• Artificial intelligence and machine learning
• Diagnosis
• Enzyme immunoassays
• Hepatitis C Virus
• Next-generation sequencing

• antiviral response
• fatty acids
• glycerolipids
• glycerophospholipids
• hepatitis C virus
• lipidome

• Humans
• Hepacivirus
• Lipidomics
• Hepatitis C
• Antiviral Agents/pharmacology
• Glycerol

• RNA virus
• SARS-CoV-2
• coronavirus
• evolution
• mutation
• quasispecies
• recombination

• Humans
• SARS-CoV-2/genetics
• COVID-19/genetics
• Mutation
• RNA, Viral/genetics
• Genome, Viral
• Evolution, Molecular

• HCC
• HCV
• biomarkers
• liver fibrosis
• lncRNAs
• type I IFN

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/virology
• Hepatitis C/complications
• Hepatitis C/genetics
• Hepatitis C/metabolism
• Humans
• Liver Cirrhosis/genetics
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/virology
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/virology
• RNA, Long Noncoding/blood
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism

DNA and RNA guanine-rich oligonucleotides can form non-canonical structures called G-quadruplexes or “G4” that are based on the stacking of G-quartets. The role of DNA and RNA G4 is documented in eukaryotic cells and in pathogens such as viruses. Yet, G4 have been identified only in a few RNA viruses, including the Flaviviridae family. In this study, we analysed the last 157 nucleotides at the 3′end of the HCV (−) strand. This sequence is known to be the minimal sequence required for an efficient RNA replication. Using bioinformatics and biophysics, we identified a highly conserved G4-prone sequence located in the stem-loop IIy’ of the negative strand. We also showed that the formation of this G-quadruplex inhibits the in vitro RNA synthesis by the RdRp. Furthermore, Phen-DC3, a specific G-quadruplex binder, is able to inhibit HCV viral replication in cells in conditions where no cytotoxicity was measured. Considering that this domain of the negative RNA strand is well conserved among HCV genotypes, G4 ligands could be of interest for new antiviral therapies.

• HCV
• cis-element
• microRNA-122
• replication
• untranslated region

• R01 AI120204 NIAID NIH HHS
• R21 AI127252 NIAID NIH HHS

• 3′X domain
• RNA
• dimer
• hepatitis C virus
• small-angle X-ray scattering
• structure

• 3' Untranslated Regions
• Dimerization
• Hepacivirus/genetics
• Inverted Repeat Sequences
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Nucleic Acid Conformation
• Osmolar Concentration
• RNA, Viral/chemistry
• RNA, Viral/genetics
• Solutions

• Ministerio de Economía y Competitividad of Spain
• US Department of Energy (DOE)

Despite advances in therapy, hepatitis C virus (HCV) infection remains an important global health issue. It is estimated that a significant part of the world population is chronically infected with the virus, and many of those affected may develop cirrhosis or liver cancer. The virus shows considerable variability, a characteristic that directly interferes with disease treatment. The response to treatment varies according to HCV genotype and subtype. The continuous generation of variants (quasispecies) allows the virus to escape control by antivirals. Historically, the combination of ribavirin and interferon therapy has represented the only treatment option for the disease. Currently, several new treatment options are emerging and are available to a large part of the affected population. In addition, the search for new substances with antiviral activity against HCV continues, promising future improvements in treatment. Researchers should consider the mutation capacity of the virus and the other variables that affect treatment success.

• Hepatitis C infection
• Hepatitis C virus
• Treatments
• Antiviral research

• Antiviral Agents/therapeutic use
• Carcinoma, Hepatocellular
• Drug Therapy, Combination
• Hepacivirus/genetics
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/virology
• Humans
• Interferon-alpha/therapeutic use
• Liver Cirrhosis
• Liver Neoplasms
• Protease Inhibitors/therapeutic use
• RNA, Viral
• Ribavirin/therapeutic use
• Sustained Virologic Response
• Viral Load

In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight.

• Lipid
• Glucose
• Cardiovascular
• Hepatitis C virus
• Core
• Nonstructural protein 5 A
• Transgenic mice

• Animals
• Antiviral Agents/therapeutic use
• Cardiovascular Diseases/metabolism
• Cardiovascular Diseases/virology
• Diabetes Mellitus/metabolism
• Diabetes Mellitus/virology
• Dyslipidemias/metabolism
• Dyslipidemias/virology
• Energy Metabolism/drug effects
• Fatty Liver/metabolism
• Fatty Liver/virology
• Genome, Viral
• Genotype
• Glucose/metabolism
• Hepacivirus/drug effects
• Hepacivirus/genetics
• Hepacivirus/metabolism
• Hepacivirus/pathogenicity
• Hepatitis C/complications
• Hepatitis C/drug therapy
• Hepatitis C/metabolism
• Hepatitis C/virology
• Host-Pathogen Interactions
• Humans
• Lipid Metabolism
• Liver/drug effects
• Liver/metabolism
• Liver/virology
• Metabolic Syndrome/metabolism
• Metabolic Syndrome/virology
• Risk Factors
• Signal Transduction

