Complex lipid metabolic remodeling is required for efficient hepatitis C virus replication

Hofmann, Sarah; Krajewski, Matthias; Scherer, Christina; Scholz, Verena; Mordhorst, Valerie; Truschow, Pavel; Schöbel, Anja; Reimer, Rudolph; Schwudke, Dominik; Herker, Eva

doi:10.1016/j.bbalip.2018.06.002

Cited by 62 publications

(66 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The accumulation of longer fatty acids and cholesterol in the infected cells could inhibit the ubiquitindependent protein degradation pathway; therefore, increasing ER stress. 99 Persistent virus replication increases cellular DNA damage response, the frequency of DNA repair, transcriptional fidelity, and genomic instability, all of which create additional cellular stress. If the viral-induced stress becomes persistent and severe, that results in irreversible injury or death of infected cells.…”

Section: Hepatocytes In the Liver Undergo Pathological Adaptation To mentioning

confidence: 99%

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

Dash¹,

Aydın²,

Widmer³

et al. 2020

JHC

View full text Add to dashboard Cite

Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFNα) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.

show abstract

Section: Hepatocytes In the Liver Undergo Pathological Adaptation To mentioning

confidence: 99%

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

Dash¹,

Aydın²,

Widmer³

et al. 2020

JHC

View full text Add to dashboard Cite

show abstract

“…One important role of lipids in viral replication lies in the fact that it contributes to organizing subcellular space for key events to occur in the viral life cycle ( Figure 5). The majority of RNA viruses such as HCV, dengue virus (DENV) and rotavirus replicate in cell cytoplasm, and some of their viral proteins co-opt in lipid signaling to establish peculiar niches for viral RNA replication [124][125][126]. For instance, cytoplasmic lipid droplets function as a scaffold to assemble non-structural viral proteins and replication complexes for infectious HCV particle production, and as a vesicle to incorporate and export virus particles outside the cells [127].…”

Section: Lipogenesismentioning

confidence: 99%

Orchestrated efforts on host network hijacking: Processes governing virus replication

et al. 2020

View full text Add to dashboard Cite

With the high pervasiveness of viral diseases, the battle against viruses has never ceased. Here we discuss five cellular processes, namely "autophagy", "programmed cell death", "immune response", "cell cycle alteration", and "lipid metabolic reprogramming", that considerably guide viral replication after host infection in an orchestrated manner. On viral infection, "autophagy" and "programmed cell death" are two dynamically synchronized cell survival programs; "immune response" is a cell defense program typically suppressed by viruses; "cell cycle alteration" and "lipid metabolic reprogramming" are two altered cell housekeeping programs tunable in both directions. We emphasize on their functionalities in modulating viral replication, strategies viruses have evolved to tune these processes for their benefit, and how these processes orchestrate and govern cell fate upon viral infection. Understanding how viruses hijack host networks has both academic and industrial values in providing insights toward therapeutic strategy design for viral disease control, offering useful information in applications that aim to use viral vectors to improve human health such as gene therapy, and providing guidelines to maximize viral particle yield for improved vaccine production at a reduced cost. ARTICLE HISTORY

show abstract

“…Target cells grown in gridded µ-dishes (Ibidi) were visualized via live-cell epifluorescence or spinning disk confocal microscopy (Nikon) and fixed following a modified OTO fixation method (Hofmann et al, 2018;Seligman et al, 1966). Cells were fixed with EM-grade 2.5% glutaraldehyde and 1% osmium tetroxide in PBS for 1-16 h, washed with PBS and then treated with 0.1% thiocarbohydrazide for 30 min, followed by staining with 1% reduced osmium tetroxide in 1.5% potassium hexacyanoferrate for 15 min.…”

Section: Transmission Electron Microscopy Electron Tomography Corrementioning

confidence: 99%

Perilipin-2 is critical for efficient lipoprotein and hepatitis C virus particle production

Lassen

Grüttner

Nguyen-Dinh

et al. 2018

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

In hepatocytes, PLIN2 is the major protein coating lipid droplets (LDs), an organelle the hepatitis C virus (HCV) hijacks for virion morphogenesis. We investigated the consequences of PLIN2 deficiency on LDs and on HCV infection. Knockdown of PLIN2 did not affect LD homeostasis, likely due to compensation by PLIN3, but severely impaired HCV particle production. PLIN2-knockdown cells had slightly larger LDs with altered protein composition, enhanced local lipase activity and higher β-oxidation capacity. Electron micrographs showed that, after PLIN2 knockdown, LDs and HCVinduced vesicular structures were tightly surrounded by ER-derived double-membrane sacs. Strikingly, the LD access for HCV core and NS5A proteins was restricted in PLIN2-deficient cells, which correlated with reduced formation of intracellular HCV particles that were less infectious and of higher density, indicating defects in maturation. PLIN2 depletion also reduced protein levels and secretion of ApoE due to lysosomal degradation, but did not affect the density of ApoE-containing lipoproteins. However, ApoE overexpression in PLIN2-deficient cells did not restore HCV spreading. Thus, PLIN2 expression is required for trafficking of core and NS5A proteins to LDs, and for formation of functional low-density HCV particles prior to ApoE incorporation.This article has an associated First Person interview with the first author of the paper.

show abstract

Complex lipid metabolic remodeling is required for efficient hepatitis C virus replication

Cited by 62 publications

References 65 publications

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

Orchestrated efforts on host network hijacking: Processes governing virus replication

Perilipin-2 is critical for efficient lipoprotein and hepatitis C virus particle production

Contact Info

Product

Resources

About