Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model.
Hepatitis C virus (HCV) is remarkably efficient in establishing persistent infection, possibly mediated by an impaired immune response to HCV infection. There is compelling evidence that HCV can infect immune cells, such as macrophages, B cells, and T cells. It has been previously reported that HCV core, the first protein expressed during the early phase of viral infection, contains the immunomodulatory function of suppressing host immune responses. This altered function of immune cells caused by HCV infection may explain the ineffective immune response to HCV. To further characterize the immunomodulatory role of HCV core in vivo, we generated transgenic (TG) mice by directing the expression of core protein to T lymphocytes by using the CD2 promoter. T-lymphocyte responses, including the production of gamma interferon and interleukin-2, were significantly diminished in these mice compared to their non-TG littermates. The inhibition of T-lymphocyte responsiveness may be due to the increased susceptibility of peripheral T lymphocytes to Fas-mediated apoptosis. Surprisingly, significant lymphocyte infiltration was observed in the portal tracts of livers isolated from core TG mice, associated with increasing serum alanine aminotransferase levels. Moreover, no intrahepatic lymphocytes or liver damage was found in non-TG littermates and core TG mice bred to Fas-deficient lpr mice. These results suggest that HCV core drives liver injury by increasing Fas-mediated apoptosis and liver infiltration of peripheral T cells.
Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.
Carolina
C
Soguero
Myungsoo
M
Joo
Kimberly A
KA
Chianese-Bullock
Duong Tony
DT
Nguyen
Kenneth
K
Tung
Young S
YS
Hahn
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000472:pathogenicity*; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007108:Immune Tolerance; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology; D014758:Viral Core Proteins / Q000276:immunology* / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D014758:Viral Core Proteins; D019014:fas Receptor; C069130:nucleocapsid protein, Hepatitis C virus