• Cirrhosis
• Direct-acting antivirals
• Hepatic fibrosis
• Hepatitis C virus
• Hepatocellular carcinoma
• Sustained virologic response

• Metabolic dysfunction-associated steatotic liver disease
• Metabolic-associated fatty liver disease
• Nonalcoholic fatty liver disease

• FAST score
• HCV infection
• liver complications
• liver stiffness
• sustained virological response

• Instituto de Salud Carlos III
• European Union (ERDF/ESF, “Investing in your future”)
• Gilead Biomedical Research Fellowship Program
• GEHEP-SEIMC
• Acción B, Acción para el Refuerzo de la Actividad Investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021
• Acción A, Acción para el Refuerzo de la Actividad Investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021
• Instituto de Salud Carlos III-ISCIII
• European Union NextGenerationEU Plan
• Spanish Junta de Andalucía

• controlled attenuation parameter
• hepatic steatosis
• hepatitis C virus
• liver fibrosis
• transient elastography

• Humans
• Liver Cirrhosis/epidemiology
• Male
• Middle Aged
• Female
• Elasticity Imaging Techniques
• Cardiometabolic Risk Factors
• Fatty Liver/epidemiology
• Fatty Liver/complications
• Adult
• Phenotype
• Prevalence
• Aged
• Hepatitis C, Chronic/complications
• Risk Factors
• Hepatitis C/complications

• NPC-178912 CIHR
• Public Health Agency of Canada
• Canadian Institutes of Health Research
• Public Health Agency of Canada

• Cardiometabolic risk factors
• Fatty liver
• Hepatitis C

• EGF
• HCV
• VEGF
• chronic hepatitis C
• cytokines
• fibrosis
• growth factor
• liver steatosis

• UIP-2019-04-7194 Croatian Science Foundation

• liver steatosis
• magnetic resonance imaging
• transfusion‐dependent thalassaemia

• Humans
• Female
• Male
• Adult
• Thalassemia/therapy
• Thalassemia/complications
• Middle Aged
• Fatty Liver/etiology
• Fatty Liver/diagnostic imaging
• Iron Overload/etiology
• Blood Transfusion
• Liver/metabolism
• Liver/diagnostic imaging
• Liver/pathology
• Magnetic Resonance Imaging
• Glucose Tolerance Test
• Prevalence
• Young Adult

• Chronic hepatitis C
• direct-acting antiviral agent
• hepatocellular carcinoma
• liver-related event
• metabolic dysfunction-associated fatty liver disease

• chronic viral hepatitis
• cirrhosis
• hepatic fibrosis
• hepatitis B virus (HBV)
• hepatitis C virus (HCV)
• hepatocellular carcinoma
• metabolic dysfunction-associated fatty liver disease (MAFLD)

• Humans
• Hepatitis B, Chronic/metabolism
• Hepatitis B, Chronic/complications
• Hepatitis C, Chronic/metabolism
• Hepatitis C, Chronic/complications
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/epidemiology
• Fatty Liver/metabolism
• Disease Progression
• Metabolic Diseases/metabolism

• chronic hepatitis C virus
• soluble inflammatory mediators
• steatosis
• sustained viral response

• 158989968, SFB900, SFB738 Deutsche Forschungsgemeinschaft
• DS354 Medical University of Lublin

• Child
• Humans
• Non-alcoholic Fatty Liver Disease/epidemiology
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/complications
• Diabetes Mellitus, Type 2/epidemiology
• Diabetes Mellitus, Type 2/genetics
• Diabetes Mellitus, Type 2/complications
• Quality of Life
• Genetic Predisposition to Disease
• Disease Progression
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/complications
• Prevalence
• Liver Neoplasms/epidemiology

• bone morphogenetic proteins
• hepatic stellate cells
• immune cells
• liver fibrosis
• β-catenin

• Humans
• Liver/pathology
• Liver Cirrhosis/diagnosis
• Elasticity Imaging Techniques/adverse effects
• Biopsy/adverse effects
• Non-alcoholic Fatty Liver Disease/diagnosis
• Non-alcoholic Fatty Liver Disease/complications
• Biomarkers

