Genomic analysis of the host response to hepatitis C virus infection

Su, Andrew I.; Pezacki, John Paul; Wodicka, Lisa; Brideau, Amy D.; Supeková, Lubica; Thimme, Robert; Wieland, Stefan; Bukh, Jens; Purcell, Robert H.; Schultz, Peter G.; Chisari, Francis V.

doi:10.1073/pnas.202608199

Cited by 798 publications

(262 citation statements)

References 72 publications

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“…Inhibition of fatty acid synthesis by inhibiting acetyl-CoA carboxylase led to a decrease in HCV replication, consistent with our previously published data (12), which demonstrated that inhibition of FAS by using the drug cerulenin inhibited replication of the subgenomic HCV RNA replicon. We have further demonstrated that saturated and monounsaturated fatty acids can enhance HCV RNA replication, consistent with the requirement of the fatty-acid-biosynthetic pathway in HCV RNA replication.…”

Section: Discussionsupporting

confidence: 92%

“…1). These data, along with previous gene-expression profiling analyses in acutely infected chimpanzees (12), suggest that HCV may directly or indirectly induce cholesterol and͞or fatty-acidbiosynthetic gene expression.…”

Section: Generation Of Ribonuclease-protection Assay (Rpa) Probes Forsupporting

confidence: 65%

“…In the current study, we have shown that geranylgeraniol and farnesol actually stimulate HCV RNA replication, suggesting that they may exert a proviral effect as a result of the induction of lipogenic gene expression in repliconcontaining Huh-7 cells (Fig. 1) and in acutely infected chimpanzees (12). Our results further demonstrate that the proviral effect of geranylgeraniol is antagonized by the acetyl-CoA carboxylase inhibitor, TOFA, suggesting that geranylgeranylation alone does not mediate efficient HCV RNA replication, but that fatty acid synthesis is required as well, perhaps to help form the fatty-acidcontaining cellular membranes to which the putative geranylgeranylated protein(s) are most likely targeted.…”

Section: Discussionmentioning

confidence: 51%

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Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids

Kapadia

Chisari²

2005

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

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467

413

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Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Our laboratory has previously demonstrated that high-level HCV replication during acute infection of chimpanzees is associated with the modulation of multiple genes involved in lipid metabolism, and that drugs that regulate cholesterol and fatty acid biosynthesis regulate the replication of the subgenomic HCV replicon in Huh-7 cells. In this article, we demonstrate that Huh-7 cells harboring replicating, full-length HCV RNAs express elevated levels of ATP citrate lyase and acetyl-CoA synthetase genes, both of which are involved in cholesterol and fatty acid biosynthesis. Further, we confirm that the cholesterol-biosynthetic pathway controls HCV RNA replication by regulating the cellular levels of geranylgeranyl pyrophosphate, we demonstrate that the impact of geranylgeranylation depends on the fatty acid content of the cell, and we show that fatty acids can either stimulate or inhibit HCV replication, depending on their degree of saturation. These results illustrate a complex cellular-regulatory network that controls HCV RNA replication, presumably by modulating the trafficking and association of cellular and͞or viral proteins with cellular membranes, suggesting that pharmacologic manipulation of these pathways may have a therapeutic effect in chronic HCV infection.cholesterol ͉ replicon H epatitis C virus (HCV), a member of the Flaviviridae family of viruses, is a major cause of chronic hepatitis and hepatocellular carcinoma (1, 2). The HCV genome is a positivestranded Ϸ9.6-kb RNA molecule consisting of a single ORF, which is flanked by 5Ј and 3Ј untranslated regions (UTR). The HCV 5Ј UTR contains a highly structured internal ribosome entry site (3-8), and the 3Ј UTR is essential for replication (9, 10). The HCV ORF encodes a single 3,008-to 3,037-aa polyprotein that is posttranslationally processed to produce Ն10 different proteins: core protein, envelope proteins E1 and E2, p7, and nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B (1,8,11). Our understanding of the biology of HCV RNA replication has been greatly facilitated by the development of subgenomic and full-length HCV replicons that express HCV proteins and replicate their RNA in stably transfected human hepatoma-cell-derived Huh-7 cells.Our laboratory has previously demonstrated (12) that multiple cellular genes involved in lipid metabolism are differentially regulated during viral spread in acutely infected chimpanzees, and that ATP citrate lyase, which is required for cholesterol and fatty acid biosynthesis, is induced during the initial rise of high-level HCV replication during acute infection in chimpanzees. There is considerable evidence suggesting that the cholesterol and fatty-acid-biosynthesis pathways may play a role in HCV replication and infection. Steatosis, i.e., the formation of hepatocellular lipid droplets, is a well documented histological characteristic of HCV infection in humans, chimpanzees, and mouse m...

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Section: Discussionsupporting

confidence: 92%

Section: Generation Of Ribonuclease-protection Assay (Rpa) Probes Forsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 51%

See 1 more Smart Citation

Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids

Kapadia

Chisari²

2005

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

Self Cite

467

413

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“…Recent reports suggest that lipid biosynthesis affects HCV replication (7)(8)(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).…”

mentioning

confidence: 99%

“…Biosynthesis of cholesterol is regulated by SREBP-2, whereas that of fatty acids, triglycerides, and phospholipids is regulated by SREBP-1c (10)(11)(12)(13)(14). In chimpanzees, host genes involved in SREBP signaling are induced during the early stages of HCV infection (8). SREBP-1c regulates the transcription of acetylCoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, leading to the production of saturated and monounsaturated fatty acids and triglycerides (15).…”

mentioning

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.

191

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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ISG20: an enigmatic antiviral RNase targeting multiple viruses

et al. 2022

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Interferon‐stimulated gene 20 kDa protein (ISG20) is a relatively understudied antiviral protein capable of inhibiting a broad spectrum of viruses. ISG20 exhibits strong RNase properties, and it belongs to the large family of DEDD exonucleases, present in both prokaryotes and eukaryotes. ISG20 was initially characterized as having strong RNase activity in vitro, suggesting that its inhibitory effects are mediated via direct degradation of viral RNAs. This mechanism of action has since been further elucidated and additional antiviral activities of ISG20 highlighted, including direct degradation of deaminated viral DNA and translational inhibition of viral RNA and nonself RNAs. This review focuses on the current understanding of the main molecular mechanisms of viral inhibition by ISG20 and discusses the latest developments on the features that govern specificity or resistance to its action.

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Genomic analysis of the host response to hepatitis C virus infection

Cited by 798 publications

References 72 publications

Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids

Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids

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

ISG20: an enigmatic antiviral RNase targeting multiple viruses

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