Many attempts have been made to define nature of viruses and to uncover their origin. Our aim within this work was to show that there are different perceptions of viruses and many concepts to explain their emergence: the virus-first concept (also called co-evolution), the escape and the reduction theories. Moreover, a relatively new concept of polyphyletic virus origin called “three RNA cells, three DNA viruses” proposed by Forterre is described herein. In this paper, not only is each thesis supported by a body of evidence but also counter-argued in the light of various findings to give more insightful considerations to the readers. As the origin of viruses and that of living cells are most probably interdependent, we decided to reveal ideas concerning nature of cellular last universal common ancestor (LUCA). Furthermore, we discuss monophyletic ancestry of cellular domains and their relationships at the molecular level of membrane lipids and replication strategies of these three types of cells. In this review, we also present the emergence of DNA viruses requiring an evolutionary transition from RNA to DNA and recently discovered giant DNA viruses possibly involved in eukaryogenesis. In the course of evolution viruses emerged many times. They have always played a key role through horizontal gene transfer in evolutionary events and in formation of the tree of life or netlike routes of evolution providing a great deal of genetic diversity. In our opinion, future findings are crucial to better understand past relations between viruses and cells and the origin of both.

• Antiviral
• HCC
• HCV
• Host cell response
• IFN
• Proviral
• lncRNAs

The 3′X domain of hepatitis C virus is a strongly conserved structure located at the 3′ terminus of the viral genomic RNA. This domain modulates the replication and translation processes of the virus in conjunction with an upstream 5BSL3.2 stem–loop, and contains a palindromic sequence that facilitates RNA dimerization. Based on nuclear magnetic resonance spectroscopy and gel electrophoresis, we report here that domain 3′X adopts a structure composed of two stem–loops, and not three hairpins or a mixture of folds, as previously proposed. This structure exposes unpaired terminal nucleotides after a double-helical stem and palindromic bases in an apical loop, favoring genomic RNA replication and self-association. At higher ionic strength the domain forms homodimers comprising an intermolecular duplex of 110 nucleotides. The 3′X sequences can alternatively form heterodimers with 5BSL3.2. This contact, reported to favor translation, likely involves local melting of one of the 3′X stem–loops.

Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a single-stranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection.

• Recombination
• Quasispecies
• Hepatitis C virus
• RNA
• Evolution
• Antiviral therapy

• HCV RNA genome
• HCV X-region
• Hepatitis C virus
• Infection
• Japanese Fulminant Hepatitis Virus
• RNA secondary structure

Described here is a methodology for selectively capturing HCV particles from human plasma samples using aptamer-conjugated magnetic nanoparticles. The aptamers were specifically bound to the E1E2 glycoprotein of HCV viruses.

• Genome packaging
• RNA structure
• Viral RNA
• Viral translation
• tRNA-like structures

• Animals
• Genome Size
• Genome, Viral
• Humans
• Protein Binding
• RNA, Viral/chemistry
• RNA, Viral/genetics
• RNA, Viral/metabolism
• Regulatory Sequences, Nucleic Acid
• Ribonucleoproteins/chemistry
• Ribonucleoproteins/metabolism
• Structure-Activity Relationship

• R01 AI077387 NIAID NIH HHS
• R01 GM113887 NIGMS NIH HHS
• T32 GM008512 NIGMS NIH HHS
• T32 GM008700 NIGMS NIH HHS

• 18S rRNA
• IRES
• base pairing
• hepatitis C virus
• translation

RNA-binding proteins (RBPs) are pivotal regulators of all the steps of gene expression. RBPs govern gene regulation at the post-transcriptional level by virtue of their capacity to assemble ribonucleoprotein complexes on certain RNA structural elements, both in normal cells and in response to various environmental stresses. A rapid cellular response to stress conditions is triggered at the step of translation initiation. Two basic mechanisms govern translation initiation in eukaryotic mRNAs, the cap-dependent initiation mechanism that operates in most mRNAs, and the internal ribosome entry site (IRES)-dependent mechanism activated under conditions that compromise the general translation pathway. IRES elements are cis-acting RNA sequences that recruit the translation machinery using a cap-independent mechanism often assisted by a subset of translation initiation factors and various RBPs. IRES-dependent initiation appears to use different strategies to recruit the translation machinery depending on the RNA organization of the region and the network of RBPs interacting with the element. In this review we discuss recent advances in understanding the implications of RBPs on IRES-dependent translation initiation.

• Gene Expression Regulation
• Humans
• Peptide Chain Initiation, Translational
• Protein Biosynthesis
• RNA, Messenger/genetics
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• Regulatory Sequences, Ribonucleic Acid/genetics
• Ribosomes/genetics