scholarly journals Lipoprotein Receptors and Lipid Enzymes in Hepatitis C Virus Entry and Early Steps of Infection

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Eve-Isabelle Pécheur
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Virus ◽  
Host Cells ◽  
Lipoprotein Receptors ◽  
Lipid Disorders ◽  
Liver Injuries ◽  
Positive Strand Rna Virus ◽  
Positive Strand Rna ◽  
Viral Host Range

Viruses are obligate intracellular agents that depend on host cells for successful propagation, hijacking cellular machineries to their own profit. The molecular interplay between host factors and invading viruses is a continuous coevolutionary process that determines viral host range and pathogenesis. The hepatitis C virus (HCV) is a strictly human pathogen, causing chronic liver injuries accompanied by lipid disorders. Upon infection, in addition to protein-protein and protein-RNA interactions usual for such a positive-strand RNA virus, HCV relies on protein-lipid interactions at multiple steps of its life cycle to establish persistent infection, making use of hepatic lipid pathways. This paper focuses on lipoproteins in HCV entry and on receptors and enzymes involved in lipid metabolism that HCV exploits to enter hepatocytes.

scholarly journals Role of RNA Structures in Genome Terminal Sequences of the Hepatitis C Virus for Replication and Assembly

2009 ◽  
Vol 83 (22) ◽  
pp. 11989-11995 ◽  
Author(s):  
Peter Friebe ◽  
Ralf Bartenschlager
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Virus ◽  
Hcv Rna ◽  
Rna Structures ◽  
Rna Packaging ◽  
Stem Loop ◽  
Nontranslated Region ◽  
Positive Strand Rna Virus ◽  
Positive Strand Rna

ABSTRACT Hepatitis C virus (HCV) is a positive-strand RNA virus replicating its genome via a negative-strand [(−)] intermediate. Little is known about replication signals residing in the 3′ end of HCV (−) RNA. Recent studies identified seven stem-loop structures (SL-I′, -IIz′, -IIy′, -IIIa′, -IIIb′, -IIIcdef′, and -IV′) in this region. In the present study, we mapped the minimal region required for RNA replication to SL-I′ and -IIz′, functionally confirmed the SL-IIz′ structure, and identified SL-IIIa′ to -IV′ as auxiliary replication elements. In addition, we show that the 5′ nontranslated region of the genome most likely does not contain cis-acting RNA structures required for RNA packaging into infectious virions.

Increase of SARS-CoV 3CL peptidase activity due to macromolecular crowding effects in the milieu composition

2010 ◽  
Vol 391 (12) ◽  
Author(s):  
Debora N. Okamoto ◽  
Lilian C.G. Oliveira ◽  
Marcia Y. Kondo ◽  
Maria H.S. Cezari ◽  
Zoltán Szeltner ◽  
...  
Keyword(s):  
Rna Virus ◽  
Antiviral Agents ◽  
Fine Tuning ◽  
Host Cells ◽  
Respiratory Syndrome Virus ◽  
Peptidase Activity ◽  
Buffer Solutions ◽  
Tuning Mechanism ◽  
Positive Strand Rna Virus ◽  
Positive Strand Rna

Abstract The 3C-like peptidase of the severe acute respiratory syndrome virus (SARS-CoV) is strictly required for viral replication, thus being a potential target for the development of antiviral agents. In contrast to monomeric picornavirus 3C peptidases, SARS-CoV 3CLpro exists in equilibrium between the monomer and dimer forms in solution, and only the dimer is proteolytically active in dilute buffer solutions. In this study, the increase of SARS-CoV 3CLpro peptidase activity in presence of kosmotropic salts and crowding agents is described. The activation followed the Hofmeister series of anions, with two orders of magnitude enhancement in the presence of Na2SO4, whereas the crowding agents polyethylene glycol and bovine serum albumin increased the hydrolytic rate up to 3 times. Kinetic determinations of the monomer dimer dissociation constant (K d) indicated that activation was a result of a more active dimer, without significant changes in K d values. The activation was found to be independent of substrate length and was derived from both k cat increase and K m decrease. The viral peptidase activation described here could be related to the crowded intracellular environment and indicates a further fine-tuning mechanism for biological control, particularly in the microenvironment of the vesicles that are induced in host cells during positive strand RNA virus infection.

scholarly journals COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

2020 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Carbon Dioxide ◽  
Rna Virus ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
The Novel ◽  
Beta Chain ◽  
Positive Strand Rna Virus ◽  
Novel Coronavirus ◽  
Positive Strand Rna ◽  
Bat Coronavirus

<p>The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking were used to compare the biological roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease. According to the validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins. Because the novel coronavirus is dependent on porphyrins, it may originate from an ancient virus. Therefore, this research is of high value to contemporary biological experiments, disease prevention, and clinical treatment.<br></p>

scholarly journals COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

2020 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Carbon Dioxide ◽  
Rna Virus ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
The Novel ◽  
Beta Chain ◽  
Positive Strand Rna Virus ◽  
Novel Coronavirus ◽  
Positive Strand Rna ◽  
Bat Coronavirus