• PAT proteins
• focal fatty change
• hepatitis B virus (HBV)
• hepatitis C virus (HCV)
• non-alcoholic steatohepatitis (NASH)

• Humans
• Perilipin-1/metabolism
• Hepatitis C, Chronic/metabolism
• Lipid Droplet Associated Proteins/metabolism
• Lipid Droplets/metabolism
• Fatty Liver/metabolism
• Liver/metabolism
• Hepatitis C/genetics
• Hepacivirus/genetics
• Biomarkers/metabolism
• Liver Neoplasms/metabolism
• Perilipin-2/genetics
• Perilipin-2/metabolism

• Female
• Humans
• Male
• Middle Aged
• Asian/statistics & numerical data
• Biopsy
• Fatty Liver/ethnology
• Fatty Liver/pathology
• Fibrosis/ethnology
• Prevalence
• United States/epidemiology
• Health Status Disparities

• K24 AA022523 NIAAA NIH HHS
• P30 DK026743 NIDDK NIH HHS
• T32 DK060414 NIDDK NIH HHS
• Liver Center, University of California, San Francisco
• National Institutes of Health

The hepatitis C virus (HCV) is an oncogenic virus that alters the cell polarization machinery in order to enter the hepatocyte and replicate. While these alterations are relatively well defined, their consequences in the evolution of the disease remain poorly documented. Since 2012, HCV infection can be effectively cured with the advent of direct acting antivirals (DAA). Nevertheless, patients cured of their HCV infection still have a high risk of developing hepatocellular carcinoma (HCC). Importantly, it has been shown that some of the deregulations induced by HCV are maintained despite a sustained virologic response (SVR), including the down-regulation of some hepatocyte functions such as bile acid metabolism, exemplifying cell dedifferentiation, and the up-regulation of the epithelial–mesenchymal transition (EMT). EMT is a process by which epithelial cells lose their differentiation and their specific polarity to acquire mesenchymal cell properties, including migration and extracellular matrix remodeling capabilities. Of note, epithelial cell polarity acts as a gatekeeper against EMT. Thus, it remains important to elucidate the mechanisms by which HCV alters polarity and promotes EMT that could participate in viral-induced hepatic carcinogenesis. In this review, we define the main steps involved in the polarization process of epithelial cells and recall the essential cellular actors involved. We also highlight the particularities of hepatocyte polarity, responsible for their unique morphology. We then focus on the alterations by HCV of epithelial cell polarity and the consequences of the transformation of hepatocytes involved in the carcinogenesis process.

• Chronic hepatitisC
• Genetic models of inheritance
• Hepatic steatosis
• Microsomal Triglyceride Transfer Protein (MTTP)
• Single Nucleotide Polymorphisms (SNPs)

• Carrier Proteins/genetics
• Fatty Liver/genetics
• Female
• Genotype
• Hepacivirus
• Hepatitis C, Chronic/genetics
• Humans
• Polymorphism, Single Nucleotide
• Triglycerides

• ALT, alanine aminotransferase
• AST, aspartate aminotransferase
• C-index, Concordance index
• External validation
• GGT, gamma glutamyl transferase
• GRS, genetic risk score
• Genetic risk scores
• HCC, hepatocellular carcinoma
• ICD, International Classification of Diseases
• IDU, injecting-drug user
• IF, interferon
• PNPLA3, patatin-like phospholipase domain-containing protein 3
• Primary liver cancer
• Prognosis
• Risk prediction
• SMR01, Scottish Inpatient Hospital Admission Database
• SMR06, Scottish Cancer Register
• STOP-HCV, STratified medicine to Optimise Treatment of Hepatitis C Virus
• SVR, sustained virological response
• THRI, Toronto HCC Risk Index
• VHA, Veteran Health Affairs
• aMAP, age-male sex-ALBI-platelet count score

• Wellcome Trust
• 29725 Cancer Research UK
• MR/K01532X/1 Medical Research Council
• MRF_MRF-054-0001-F-INNE-C0825 MRF

• NAFLD/NASH (MAFLD)
• hepatitis C virus
• hepatocellular carcinoma
• interferon-based therapy
• interferon-free direct-acting antivirals
• metabolic syndrome
• steatosis

