Infection of Human Liver Myofibroblasts by Hepatitis C Virus: A Direct Mechanism of Liver Fibrosis in Hepatitis C

Lynda Aoudjehane (1, 2) , Grégoire Bisch (2) , Olivier Scatton (3, 1, 2) , Christelle Granier (4, 5) , Jesintha Gaston (6) , Chantal Housset (1) , Philippe Roingeard (7) , Cosset François-Loïc (5, 8) , Fabiano Perdigao (3) , Pierre Balladur (2, 1) , Takaji Wakita (9) , Yvon Calmus (1, 3) , Filomena Conti (1, 3)

1 UMRS893 - Centre de Recherche Saint-Antoine
2 CHU Saint-Antoine [AP-HP]
3 CHU Pitié-Salpêtrière [AP-HP]
4 CIRI - Centre International de Recherche en Infectiologie
5 LabEx ECOFECT Inserm U1111
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
7 Centre national de référence du VIH INSERM U966
8 EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy
9 National Institute of Infectious Diseases [Tokyo]

Background Chronic hepatitis C is a major cause of liver fibrosis and cirrhosis. It is generally accepted that inflammation that occurs in response to hepatocyte infection by the hepatitis C virus (HCV) is the main mechanism that triggers myofibroblast differentiation and stimulation in chronic hepatitis C. The aim of this study was to determine if HCV might infect human liver myofibroblasts (HLMF) and directly stimulate their fibrogenic activities. Methods We evaluated the expression of the viral entry receptors, levels of HCV-RNA and HCV-protein and the expression of fibrosis markers in HLMF by using quantitative PCR, western blot and immunofluorescence analyses. Pseudoparticles (HCVpp) and cell culture–derived HCV (HCVcc) were used to study the ability of HLMF to support viral entry, replication and fibrosis induction. Results We showed that HLMF expressed all known molecules of the HCV receptor complex, i.e. CD81, LDL-R, scavenger receptor-BI, claudin-1 and occludin. These cells were also permissive to HCVpp entry. Inoculation with HCVcc caused short-term infection of these cells, as shown by their content in positive- and negative-strand HCV RNA, in core and NS3 viral proteins, and by their release of core protein levels in the culture supernatants. HCV infection stimulated myofibroblastic differentiation, proliferation and collagen production in these cells. In addition, evidence of in vivo infection was provided by the detection of positive- and negative-strand HCV RNA in preparations of HLMF obtained from HCV-infected patients. Conclusion These findings indicate that HCV infection of HLMF can occur and trigger extracellular matrix overproduction, thereby contributing to the development of HCV-related liver fibrosis.

Domaines: Médecine humaine et pathologie

Lynda Aoudjehane, Grégoire Bisch, Olivier Scatton, Christelle Granier, Jesintha Gaston, et al.. Infection of Human Liver Myofibroblasts by Hepatitis C Virus: A Direct Mechanism of Liver Fibrosis in Hepatitis C. PLoS ONE, 2015, 12 (7), pp.e0134141. ⟨10.1371/journal.pone.0134141⟩. ⟨hal-01230857⟩