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Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus.

ABSTRACT: Hepatitis C virus (HCV) is a major cause of chronic liver diseases. A high risk of chronicity is the major concern of HCV infection, since chronic HCV infection often leads to liver cirrhosis and hepatocellular carcinoma. Infection with the HCV genotype 1 in particular is considered a clinical risk factor for the development of hepatocellular carcinoma, although the molecular mechanisms of the pathogenesis are largely unknown. Autophagy is involved in the degradation of cellular organelles and the elimination of invasive microorganisms. In addition, disruption of autophagy often leads to several protein deposition diseases. Although recent reports suggest that HCV exploits the autophagy pathway for viral propagation, the biological significance of the autophagy to the life cycle of HCV is still uncertain. Here, we show that replication of HCV RNA induces autophagy to inhibit cell death. Cells harboring an HCV replicon RNA of genotype 1b strain Con1 but not of genotype 2a strain JFH1 exhibited an incomplete acidification of the autolysosome due to a lysosomal defect, leading to the enhanced secretion of immature cathepsin B. The suppression of autophagy in the Con1 HCV replicon cells induced severe cytoplasmic vacuolation and cell death. These results suggest that HCV harnesses autophagy to circumvent the harmful vacuole formation and to maintain a persistent infection. These findings reveal a unique survival strategy of HCV and provide new insights into the genotype-specific pathogenicity of HCV.

SUBMITTER: Taguwa S

PROVIDER: S-EPMC3233170 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus.

Taguwa Shuhei S Kambara Hiroto H Fujita Naonobu N Noda Takeshi T Yoshimori Tamotsu T Koike Kazuhiko K Moriishi Kohji K Matsuura Yoshiharu Y

Journal of virology 20111012 24

Hepatitis C virus (HCV) is a major cause of chronic liver diseases. A high risk of chronicity is the major concern of HCV infection, since chronic HCV infection often leads to liver cirrhosis and hepatocellular carcinoma. Infection with the HCV genotype 1 in particular is considered a clinical risk factor for the development of hepatocellular carcinoma, although the molecular mechanisms of the pathogenesis are largely unknown. Autophagy is involved in the degradation of cellular organelles and t ...[more]

PMID: 21994453

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Project description:Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV.IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.

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Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus.

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Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C virus.

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