Visualizing Hepatitis C Virus Infections in Human Liver by Two-Photon Microscopy

Liang, Yuqiong; Shilagard, Tuya; Xiao, Shu‐Yuan; Snyder, Ned; Lau, Daryl T.Y.; Cicalese, Luca; Weiss, Helen A.; Vargas, Gracie; Lemon, Stanley M.

doi:10.1053/j.gastro.2009.07.050

Cited by 164 publications

(190 citation statements)

References 31 publications

Supporting

Mentioning

146

Contrasting

Order By: Relevance

“…However, the low abundance of HCV proteins expressed within the liver, together with the nearly uniform presence of tissue autofluorescence in liver specimens, make a reliable detection of HCV in human liver tissue highly difficult. 19 The present data show that the ability of HCV to increase autophagic vesicles is not limited to one HCV genotype. This is in accordance with data obtained in vitro showing induction of autophagic vesicles in cells harboring the genotype 2a HCV JFH1 strain, or the genotype 1b Con1 virus subgenomic RNA replicon.…”

Section: Autophagy In Hcv Patients 2713mentioning

confidence: 48%

Changes in Autophagic Response in Patients with Chronic Hepatitis C Virus Infection

Rautou

Cazals–Hatem

Feldmann

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Autophagy is a regulated process that can be involved in the elimination of intracellular microorganisms and in antigen presentation. Some in vitro studies have shown an altered autophagic response in hepatitis C virus infected hepatocytes. The present study aimed at evaluating the autophagic process in the liver of chronic hepatitis C (CHC) patients. Fifty-six CHC patients and 47 control patients (8 with nonalcoholic steatohepatitis or alcoholic liver disease, 18 with chronic heptatitis B virus infection, and 21 with no or mild liver abnormalities at histological examination) were included. Autophagy was assessed by means of electron microscopy and microtubule-associated protein light chain 3 immunoblotting. Using light chain 3 immunoblotting, the form present on autophagic vesicle (light chain 3-II) was significantly higher in CHC patients than in controls (P < 0.05). Using quantitative electron microscopy analysis, the median number of autophagic vesicles observed in hepatocytes from CHC patients was sixfold higher than in overall controls (P < 0.001). In contrast, there was no difference between CHC patients and controls in the number of mature lysosomes with electron-dense contents arguing in favor of a lack of fusion between autophagosome and lysosome. Neither genotype nor viral load influenced the autophagy level. In conclusion, autophagy is altered in hepatocytes from CHC patients, likely due to a blockade of the last step of the autophagic process.

show abstract

Section: Autophagy In Hcv Patients 2713mentioning

confidence: 48%

Changes in Autophagic Response in Patients with Chronic Hepatitis C Virus Infection

Rautou

Cazals–Hatem

Feldmann

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Its principle application in liver has been demonstrated using frozen sections of human livers infected with hepatitis C virus (29). Few studies have applied this method for liver in living mice, mostly because of artifacts created by breath movements and the autofluorescence of hepatic tissue (27,30).…”

Section: Discussionmentioning

confidence: 99%

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Wehr

Baeck

Heymann

et al. 2013

The Journal of Immunology

228

198

View full text Add to dashboard Cite

Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6+/gfp and Cxcr6gfp/gfp mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6−/− mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6−/− mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.

show abstract

“…Previous studies performed by in situ PCR (33,34), fluorescence microscopy (35), or laser-capture microdissection followed by RT-PCR (36,37) indicated that the distribution of HCV RNA in the liver is focal and that the percentage of infected hepatocytes is low (never >35% of the total population). However, the focal distribution of HCV-infected cells (37) cannot explain the restricted viral replication that we detected exclusively within the tumor.…”

Section: Discussionmentioning

confidence: 99%

Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue

Harouaka

Engle

Wollenberg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Analysis of hepatitis C virus (HCV) replication and quasispecies distribution within the tumor of patients with HCV-associated hepatocellular carcinoma (HCC) can provide insight into the role of HCV in hepatocarcinogenesis and, conversely, the effect of HCC on the HCV lifecycle. In a comprehensive study of serum and multiple liver specimens from patients with HCC who underwent liver transplantation, we found a sharp and significant decrease in HCV RNA in the tumor compared with surrounding nontumorous tissues, but found no differences in multiple areas of control non-HCC cirrhotic livers. Diminished HCV replication was not associated with changes in miR-122 expression. HCV genetic diversity was significantly higher in livers containing HCC compared with control non-HCC cirrhotic livers. Tracking of individual variants demonstrated changes in the viral population between tumorous and nontumorous areas, the extent of which correlated with the decline in HCV RNA, suggesting HCV compartmentalization within the tumor. In contrast, compartmentalization was not observed between nontumorous areas and serum, or in controls between different areas of the cirrhotic liver or between liver and serum. Our findings indicate that HCV replication within the tumor is restricted and compartmentalized, suggesting segregation of specific viral variants in malignant hepatocytes.hepatitis C virus | hepatocellular carcinoma | HCV RNA levels | HCV quasispecies | liver H epatitis C virus (HCV) is a hepatotropic, single-stranded RNA virus that replicates in the cytoplasm of hepatocytes and does not integrate into the host genome (1). HCV circulates in vivo as a dynamic distribution of closely related viral variants that are commonly referred to as "quasispecies" (2). Such diversity confers a remarkable advantage to the virus under host selective constraints (3-5). One of the most important features of HCV is its extraordinary ability to persist in up to 80% of infected individuals (6). Approximately 20-30% of chronic HCV carriers develop cirrhosis and its long-term sequelae, including hepatic decompensation and hepatocellular carcinoma (HCC), leading to orthotopic liver transplantation (OLT) or liver-related death (6). The incidence of HCC in the United States has more than tripled over the past 3 decades (7), an alarming trend due primarily, if not exclusively, to HCV infection (8).Although epidemiologic evidence has linked chronic HCV infection to a significantly elevated risk of developing HCC (9), the mechanisms whereby HCV promotes hepatocarcinogenesis remain to be elucidated (10). Whether HCV elicits liver cancer indirectly, through chronic inflammation, fibrosis, and continuous liver regeneration (11), or directly, through the expression of tumor-promoting viral proteins, in a manner analogous to other oncogenic viruses, such as human papillomaviruses and EpsteinBarr virus (12, 13), remains unknown. The major challenges in defining the role of HCV in the pathogenesis of HCC include the inherent limitations of available experimental...

show abstract

Visualizing Hepatitis C Virus Infections in Human Liver by Two-Photon Microscopy

Cited by 164 publications

References 31 publications

Changes in Autophagic Response in Patients with Chronic Hepatitis C Virus Infection

Changes in Autophagic Response in Patients with Chronic Hepatitis C Virus Infection

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue

Contact Info

Product

Resources

About