<p>The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking were used to compare the biological roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease. According to the validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins. Because the novel coronavirus is dependent on porphyrins, it may originate from an ancient virus. Therefore, this research is of high value to contemporary biological experiments, disease prevention, and clinical treatment.<br></p>

scholarly journals N-Myc Downstream-Regulated Gene 1 Restricts Hepatitis C Virus Propagation by Regulating Lipid Droplet Biogenesis and Viral Assembly

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Cameron J. Schweitzer ◽  
Fang Zhang ◽  
Audrey Boyer ◽  
Kristin Valdez ◽  
Maggie Cam ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Cancer ◽  
Lipid Droplet ◽  
Viral Infections ◽  
Rna Virus ◽  
Viral Assembly ◽  
Hcv Infection ◽  
Host Cells ◽  
Virus Propagation

ABSTRACT Host cells harbor various intrinsic mechanisms to restrict viral infections as a first line of antiviral defense. Viruses have evolved various countermeasures against these antiviral mechanisms. Here we show that N-Myc downstream-regulated gene 1 (NDRG1) limits productive hepatitis C virus (HCV) infection by inhibiting viral assembly. Interestingly, HCV infection downregulates NDRG1 protein and mRNA expression. The loss of NDRG1 increases the size and number of lipid droplets, which are the sites of HCV assembly. HCV suppresses NDRG1 expression by upregulating MYC, which directly inhibits the transcription of NDRG1. The upregulation of MYC also leads to the reduced expression of the NDRG1-specific kinase serum/glucocorticoid-regulated kinase 1 (SGK1), resulting in a markedly diminished phosphorylation of NDRG1. The knockdown of MYC during HCV infection rescues NDRG1 expression and phosphorylation, suggesting that MYC regulates NDRG1 at both the transcriptional and posttranslational levels. Overall, our results suggest that NDRG1 restricts HCV assembly by limiting lipid droplet formation. HCV counteracts this intrinsic antiviral mechanism by downregulating NDRG1 via a MYC-dependent mechanism. IMPORTANCE Hepatitis C virus (HCV) is an enveloped single-stranded RNA virus that targets hepatocytes in the liver. HCV is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, and estimates suggest a global prevalence of 2.35%. Up to 80% of acutely infected individuals will develop chronic infection, and as many as 5% eventually progress to liver cancer. An understanding of the mechanisms behind virus-host interactions and viral carcinogenesis is still lacking. The significance of our research is that it identifies a previously unknown relationship between HCV and a known tumor-associated gene. Furthermore, our data point to a new role for this gene in the liver and in lipid metabolism. Thus, HCV infection serves as a great biological model to advance our knowledge of liver functions and the development of liver cancer.

scholarly journals Nucleotide requirements at positions +1 to +4 for the initiation of hepatitis C virus positive-strand RNA synthesis

2011 ◽  
Vol 92 (5) ◽  
pp. 1082-1086 ◽  
Author(s):  
Udvitha Nandasoma ◽  
Christopher McCormick ◽  
Stephen Griffin ◽  
Mark Harris
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Virus ◽  
Hammerhead Ribozyme ◽  
Rna Replication ◽  
Genome Replication ◽  
Wild Type ◽  
Subgenomic Replicon ◽  
Positive Strand ◽  
Positive Strand Rna

RNA virus genome replication requires initiation at the precise terminus of the template RNA. To investigate the nucleotide requirements for initiation of hepatitis C virus (HCV) positive-strand RNA replication, a hammerhead ribozyme was inserted at the 5′ end of an HCV subgenomic replicon, allowing the generation of replicons with all four possible nucleotides at position 1. This analysis revealed a preference for a purine nucleotide at this position for initiation of RNA replication. The sequence requirements at positions 2–4 in the context of the J6/JFH-1 virus were also examined by selecting replication-competent virus from a pool containing randomized residues at these positions. There was strong selection for both the wild-type cytosine at position 2, and the wild-type sequence at positions 2–4 (CCU). An adenine residue was well tolerated at positions 3 and 4, which suggests that efficient RNA replication is less dependent on these residues.

scholarly journals COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

2020 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Carbon Dioxide ◽  
Rna Virus ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
The Novel ◽  
Beta Chain ◽  
Positive Strand Rna Virus ◽  
Novel Coronavirus ◽  
Positive Strand Rna ◽  
Bat Coronavirus

<p>The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking were used to compare the biological roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease. According to the validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress. Since the ability of chloroquine to inhibit structural proteins is not particularly obvious, the therapeutic effect on different people may be different. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins. This paper is only for academic discussion, the correctness needs to be confirmed by other laboratories. Due to the side effects and allergic reactions of drugs such as chloroquine, please consult a qualified doctor for treatment details, and do not take the medicine yourself.</p>

scholarly journals Expressionof Unmodified Hepatitis C Virus Envelope Glycoprotein-Coding SequencesLeads to Cryptic Intron Excision and Cell Surface Expression of E1/E2Heterodimers Comprising Full-Length and Partially DeletedE1