• 108-2314-B-037-079-MY3 Ministry of Science and Technology, Taiwan
• 110-2314-B-037-102, 110-2314-B-037-119 Ministry of Science and Technology, Taiwan
• KMU-KI110002 Kaohsiung Medical University
• KMUH-DK(C)110011 Kaohsiung Medical University Hospital

Chronic hepatitis C virus (HCV) infection often leads to fibrosis and chronic hepatitis, then cirrhosis and ultimately hepatocellular carcinoma (HCC). The processes of the HVC life cycle involve intimate interactions between viral and host cell proteins and lipid metabolism. However, the molecules and mechanisms involved in this tripartite interaction remain poorly understood. Herein, we show that the infection of HCC-derived Huh7.5 cells with HCV promotes upregulation of the protein inhibitor of activated STAT1 (PIAS1). Reciprocally, PIAS1 regulated the expression of HCV core protein and HCV-induced LD accumulation and impaired HCV replication. Furthermore, PIAS1 controlled HCV-promoted septin 9 filament formation and microtubule polymerization. Subsequently, we found that PIAS1 interacted with septin 9 and controlled its assembly on filaments, which thus affected septin 9-induced lipid droplet accumulation. Taken together, these data reveal that PIAS1 regulates the accumulation of lipid droplets and offer a meaningful insight into how HCV interacts with host proteins.

• HCV
• PIAS1
• lipid droplets
• septin 9

• DAAs
• De novo steatosis
• HCV
• Hypertriglyceridemia
• Male sex
• Overweight
• SVR

• Attenuation coefficient
• Hepatic steatosis
• Non-alcoholic fatty liver disease
• Ultrasound-guided attenuation parameter

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.

• AFP
• AFP-L3
• DCP
• GALAD
• HBV
• HCC
• HCV
• chronic hepatitis B
• chronic hepatitis C
• hepatocellular carcinoma

• viral infection
• liver
• tumour virus infections

• Adult
• Alkaline Phosphatase/blood
• Antiviral Agents/therapeutic use
• Biopsy
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Fatty Liver/pathology
• Fatty Liver/virology
• Female
• Hepatitis C/drug therapy
• Hepatitis C/pathology
• Humans
• Liver/drug effects
• Liver/pathology
• Liver/virology
• Liver Cirrhosis/pathology
• Liver Cirrhosis/virology
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Male
• Middle Aged
• Retrospective Studies
• Treatment Outcome

• KL2 TR001441 NCATS NIH HHS
• P50 CA217674 NCI NIH HHS
• R01 DK125730 NIDDK NIH HHS
• T32 DK007639 NIDDK NIH HHS
• National Center for Advancing Translational Services Clinical and Translational Science Awards Grant NCATS CTSA Grant KL2 Scholars Program
• Moody Endowment Award, Galveston, TX
• MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma Grant
• National Institute of Diabetes and Digestive and Kidney Diseases

• Helicobacter pylori
• Hepatitis C
• Human immunodeficiency virus
• Infectious diseases
• Klebsiella pneumoniae
• Lipid metabolism
• Liver
• Metabolic-associated fatty liver disease (MAFLD)
• Non-alcoholic steatohepatitis (NASH)
• SARS-CoV-2

• Acquired Immunodeficiency Syndrome/complications
• Bacterial Infections/complications
• Bacterial Infections/microbiology
• COVID-19/complications
• Hepatitis, Viral, Human/complications
• Humans
• Liver/physiopathology
• Metabolic Syndrome
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/microbiology
• Non-alcoholic Fatty Liver Disease/parasitology
• Non-alcoholic Fatty Liver Disease/virology
• Parasitic Diseases/complications
• Parasitic Diseases/parasitology
• Peptic Ulcer
• Periodontitis
• Risk Factors
• Symptom Flare Up
• Virus Diseases/complications
• Virus Diseases/virology

• 1S10518N Fonds Wetenschappelijk Onderzoek
• 12H2216N Fonds Wetenschappelijk Onderzoek
• 1S73019N Fonds Wetenschappelijk Onderzoek
• G042019N Fonds Wetenschappelijk Onderzoek
• Onderzoeksraad Vrije Universiteit Brussel
• Research Chair Mireille Aerens for the development Alternatives to Animal Testing

