HCV infection by serving as an attachment receptor for binding to PS exposed on the HCV envelope.


OBJECTIVE
TIM family proteins were recently found to enhance infections by many different viruses, including several members of the Flaviviridae family. However, their importance in HCV infection has not previously been examined experimentally. The TIM family proteins include three members in humans: TIM-1, TIM-3, and TIM-4. The findings derived from our studies demonstrate that TIM-1, but not TIM-3 or TIM-4, promotes HCV infection by functioning as an HCV attachment factor. Knockout of the TIM-1 gene resulted in a remarkable reduction of HCV cell attachment and infection. PS-containing liposomes blocked HCV cell attachment and subsequent HCV infection. HCV particles could also be precipitated with a PS-specific monoclonal antibody. These findings suggest that TIM-1 and its binding ligand, PS, may serve as novel targets for antiviral intervention.
Department of Microbiology, Peking University Health Science Center, Beijing, China.|University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Jing
J
Wang
Department of Microbiology, Peking University Health Science Center, Beijing, China.|University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Luhua
L
Qiao
University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Zhouhua
Z
Hou
Department of Microbiology, Peking University Health Science Center, Beijing, China gluo@uab.edu.|University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
Guangxiang
G
Luo
D000066630:Ectopic Gene Expression; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D016174:Hepacivirus / Q000502:physiology*; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000235:genetics / Q000378:metabolism*; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D053585:Virus Attachment; D014779:Virus Replication
C491143:HAVCR1 protein, human; C448908:HAVCR2 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C512411:TIMD4 protein, human
TIM-1; TIM-3; TIM-4; attachment; hepatitis C virus; infection; receptor