2003 ◽  
Vol 77 (24) ◽  
pp. 13418-13424 ◽  
Author(s):  
Julie Dumonceaux ◽  
Emmanuel G. Cormier ◽  
Francis Kajumo ◽  
Gerald P. Donovan ◽  
Jayanta Roy-Chowdhury ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Virus ◽  
Expression System ◽  
Surface Expression ◽  
Viral Envelope ◽  
Cell Surface Expression ◽  
Envelope Glycoproteins ◽  
Virus Envelope ◽  
Positive Strand Rna

ABSTRACT Hepatitis C virus (HCV) is a positive-strand RNA virus that replicates exclusively in the cytoplasm of infected cells. The viral envelope glycoproteins, E1 and E2, appear to be retained in the endoplasmic reticulum, where viral budding is thought to occur. Surprisingly, we found that the expression system used to generate HCV envelope glycoproteins influences their subcellular localization and processing. These findings have important implications for optimizing novel HCV fusion and entry assays as well as for budding and virus particle formation.

scholarly journals Kissing-Loop Interaction in the 3′ End of the Hepatitis C Virus Genome Essential for RNA Replication

2005 ◽  
Vol 79 (1) ◽  
pp. 380-392 ◽  
Author(s):  
Peter Friebe ◽  
Julien Boudet ◽  
Jean-Pierre Simorre ◽  
Ralf Bartenschlager
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structure Prediction ◽  
Secondary Structure Prediction ◽  
Rna Virus ◽  
Rna Replication ◽  
Resonance Spectroscopy ◽  
Stem Loop ◽  
Loop Region ◽  
Positive Strand Rna

ABSTRACT The hepatitis C virus (HCV) is a positive-strand RNA virus belonging to the Flaviviridae. Its genome carries at either end highly conserved nontranslated regions (NTRs) containing cis-acting RNA elements that are crucial for replication. In this study, we identified a novel RNA element within the NS5B coding sequence that is indispensable for replication. By using secondary structure prediction and nuclear magnetic resonance spectroscopy, we found that this RNA element, designated 5BSL3.2 by analogy to a recent report (S. You, D. D. Stump, A. D. Branch, and C. M. Rice, J. Virol. 78:1352-1366, 2004), consists of an 8-bp lower and a 6-bp upper stem, an 8-nucleotide-long bulge, and a 12-nucleotide-long upper loop. Mutational disruption of 5BSL3.2 structure blocked RNA replication, which could be restored when an intact copy of this RNA element was inserted into the 3′ NTR. By using this replicon design, we mapped the elements in 5BSL3.2 that are critical for RNA replication. Most importantly, we discovered a nucleotide sequence complementarity between the upper loop of this RNA element and the loop region of stem-loop 2 in the 3′ NTR. Mismatches introduced into the loops inhibited RNA replication, which could be rescued when complementarity was restored. These data provide strong evidence for a pseudoknot structure at the 3′ end of the HCV genome that is essential for replication.

scholarly journals The landscape of SARS-CoV-2 RNA modifications

2020 ◽  
Author(s):  
Milad Miladi ◽  
Jonas Fuchs ◽  
Wolfgang Maier ◽  
Sebastian Weigang ◽  
Núria Díaz i Pedrosa ◽  
...  
Keyword(s):  
Host Cell ◽  
Rna Virus ◽  
Open Reading Frames ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Rna Modification ◽  
Rna Modifications ◽  
Positive Strand Rna Virus ◽  
Novel Therapeutic Strategies ◽  
Positive Strand Rna

AbstractIn 2019 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the first documented cases of severe lung disease COVID-19. Since then, SARS-CoV-2 has been spreading around the globe resulting in a severe pandemic with over 500.000 fatalities and large economical and social disruptions in human societies. Gaining knowledge on how SARS-Cov-2 interacts with its host cells and causes COVID-19 is crucial for the intervention of novel therapeutic strategies. SARS-CoV-2, like other coronaviruses, is a positive-strand RNA virus. The viral RNA is modified by RNA-modifying enzymes provided by the host cell. Direct RNA sequencing (DRS) using nanopores enables unbiased sensing of canonical and modified RNA bases of the viral transcripts. In this work, we used DRS to precisely annotate the open reading frames and the landscape of SARS-CoV-2 RNA modifications. We provide the first DRS data of SARS-CoV-2 in infected human lung epithelial cells. From sequencing three isolates, we derive a robust identification of SARS-CoV-2 modification sites within a physiologically relevant host cell type. A comparison of our data with the DRS data from a previous SARS-CoV-2 isolate, both raised in monkey renal cells, reveals consistent RNA modifications across the viral genome. Conservation of the RNA modification pattern during progression of the current pandemic suggests that this pattern is likely essential for the life cycle of SARS-CoV-2 and represents a possible target for drug interventions.

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