Ultrastructural evidences of HCV infection in hepatocytes of chronically HCV-infected patients

Falcón, Viviana; Acosta‐Rivero, Nelson; Chinea, Glay; Gavilondo, Jorge V.; Rosa, María-C de la; Menéndez, Ivón; Dueñas‐Carrera, Santiago; Viña, Ariel; Garcı́a, Waldo; Gra, Bienvenido; Noa, Miríam; Reytor, Edel; Barceló, María Teresa; Alvarez, Felix; Morales-Grillo, Juan

doi:10.1016/s0006-291x(03)00884-2

Cited by 39 publications

(37 citation statements)

References 25 publications

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“…HCV core protein has been detected at various sites, such as the endoplasmic reticulum, mitochondria, lipid droplets, and nucleus of cultured cell lines, as well as in hepatocytes of PA28␥ ϩ/ϩ CoreTg mice and hepatitis C patients (6,23,24). Although HCV core protein is predominantly detected in the cytoplasm of the liver cells of PA28␥ ϩ/ϩ CoreTg mice, as reported in ref.…”

Section: Pa28␥ Is Required For Degradation Of Hcv Core Protein In Thesupporting

confidence: 58%

See 1 more Smart Citation

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Moriishi

Mochizuki

Moriya

et al. 2007

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

190

196

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Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28␥/REG␥ regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28␥ gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28␥-dependent manner. Heterodimer composed of liver X receptor ␣ (LXR␣) and retinoid X receptor ␣ (RXR␣) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXR␣/RXR␣ to LXR-response element in the presence but not the absence of PA28␥. These findings suggest that PA28␥ plays a crucial role in the development of liver pathology induced by HCV infection.fatty acid ͉ proteasome ͉ sterol regulatory element-binding protein (SREBP) ͉ RXR␣ ͉ LXR␣ H epatitis C virus (HCV) belongs to the Flaviviridae family, and it possesses a positive, single-stranded RNA genome that encodes a single polyprotein composed of Ϸ3,000 aa. The HCV polyprotein is processed by host and viral proteases, resulting in 10 viral proteins. Viral structural proteins, including the capsid (core) protein and two envelope proteins, are located in the N-terminal one-third of the polyprotein, followed by nonstructural proteins.HCV infects Ͼ170 million individuals worldwide, and then it causes liver disease, including hepatic steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC) (1). The prevalence of fatty infiltration in the livers of chronic hepatitis C patients has been reported to average Ϸ50% (2, 3), which is higher than the percentage in patients infected with hepatitis B virus and other liver diseases. However, the precise functions of HCV proteins in the development of fatty liver remain unknown because of the lack of a system sufficient to investigate the pathogenesis of HCV. HCV core protein expression has been shown to induce lipid droplets in cell lines and hepatic steatosis and HCC in transgenic mice (4-6). These reports suggest that HCV core protein plays an important role in the development of various types of liver failure, including steatosis and HCC.Recent reports suggest that lipid biosynthesis affects HCV replication (7-9). Involvement of a geranylgeranylated host protein, FBL2, in HCV replication through the interaction with NS5A suggests that the cholesterol biosynthesis pathway is also important for HCV replication (9). Increases in saturated and monounsaturated fatty acids enhance HCV RNA replication, whereas increases in polyunsaturat...

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Section: Pa28␥ Is Required For Degradation Of Hcv Core Protein In Thesupporting

confidence: 58%

“…HCV core protein is detected in the cytoplasm and partially in the nucleus and mitochondria of culture cells and hepatocytes of transgenic mice and hepatitis C patients (6,23,24,26). Degradation of HCV core protein was enhanced by deletion of the C-terminal transmembrane region through a ubiquitin/proteasome-dependent pathway (27).…”

