Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes.
The mechanisms of liver injury associated with chronic HCV infection, as well as the individual roles of both viral and host factors, are not clearly defined. However, it is becoming increasingly clear that direct cytopathic effects, in addition to immune-mediated processes, play an important role in liver injury. Gene expression profiling during multiple time-points of acute HCV infection of cultured Huh-7.5 cells was performed to gain insight into the cellular mechanism of HCV-associated cytopathic effect. Maximal induction of cell-death-related genes and appearance of activated caspase-3 in HCV-infected cells coincided with peak viral replication, suggesting a link between viral load and apoptosis. Gene ontology analysis revealed that many of the cell-death genes function to induce apoptosis in response to cell cycle arrest. Labeling of dividing cells in culture followed by flow cytometry also demonstrated the presence of significantly fewer cells in S-phase in HCV-infected relative to mock cultures, suggesting HCV infection is associated with delayed cell cycle progression. Regulation of numerous genes involved in anti-oxidative stress response and TGF-beta1 signaling suggest these as possible causes of delayed cell cycle progression. Significantly, a subset of cell-death genes regulated during in vitro HCV infection was similarly regulated specifically in liver tissue from a cohort of HCV-infected liver transplant patients with rapidly progressive fibrosis. Collectively, these data suggest that HCV mediates direct cytopathic effects through deregulation of the cell cycle and that this process may contribute to liver disease progression. This in vitro system could be utilized to further define the cellular mechanism of this perturbation.
Walters
Kathie-Anne
KA
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, United States of America.
Syder
Andrew J
AJ
Lederer
Sharon L
SL
Diamond
Deborah L
DL
Paeper
Bryan
B
Rice
Charles M
CM
Katze
Michael G
MG
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D006526:Hepatitis C / Q000503:physiopathology*; D022781:Hepatocytes / Q000166:cytology / Q000821:virology; D006801:Humans; D016031:Liver Transplantation / Q000473:pathology / Q000502:physiology
D016207:Cytokines