• virus-host interactions
• cellular microbiology

• Humans
• Receptors, LDL/metabolism
• Virus Internalization
• Apolipoproteins E/metabolism
• Apolipoproteins E/genetics
• Hemorrhagic Fever Virus, Crimean-Congo/metabolism
• Hemorrhagic Fever Virus, Crimean-Congo/physiology
• Animals
• HEK293 Cells
• Chlorocebus aethiops
• Hemorrhagic Fever, Crimean/virology
• Hemorrhagic Fever, Crimean/metabolism
• Virion/metabolism
• Vero Cells

• EQU202203014673 Agence Nationale de la Recherche (French National Research Agency)
• ANR-22-ASTR-0031 Agence Nationale de la Recherche (French National Research Agency)

Viral hepatitis is a major public health concern. It is associated with life threatening conditions including liver cirrhosis and hepatocellular carcinoma. Hepatitis C virus infects around 71 million people annually, resultantly 700,000 deaths worldwide. Extrahepatic associated chronic hepatitis C virus accounts for one fourth of total healthcare load. This review included a total of 150 studies that revealed almost 19 million people are infected with hepatitis C virus and 240,000 new cases are being reported each year. This trend is continually rising in developing countries like Pakistan where intravenous drug abuse, street barbers, unsafe blood transfusions, use of unsterilized surgical instruments and recycled syringes plays a major role in virus transmission. Almost 123–180 million people are found to be hepatitis C virus infected or carrier that accounts for 2%–3% of world’s population. The general symptoms of hepatitis C virus infection include fatigue, jaundice, dark urine, anorexia, fever malaise, nausea and constipation varying on severity and chronicity of infection. More than 90% of hepatitis C virus infected patients are treated with direct-acting antiviral agents that prevent progression of liver disease, decreasing the elevation of hepatocellular carcinoma. Standardizing the healthcare techniques, minimizing the street practices, and screening for viral hepatitis on mass levels for early diagnosis and prompt treatment may help in decreasing the burden on already fragmented healthcare system. However, more advanced studies on larger populations focusing on mode of transmission and treatment protocols are warranted to understand and minimize the overall infection and death stigma among masses.

• Direct-acting antiviral agents
• Pakistan
• epidemiology/public health
• hepatitis C virus
• infectious diseases
• pathogenesis
• risk factors

Cell entry of enveloped viruses relies on the fusion between the viral and plasma or endosomal membranes, through a mechanism that is triggered by a cellular signal. Here we used a combination of computational and experimental approaches to unravel the main determinants of hepatitis B virus (HBV) membrane fusion process. We discovered that ERp57 is a host factor critically involved in triggering HBV fusion and infection. Then, through modeling approaches, we uncovered a putative allosteric cross-strand disulfide (CSD) bond in the HBV S glycoprotein and we demonstrate that its stabilization could prevent membrane fusion. Finally, we identified and characterized a potential fusion peptide in the preS1 domain of the HBV L glycoprotein. These results underscore a membrane fusion mechanism that could be triggered by ERp57, allowing a thiol/disulfide exchange reaction to occur and regulate isomerization of a critical CSD, which ultimately leads to the exposition of the fusion peptide.

• cell entry
• computational biology
• hepatitis B virus
• infectious disease
• membrane fusion
• microbiology
• systems biology
• virus

• HeLa and Beas-2B cells
• Nanoparticle uptake
• Poly (glycerol-adipate)
• Polymer nanoparticles
• Virus infection

• Cell Line
• Cell Survival/drug effects
• DNA, Viral
• Endocytosis
• Genome, Viral
• Humans
• Nanoparticles/administration & dosage
• Picornaviridae Infections/metabolism
• Polyesters/administration & dosage
• Rhinovirus/genetics

Despite the existence of a preventive vaccine, chronic infection with Hepatitis B virus (HBV) affects more than 250 million people and represents a major global cause of hepatocellular carcinoma (HCC) worldwide. Current clinical treatments, in most of cases, do not eliminate viral genome that persists as a DNA episome in the nucleus of hepatocytes and constitutes a stable template for the continuous expression of viral genes. Several studies suggest that, among viral factors, the HBV core protein (HBc), well-known for its structural role in the cytoplasm, could have critical regulatory functions in the nucleus of infected hepatocytes. To elucidate these functions, we performed a proteomic analysis of HBc-interacting host-factors in the nucleus of differentiated HepaRG, a surrogate model of human hepatocytes. The HBc interactome was found to consist primarily of RNA-binding proteins (RBPs), which are involved in various aspects of mRNA metabolism. Among them, we focused our studies on SRSF10, a RBP that was previously shown to regulate alternative splicing (AS) in a phosphorylation-dependent manner and to control stress and DNA damage responses, as well as viral replication. Functional studies combining SRSF10 knockdown and a pharmacological inhibitor of SRSF10 phosphorylation (1C8) showed that SRSF10 behaves as a restriction factor that regulates HBV RNAs levels and that its dephosphorylated form is likely responsible for the anti-viral effect. Surprisingly, neither SRSF10 knock-down nor 1C8 treatment modified the splicing of HBV RNAs but rather modulated the level of nascent HBV RNA. Altogether, our work suggests that in the nucleus of infected cells HBc interacts with multiple RBPs that regulate viral RNA metabolism. Our identification of SRSF10 as a new anti-HBV restriction factor offers new perspectives for the development of new host-targeted antiviral strategies.