Chronic infection with hepatitis C virus (HCV) is one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC). Surveillance of these patients is an essential strategy in the prevention chain, including in the pre/post-antiviral treatment states. Ultrasound elastography techniques are emerging as key methods in the assessment of liver diseases, with a number of advantages such as their rapid, noninvasive, and cost-effective characters. The present paper critically reviews the performance of vibration-controlled transient elastography (VCTE) in the assessment of HCV patients. VCTE measures liver stiffness (LS) and the ultrasonic attenuation through the embedded controlled attenuation parameter (CAP), providing the clinician with a tool for assessing fibrosis, cirrhosis, and steatosis in a noninvasive manner. Moreover, standardized LS values enable proper staging of the underlying fibrosis, leading to an accurate identification of a subset of HCV patients that present a high risk for complications. In addition, VCTE is a valuable technique in evaluating liver fibrosis prior to HCV therapy. However, its applicability in monitoring fibrosis regression after HCV eradication is currently limited and further studies should focus on extending the boundaries of VCTE in this context. From a different perspective, VCTE may be effective in identifying clinically significant portal hypertension (CSPH). An emerging prospect of clinical significance that warrants further study is the identification of esophageal varices. Our opinion is that the advantages of VCTE currently outweigh those of other surveillance methods.

• chronic hepatitis C
• fibrosis
• hepatocellular carcinoma
• steatosis
• vibration controlled transient elastography

Background: The prevalence of metabolic and cardiovascular diseases is rising worldwide. However, little is known about the impact of such disorders on hepatic disease progression in chronic hepatitis B (CHB) during the era of potent nucleo(s)tide analogues (NAs). Methods: We retrospectively analyzed a single-center cohort of 602 CHB patients, comparing the frequency of liver cirrhosis at baseline and incidences of liver-related events during follow-up (hepatocellular carcinoma, liver transplantation and liver-related death) between CHB patients with a history of diabetes, obesity, hypertension or coronary heart disease (CHD). Results: Rates of cirrhosis at baseline and liver-related events during follow-up (median follow-up time: 2.51 years; NA-treated: 37%) were substantially higher in CHB patients with diabetes (11/23; 3/23), obesity (6/13; 2/13), CHD (7/11; 2/11) or hypertension (15/43; 4/43) compared to CHB patients without the indicated comorbidities (26/509; 6/509). Multivariate analysis identified diabetes as the most significant predictor for cirrhosis (p = 0.0105), while comorbidities did not correlate with liver-related events in pre-existing cirrhosis. Conclusion: The combination of metabolic diseases and CHB is associated with substantially increased rates of liver cirrhosis and secondary liver-related events compared to CHB alone, indicating that hepatitis B patients with metabolic comorbidities warrant particular attention in disease surveillance and evaluation of treatment indication.

• HBV
• HCC
• NAFLD
• cirrhosis
• metabolic

• MELD score
• Proprotein convertase subtilisin/kexin 9 (PCSK9)
• genotype
• hepatitis C
• liver cirrhosis
• low-density lipoprotein

Chronic infection with hepatitis C virus (HCV) is one of the leading causes of liver disease globally, affecting approximately 71 million people. The majority of them are infected with genotype (GT) 1 but infections with GT3 are second in frequency. For many years, GT3 was considered to be less pathogenic compared to other GTs in the HCV family due to its favorable response to interferon (IFN)-based regimen. However, the growing evidence of a higher rate of steatosis, more rapid progression of liver fibrosis, and lower efficacy of antiviral treatment compared to infection with other HCV GTs has changed this conviction. This review presents the specifics of the course of GT3 infection and the development of therapeutic options for GT3-infected patients in the era of direct-acting antivirals (DAA). The way from a standard of care therapy with pegylated IFN-alpha (pegIFNα) and ribavirin (RBV) through a triple combination of pegIFNα + RBV and DAA to the highly potent IFN-free pangenotypic DAA regimens is discussed along with some treatment options which appeared to be dead ends. Although the implementation of highly effective pangenotypic regimens is the most recent stage of revolution in the treatment of GT3 infection, there is still room for improvement, especially in patients with liver cirrhosis and those who fail to respond to DAA therapies, particularly those containing inhibitors of HCV nonstructural protein 5A.

