Hepatitis C virus infection and apoptosis

Fischer, Richard; Baumert, Thomas F.; Blum, Hubert E.

doi:10.3748/wjg.v13.i36.4865

Cited by 117 publications

(98 citation statements)

References 106 publications

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“…Moreover, other authors showed that HCV induces TRIAL-dependent apoptosis in HCVinfected liver cells (15,27). Additionally, the ability of HCV to sensitize human hepatocytes to apoptosis has been demonstrated in the model of Scid-Alb-uPA mice with humanized livers (23).…”

Section: Discussionmentioning

confidence: 99%

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Ganesan

Natarajan

Zhang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Alcohol consumption exacerbates hepatitis C virus (HCV) pathogenesis and promotes disease progression, although the mechanisms are not quite clear. We have previously observed that acetaldehyde (Ach) continuously produced by the acetaldehyde-generating system (AGS), temporarily enhanced HCV RNA levels, followed by a decrease to normal or lower levels, which corresponded to apoptosis induction. Here, we studied whether Ach-induced apoptosis caused depletion of HCV-infected cells and what role apoptotic bodies (AB) play in HCV-alcohol crosstalk. In liver cells exposed to AGS, we observed the induction of miR-122 and miR-34a. As miR-34a has been associated with apoptotic signaling and miR-122 with HCV replication, these findings may suggest that cells with intensive viral replication undergo apoptosis. Furthermore, when AGS-induced apoptosis was blocked by a pan-caspase inhibitor, the expression of HCV RNA was not changed. AB from HCV-infected cells contained HCV core protein and the assembled HCV particle that infect intact hepatocytes, thereby promoting the spread of infection. In addition, AB are captured by macrophages to switch their cytokine profile to the proinflammatory one. Macrophages exposed to HCV ϩ AB expressed more IL-1␤, IL-18, IL-6, and IL-10 mRNAs compared with those exposed to HCV Ϫ AB. The generation of AB from AGS-treated HCV-infected cells even enhanced the induction of aforementioned cytokines. We conclude that HCV and alcohol metabolites trigger the formation of AB containing HCV particles. The consequent spread of HCV to neighboring hepatocytes via infected AB, as well as the induction of liver inflammation by AB-mediated macrophage activation potentially exacerbate the HCV infection course by alcohol and worsen disease progression. HCV RNA; acetaldehyde; apoptosis; hepatocytes; macrophages ALCOHOL EXPOSURE EXACERBATES hepatitis C virus (HCV) infection severity, increases liver inflammation, and potentiates liver injury progression. However, the pathogenesis of HCV-alcohol interactions is not clear yet. The major difficulty in HCValcohol studies is related to the lack of adequate models that can recapitulate both viral replication and ethanol metabolism-two important features that potentiate liver injury progression in alcohol-abusing HCV patients. Human liver cell lines permissive for HCV (Huh7.5 or Huh 7.5.1) that are currently used for HCV-alcohol-related in vitro studies do not metabolize ethanol, while ethanol-metabolizing rodent liver cells cannot support HCV replication. Studies conducted with isolated human hepatocytes also have failed, since these cells require at least 4 -5 days to become infected with HCV; however, by this time, hepatocytes lose the expression and functional activity of CYP2E1 and alcohol dehydrogenase (ADH), the main ethanol-metabolizing enzymes (47). In vivo models of HCV infection are also questionable, since small rodents cannot be infected with human HCV, and they only transgenically express HCV proteins, in the absence of replicating virus. The best option i...

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Section: Discussionmentioning

confidence: 99%

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Ganesan

Natarajan

Zhang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…1 On top of several mechanisms of interference with the type 1 interferon production and response, antigen presentation, and cellmediated immune response, 23,24 HCV also modulates ap- optosis of the infected cell. 25 We previously reported that the HCV viral proteins decrease the expression of the proapoptotic protein Bid. 4 Bid is a ubiquitously expressed BH3-only member of the Bcl-2 family.…”

