Abstract
Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression.
Highlights
Introduction to HCV Infection and LiverDiseaseHepatitis C virus (HCV) is a blood-borne pathogen that infects the liver
Our results show endoplasmic reticulum (ER) stress and autophagy marker expression are induced in HCV-infected primary human hepatocytes and liver tissues of patients with chronic liver disease (CLD)
We propose that additional research is needed to determine why the interplay of chronic ER-stress, autophagy and cell survival pathways lead to liver cirrhosis and hepatocellular carcinoma (HCC) induced by chronic HCV infection Understanding the mechanisms of unfolded protein response (UPR) and autophagy regulation during the progression of chronic liver disease is highly significant since defective autophagy response has been linked to cancer development [102]
Summary
Hepatitis C virus (HCV) is a blood-borne pathogen that infects the liver. The molecular mechanisms by which HCV develops persistent infection in the hepatocytes by maintaining a delicate balance between viral induced stress response and cell survival is not well understood. The expression of UPR genes does not return to base line expression levels, rather, it remain elevated throughout the infection, leading to chronic ER-stress This is because many positive strand RNA viruses, including HCV, house the virus replication machinery in the protective ER-membrane. We will review the work of many researchers, including our own, regarding how the HCV infection and other non-viral insults induce ER-stress and UPR in chronic liver diseases
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