Section: Discussionmentioning

confidence: 99%

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Moriishi

Mochizuki

Moriya

et al. 2007

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

190

196

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“…Recent reports considered the presence of negative strand RNA HCV as indicative of viral replication and its correlation with cytological alterations in human liver (Chang et al 2000, Quadri et al 2001, Falcón et al 2003, Yuki et al 2006). HCV do not replicate easily in cell cultures, and the infection titer in vivo is usually quite low; consequently, details about its replication cycle, both in vivo and in vitro, are not completely understood.…”

Section: Virus Reviews and Research 14 Nr 1 2009mentioning

confidence: 99%

“…Shimizu et al (1996) observed a positive reaction in the liver biopsies of HCV infected chimpanzees, using the immunofluorescence technique with anti-HCV envelope protein. Ultrastructural observations of hepatocytes of chimpanzee and human liver biopsies showed the HCV core protein localized around lipids droplets and endoplasmic reticulum membranes (Barba et al 1997, Falcón et al 2003. Since the development of HCV replicons capable of replication in a human hepatoma Huh-7 cell line (Lohmann et al 1999) was realized, several studies of HCV morphogenesis were published.…”

Section: Virus Reviews and Research 14 Nr 1 2009mentioning

confidence: 99%

Ultrastructural Localization of Hepatitis C Virus Positive and Negative Strand Rna and Proteins in Hepatocytes of a Rhesus Monkey (Macaca Mulatta)

Majerowicz¹,

Grief²,

Pinto³

et al. 2009

VR&R

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Morphological alterations of the liver from rhesus macaque (Macaca mulatta)experimentally infected with hepatitis C virus (HCV) were analyzed using electron microscopy. The localization of viral RNA and proteins inside hepatocytes was demonstrated using in situ hybridization and immunoelectron microscopy techniques. The animals were inoculated by different routes. The infection was successful only by use of the intrasplenic approach to HCV infected autogenic hepatocyte transplant. The inoculum used to infect the hepatocytes was characterized as genotype 3 with 10 7 RNA copies/mL. In situ hybridization was performed using a complementary negative and positive strand probe made with the specific primer. Despite that the level of HCV infection was considered to be low, we were able to detect and localize viral positive and negative RNA strands and viral proteins in altered membranes of the rough endoplasmic reticulum in infected liver cells, showing evidence of viral replication in vivo.

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“…In sharp contrast, HCV has never been characterised by EM, and little is known about its structure and morphogenesis in host cells, due to the lack of an efficient in vitro culture system (Bartenschlager and Lohman, 2000). In addition, the direct visualisation of virus particles from infected serum (Kaito et al, 1994;Kanto et al, 1994;Prince et al, 1996;Trestard et al, 1998;Schmidt et al, 2000) or liver tissue (De Vos et al, 2002;Falcon et al, 2003) has proved very difficult. In these studies, putative HCV particles were observed that varied in shape and size, between 30 and 60 nm in diameter.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus ultrastructure and morphogenesis

Roingeard

Hourioux

Blanchard

et al. 2004

Biology of the Cell

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Details of the ultrastructure of hepatitis C virus (HCV) virion remain unclear because it has proved extremely difficult to visualise virus particles from infected serum and tissues directly. In addition, although much is known about the viral genome, first cloned in 1989, little is known about HCV morphogenesis, due to the lack of an efficient in vitro culture system for HCV propagation. Virus-like particles (VLPs) obtained by expressing genes encoding the HCV structural proteins in mammalian cells can be used as an alternative model for studying HCV morphogenesis. In particular, this HCV-LP model has made it possible to demonstrate that HCV budding occurs at the ER membrane and that the core protein drives this process. The HCV-LP model opens up new possibilities for the investigation of viral morphogenesis and virus-host cell interactions, which may make it possible to establish the long-awaited in vitro culture system for HCV.

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Ultrastructural evidences of HCV infection in hepatocytes of chronically HCV-infected patients

Cited by 39 publications

References 25 publications

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Ultrastructural Localization of Hepatitis C Virus Positive and Negative Strand Rna and Proteins in Hepatocytes of a Rhesus Monkey (Macaca Mulatta)

Hepatitis C virus ultrastructure and morphogenesis

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