Section: Discussionmentioning

confidence: 99%

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway #

et al. 2009

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An unresolved question regarding the physiopathology of hepatitis C virus (HCV) infection is the remarkable efficiency with which host defenses are neutralized to establish chronic infection. Modulation of an apoptotic response is one strategy used by viruses to escape immune surveillance. We previously showed that HCV proteins down-regulate expression of BH3-only Bcl2 interacting domain (Bid) in hepatocytes of HCV transgenic mice. As a consequence, cells acquire resistance to Fas-mediated apoptosis, which in turn leads to increased persistence of experimental viral infections in vivo. This mechanism might participate in the establishment of chronic infections and the resulting pathologies, including hepatocellular carcinoma. We now report that Bid is also down-regulated in patients in the context of noncirrhotic HCV-linked tumorigenesis and in the HCV RNA replicon system. We show that the nonstructural HCV viral protein NS5A is sufficient to activate a calpain cysteine protease, leading to degradation of Bid. Moreover, pharmacological inhibitors of calpains restore both the physiological levels of Bid and the sensitivity of cells toward a death receptor-mediated apoptotic signal. Finally, human HCV-related tumors and hepatocytes from HCV transgenic mice that display low Bid expression contain activated calpains. Conclusion: Calpains activated by HCV proteins degrade Bid and thus dampen apoptotic signaling. These results suggest that inhibiting calpains could lead to an improved efficiency of immune-mediated elimination of HCV-infected cells. (HEPATOLOGY 2009;50:1370-1379.)P ersistent infection with hepatitis C virus (HCV) is among the most common infectious causes of chronic liver disease. The majority of patients fail to clear the virus and become chronic carriers, with a persistent presence of detectable virus in the serum. 1 Patients with chronic hepatitis C are at risk for hepatic fibrosis, frequently culminating in hepatic cirrhosis and hepatocellular carcinoma (HCC). 2 FL-N/35 transgenic mice, with hepatocyte-targeted expression of the entire open reading frame of the genotype 1b HCV, are at risk for steatosis and hepatocellular adenoma and carcinoma. 3 We previously showed that the FL-N/35 hepatocytes are resistant to apoptosis induced by the Fas/CD95 death receptor stimulation. The lack of sensitivity to apoptotic stimulation was related to decreased expression of BH3-only Bcl2 interacting domain (Bid), a BH3-only member of the Bcl-2 family of apoptosis regulators. 4 Importantly, Bid-deficient hepatocytes are refractory to T lymphocyte-induced cell death, suggesting that apoptosis contributes to HCV persistence and, as a consequence, to liver pathologies characteristic of chronic HCV infection. 4 Here, we report that Bid is also down-regulated in the context of the subgenomic and genome-length HCV replicons and in a subset of HCV-linked human HCC.

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“…For both HCV structural and nonstructural proteins, pro-and antiapoptotic properties have been described (13). Viral RNA has been shown to be able to induce apoptosis via activation of protein kinase R and the retinoic acid inducible gene-I-Cardif pathway (14 -16).…”

Section: H Epatitis C Virus (Hcv)mentioning

confidence: 99%

“…Thus, the relevance of these observations for HCV infection remained uncertain. Limitations of surrogate models of HCV infection are, among others, artificially elevated levels of expressed HCV proteins or the lack of genetic elements in subgenomic replicons (13). To overcome these limitations and to study the mechanism of apoptosis in a model system closer to HCV infection in vivo, we used the HCVcc model system allowing us to study HCV-host interactions in the context of the complete viral life cycle (18 -20).…”

Section: Viral Factors Required For Sensitization To Trail-induced Apmentioning

confidence: 99%

Hepatitis C Virus Infection Sensitizes Human Hepatocytes to TRAIL-Induced Apoptosis in a Caspase 9-Dependent Manner

Lin

Gorke

Rau

et al. 2008

The Journal of Immunology

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Apoptosis of infected cells represents a key host defense mechanism against viral infections. The impact of apoptosis on the elimination of hepatitis C virus (HCV)-infected cells is poorly understood. The TRAIL has been implicated in the death of liver cells in hepatitis-infected but not in normal liver cells. To determine the impact of TRAIL on apoptosis of virus-infected host cells, we studied TRAIL-induced apoptosis in a tissue culture model system for HCV infection. We demonstrated that HCV infection sensitizes primary human hepatocytes and Huh7.5 hepatoma cells to TRAIL induced apoptosis in a dose- and time-dependent manner. Mapping studies identified the HCV nonstructural proteins as key mediators of sensitization to TRAIL. Using a panel of inhibitors targeting different apoptosis pathways, we demonstrate that sensitization to TRAIL is caspase-9 dependent and mediated in part via the mitochondrial pathway. Sensitization of hepatocytes to TRAIL-induced apoptosis by HCV infection represents a novel antiviral host defense mechanism that may have important implications for the pathogenesis of HCV infection and may contribute to the elimination of virus-infected hepatocytes.

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Hepatitis C virus infection and apoptosis

Cited by 117 publications

References 106 publications

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway #

Hepatitis C Virus Infection Sensitizes Human Hepatocytes to TRAIL-Induced Apoptosis in a Caspase 9-Dependent Manner

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