Chronic infection with Hepatitis B virus (HBV) affects more than 250 million of people world-wide and is a major global cause of liver cancer. Current treatments lead to a significant reduction of viremia in patients. However, viral clearance is rarely obtained and the persistence of the HBV genome in the hepatocyte’s nucleus generates a stable source of viral RNAs and subsequently proteins which play important roles in immune escape mechanisms and liver disease progression. Therapies aiming at efficiently and durably eliminating viral gene expression are still required. In this study, we identified the nuclear partners of the HBV Core protein (HBc) to understand how this structural protein, responsible for capsid assembly in the cytoplasm, could also regulate viral gene expression. The HBc interactome was found to consist primarily of RNA-binding proteins (RBPs). One of these RBPs, SRSF10, was demonstrated to restrict HBV RNA levels and a drug, able to alter its phosphorylation, behaved as an antiviral compound capable of reducing viral gene expression. Altogether, this study sheds new light on novel regulatory functions of HBc and provides information relevant for the development of antiviral strategies aiming at preventing viral gene expression.

• cell entry
• hepatitis C virus
• immune escape
• lipidation
• lipoproteins

• Animals
• Endoplasmic Reticulum/metabolism
• Hepacivirus/physiology
• Hepatitis C/immunology
• Hepatitis C/metabolism
• Hepatitis C/virology
• Host-Pathogen Interactions
• Humans
• Lipid Metabolism
• Lipoproteins/biosynthesis
• Lipoproteins/metabolism
• Protein Transport
• Signal Transduction
• Virion
• Virus Assembly
• Virus Internalization

• Density
• Hepatitis C virus
• Infectivity
• Lipidation
• Lipoprotein
• Serum

Hepatitis C infection is the leading cause of liver diseases worldwide and a major health concern that affects an estimated 3% of the global population. Novel therapies available since 2014 and 2017 are very efficient and the WHO considers HCV eradication possible by the year 2030. These treatments are based on the so-called direct acting antivirals (DAAs) that have been developed through research efforts by academia and industry since the 1990s. After a brief overview of the HCV life cycle, we describe here the functions of the different targets of current DAAs, the mode of action of these DAAs and potential future inhibitors.

• DAA
• HCV
• antiviral targets

• Antiviral Agents/pharmacology
• Hepacivirus/drug effects
• Hepacivirus/physiology
• Hepatitis C/drug therapy
• Humans
• Molecular Targeted Therapy
• Protease Inhibitors/pharmacology

• Infectious Hepatitis C Virus Particles
• Lipid Metabolism
• Release
• Steatosis

With more than 71 million chronically infected people, the hepatitis C virus (HCV) is a major global health concern. Although new direct acting antivirals have significantly improved the rate of HCV cure, high therapy cost, potential emergence of drug-resistant viral variants, and unavailability of a protective vaccine represent challenges for complete HCV eradication. Relevant animal models are required, and additional development remains necessary, to effectively study HCV biology, virus–host interactions and for the evaluation of new antiviral approaches and prophylactic vaccines. The chimpanzee, the only non-human primate susceptible to experimental HCV infection, has been used extensively to study HCV infection, particularly to analyze the innate and adaptive immune response upon infection. However, financial, practical, and especially ethical constraints have urged the exploration of alternative small animal models. These include different types of transgenic mice, immunodeficient mice of which the liver is engrafted with human hepatocytes (humanized mice) and, more recently, immunocompetent rodents that are susceptible to infection with viruses that are closely related to HCV. In this review, we provide an overview of the currently available animal models that have proven valuable for the study of HCV, and discuss their main benefits and weaknesses.

• animal models
• antiviral therapy
• hepatitis C virus
• homologs
• humanized mice
• vaccine

Current therapies for chronic hepatitis B virus (HBV) infections are effective at decreasing the viral load in serum, but do not lead to viral eradication. Recent studies highlighted the therapeutic or “adjuvant” potential of immune-modulators. Our aim was to explore the direct anti-HBV effect of Toll-Like-Receptors (TLR) agonists in hepatocytes. HBV-infected primary human hepatocytes (PHH) or differentiated HepaRG cells (dHepaRG) were treated with various TLR agonists. Amongst all TLR ligands tested, Pam3CSK4 (TLR1/2-ligand) and poly(I:C)-(HMW) (TLR3/MDA5-ligand) were the best at reducing all HBV parameters. No or little viral rebound was observed after treatment arrest, implying a long-lasting effect on cccDNA. We also tested Riboxxol that features improved TLR3 specificity compared to poly(I:C)-(HMW). This agonist demonstrated a potent antiviral effect in HBV-infected PHH. Whereas, poly(I:C)-(HMW) and Pam3CSK4 mainly induced the expression of classical genes from the interferon or NF-κB pathway respectively, Riboxxol had a mixed phenotype. Moreover, TLR2 and TLR3 ligands can activate hepatocytes and immune cells, as demonstrated by antiviral cytokines produced by stimulated hepatocytes and peripheral blood mononuclear cells. In conclusion, our data highlight the potential of innate immunity activation in the direct control of HBV replication in hepatocytes, and support the development of TLR-based antiviral strategies.

