Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

Colpitts, Che C.; Tsai, Pei-Ling; Zeisel, Mirjam B.

doi:10.3390/ijms21062091

Cited by 30 publications

(31 citation statements)

References 160 publications

(200 reference statements)

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“…HCV infects predominantly hepatocytes, but additional reservoirs in peripheral blood mononuclear cells (PBMC), including dendritic cells, B cells, and T cells have been suggested [12][13][14][15]. HCV entry in hepatocytes requires an unusually large number of host factors for binding, post-binding, internalization and fusion with endosomal membranes (reviewed in [16]), also engaging host signaling pathways involved in cell proliferation and survival. Translation of the released viral genome at the endoplasmic reticulum is initiated by a viral internal ribosomal entry site (IRES), which requires the microRNA (miRNA) miR-122 for its stabilization [17,18].…”

Section: Hcv Life Cyclementioning

confidence: 99%

“…The replication complex accumulates lipid droplets and lipoproteins, which are essential for virus assembly [19]. HCV lipoviral particles are released via the Golgi compartment in a non-lytic manner to the extracellular space [21] or are transmitted to the neighboring hepatocytes in a cell-free manner [16].…”

Section: Hcv Life Cyclementioning

confidence: 99%

“…Its expression on exhausted T cells is at least partially maintained even following DAA cure [108,109], potentially due to epigenetic modifications induced by long term exposure to HCV. Additionally, multiple reports suggest that immune cells, including T cells can also be productively infected by HCV [12][13][14][15], although it remains unclear to which degree this might affect the HCV-specific immune response [13,15,16]. HCV infection has been linked to the presence of myeloid-derived suppressor cells (MDSCs), a population of myeloid cells that negatively regulates the function of NK, CD4+ and CD8+ T cells [110].…”

Section: Immune-mediated Contribution To Liver Disease Progression Dumentioning

confidence: 99%

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Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

Goto

Suarez

Wrensch

et al. 2020

IJMS

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Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virologic response; however, the HCC risk remains elevated in cured patients, especially those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies.

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Section: Hcv Life Cyclementioning

confidence: 99%

Section: Hcv Life Cyclementioning

confidence: 99%

Section: Immune-mediated Contribution To Liver Disease Progression Dumentioning

confidence: 99%

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Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

Goto

Suarez

Wrensch

et al. 2020

IJMS

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“…Hepatitis C virus (HCV) is an enveloped RNA virus classified in the family Flaviviridae, genus Hepacivirus. The virus comes as a mixed lipo-viro particle and mostly infects human liver hepatocytes by binding to a variety of receptors [1,2]. In many cases, HCV infection is not eliminated by the immune system but becomes chronic, often also leading to liver cirrhosis and liver cancer (hepatocellular carcinoma; HCC) [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication

Gerresheim

Hess

Shalamova

et al. 2020

IJMS

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Hepatitis C virus (HCV) infects liver cells and often causes chronic infection, also leading to liver cirrhosis and cancer. In the cytoplasm, the viral structural and non-structural (NS) proteins are directly translated from the plus strand HCV RNA genome. The viral proteins NS3 to NS5B proteins constitute the replication complex that is required for RNA genome replication via a minus strand antigenome. The most C-terminal protein in the genome is the NS5B replicase, which needs to initiate antigenome RNA synthesis at the very 3′-end of the plus strand. Using ribosome profiling of cells replicating full-length infectious HCV genomes, we uncovered that ribosomes accumulate at the HCV stop codon and about 30 nucleotides upstream of it. This pausing is due to the presence of conserved rare, inefficient Wobble codons upstream of the termination site. Synonymous substitution of these inefficient codons to efficient codons has negative consequences for viral RNA replication but not for viral protein synthesis. This pausing may allow the enzymatically active replicase core to find its genuine RNA template in cis, while the protein is still held in place by being stuck with its C-terminus in the exit tunnel of the paused ribosome.

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“…The use of entry inhibitors perioperatively upon liver transplantation, either alone or in combination with DAAs, may improve treatment outcomes significantly. 34,37 Thus, although the effectiveness of DAAs is not in question, there still are unmet needs that may be addressed through the use of entry inhibitors.…”

mentioning

confidence: 99%

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model

Dent¹,

Hamorsky²,

Vausselin³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Hepatitis C virus (HCV) infection remains a major cause of end-stage liver disease. Here, we show the efficacy and safety of a novel biotherapeutic targeting a HCV glycobiomarker in a mouse model, providing a foundation for a new anti-HCV strategy. BACKGROUND & AIMS: Infection with hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, there is no approved therapeutic targeting this potentially druggable biomarker. METHODS: The anti-HCV activity of Avaren-Fc (AvFc Q7) was evaluated through the use of in vitro neutralization assays as well as an in vivo challenge in the PXB Q8 chimeric human liver mouse model. Drug toxicity was assessed by histopathology, serum alanine aminotransferase, and mouse body weights. RESULTS: AvFc was capable of neutralizing cell culture-derived HCV in a genotype-independent manner, with 50% inhibitory concentration values in the low nanomolar range. Systemic administration of AvFc in a histidine-based buffer was well tolerated; after 11 doses every other day at 25 mg/kg there were no significant changes in body or liver weights or in blood human albumin or serum alanine aminotransferase activity. Gross necropsy and liver pathology confirmed the lack of toxicity. This regimen successfully prevented genotype 1a HCV infection in all animals, although an AvFc mutant lacking HMG binding activity failed. CONCLUSIONS: These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection, and AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCVrelated end-stage liver disease patients.

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Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

Cited by 30 publications

References 160 publications

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication

Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model

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