• Hepatitis C virus
• In vitro and ex vivo models of hepatitis C virus infection
• Molecular biology
• Pathogenesis
• Transmission
• Treatment

• Amino Acid Sequence
• Cell Line
• HEK293 Cells
• Hepacivirus/genetics
• Hepacivirus/pathogenicity
• Hepacivirus/physiology
• Hepatitis C/etiology
• Hepatitis C/virology
• Host-Pathogen Interactions/genetics
• Host-Pathogen Interactions/physiology
• Humans
• Models, Biological
• Mutation
• Protein Processing, Post-Translational
• Viral Envelope Proteins/chemistry
• Viral Envelope Proteins/genetics
• Viral Envelope Proteins/physiology
• Viral Nonstructural Proteins/physiology
• Viral Proteins/chemistry
• Viral Proteins/genetics
• Viral Proteins/physiology
• Virulence/genetics
• Virulence/physiology
• Virus Assembly/genetics
• Virus Assembly/physiology

• R01 AI087925 NIAID NIH HHS
• European Research Council (BE)
• Agence Nationale de la Recherche sur le SIDA et les hépatites virales
• Agence Nationale de la Recherche (FR)

• 2D, 2-dimensional
• 3D
• 3D, 3-dimensional
• EBOV, Ebola virus
• Falciparum
• HBC, hepatitis C virus
• HBV
• HBV, hepatitis B virus
• HCV
• HLC, hepatocyte-like cells
• Hepatotropic
• LASV, Lassa virus
• Liver
• Liver Models
• MPCC, micropatterned coculture system
• Malaria
• PCR, polymerase chain reaction
• Pathogen
• SACC, self-assembling coculture
• Vivax
• iHLC, induced pluripotent stem cell–derived hepatocyte-like cells
• in vitro
• in vivo

• Alb-uPA, Albumin-urokinase plasminogen activator
• CETP, cholesterol ester transfer protein
• FAH, fumaryl acetoacetate hydrolase
• FNRG, absence of fumaryl acetoacetate hydrolase on a immunodeficient NOD Rag gamma IL2 deficient mouse background
• FPLC, fast-performance liquid chromatography
• HCV
• HCV, hepatitis C virus
• HCVcc, cell culture–derived hepatitis C virus
• HDL, high-density lipoprotein
• Human Liver Chimeric Mice
• LVP, lipoviroparticle
• Lipoprotein
• Mouse Model
• NRG, nod rag γ
• NTBC, nitisinone
• PBS, phosphate-buffered saline
• SCID, severe combined immunodeficiency disease
• VLDL, very low density lipoprotein
• apo, apolipoprotein

• F32 AI091207 NIAID NIH HHS
• K08 DK090576 NIDDK NIH HHS
• P30 DK020541 NIDDK NIH HHS
• R01 DK085713 NIDDK NIH HHS

• Hepatitis C virus
• Lipid metabolism
• Lipoproteins
• Virus assembly
• Virus entry

• Chronic Hepatitis C
• DAA
• Direct-Acting Antiviral Agent

• Hepatitis C virus
• Viral life cycle
• Virus morphogenesis
• Virus replication
• Virus–host interactions

• Animal models
• Antivirals
• Evolution
• Genotypes
• HCV
• MicroRNA
• Neutralizing antibodies
• Phylogeny
• Receptors
• Vaccine

While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to the emergence of resistant viral variants. Meanwhile, multiple direct acting antiviral agents (DAAs) targeting either the HCV NS3/4A protease, NS5A or NS5B polymerase have been approved and these have varying potencies and distinct propensities to provoke resistance. The pre-clinical in vivo assessment of drug efficacy and resistant variant emergence underwent a great evolution over the last decade. This field had long been hampered by the lack of suitable small animal models that robustly support the entire HCV life cycle. In particular, chimeric mice with humanized livers (humanized mice) and chimpanzees have been instrumental for studying HCV inhibitors and the evolution of drug resistance. In this review, we present the different in vivo HCV infection models and discuss their applicability to assess HCV therapy response and emergence of resistant variants.

• HCV
• animal models
• deep sequencing
• direct acting antiviral agents
• humanized mice
• resistance
• therapy

• HCV RNA
• acetaldehyde
• apoptosis
• hepatocytes
• macrophages

• Acetaldehyde/metabolism
• Apoptosis
• Cell Line
• Cells, Cultured
• Hepacivirus/pathogenicity
• Hepacivirus/physiology
• Hepatocytes/metabolism
• Hepatocytes/virology
• Humans
• Interleukins/genetics
• Interleukins/metabolism
• Macrophages/metabolism
• Macrophages/virology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Viral/genetics
• Viral Proteins/genetics
• Viral Proteins/metabolism
• Virus Replication

• I01 BX001155 BLRD VA
• I01 BX001673 BLRD VA
• R24 OD018546 NIH HHS