• Hepatitis C virus
• Genotype 3
• Antiviral treatment
• Interferon
• Direct-acting antivirals
• Pangenotypic

• Antiviral Agents/therapeutic use
• Drug Therapy, Combination
• Genotype
• Hepacivirus/genetics
• Hepatitis C/diagnosis
• Hepatitis C/drug therapy
• Hepatitis C/genetics
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/drug therapy
• Hepatitis C, Chronic/genetics
• Humans
• Ribavirin/therapeutic use
• Treatment Outcome

• Fatty liver
• Insulin resistance
• Metabolic syndrome
• NAFLD
• Obesity
• Steatosis
• Thiamine

• Cannabis
• chronic
• fatty liver
• hepatitis C
• human immunodeficiency virus
• metabolic diseases

Coevolution occurs between viruses and their hosts. The hosts need to evolve means to eliminate pathogenic virus infections, and the viruses, for their own survival and multiplication, have to develop mechanisms to escape clearance by hosts. Hepatitis C virus (HCV) of Flaviviridae is a pathogen which infects human liver and causes hepatitis, a condition of liver inflammation. Unlike most of the other flaviviruses, HCV has an excellent ability to evade host immunity to establish chronic infection. The persistent liver infection leads to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), as well as extrahepatic HCV-related diseases. HCV genomic RNA only expresses 10 proteins, many of which bear functions, in addition to those involved in HCV life cycle, for assisting the virus to develop its persistency. HCV core protein is a structural protein which encapsulates HCV genomic RNA and assembles into nucleocapsids. The core protein is also found to exert functions to affect host inflammation and immune responses by altering a variety of host pathways. This paper reviews the studies regarding the HCV core protein-induced alterations of host immunity and inflammatory responses, as well as the involvements of the HCV core protein in pro- and anti-inflammatory cytokine stimulations, host cellular transcription, lipid metabolism, cell apoptosis, cell proliferations, immune cell differentiations, oxidative stress, and hepatocyte steatosis, which leads to liver fibrosis, cirrhosis, and HCC. Implications of roles played by the HCV core protein in therapeutic resistance are also discussed.

• Epidemiology
• Hepatocellular carcinoma
• Immunological classification
• Metabolic classification
• Molecular classification
• Risks and causative factors

• Animals
• Carcinoma, Hepatocellular/classification
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Humans
• Liver Neoplasms/classification
• Liver Neoplasms/epidemiology
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology

• R01 CA230561 NCI NIH HHS
• R01 CA240004 NCI NIH HHS
• R01 CA244993 NCI NIH HHS
• R01 DK107451 NIDDK NIH HHS

Hepatitis C virus (HCV)-induced inflammation contributes to progressive liver disease. The chemoattractant protein chemerin is associated with systemic inflammation. We hypothesized that chemerin is a biomarker that predicts the severity of liver disease in HCV patients. Furthermore, we investigated whether serum chemerin levels change during the course of HCV treatment using direct-acting antivirals (DAAs). Therefore, we measured serum concentration of chemerin in a cohort of 82 HCV-infected patients undergoing DAA treatment. Serum chemerin was positively associated with leukocyte count and negatively with markers of hepatic function and the model of end-stage liver disease (MELD) score. Low circulating chemerin levels significantly correlated with advanced liver fibrosis and cirrhosis as measured by the fibrosis-4 (FIB-4) score, the aminotransferase/platelet (AST/PLT) ratio index (APRI) score and the non-alcoholic fatty liver disease (NAFLD) score. Chemerin did not correlate with viral load or viral genotype. Treatment with DAAs did not improve MELD score and leukocyte count within the observation period, up to three months after the end of DAA treatment. Accordingly, chemerin levels remained unchanged during the treatment period. We conclude that low circulating chemerin is a noninvasive biomarker for hepatic dysfunction and advanced liver fibrosis and cirrhosis in HCV infection.

• DAA
• HCV infection
• MELD score
• body mass index
• liver fibrosis

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Abnormal de novo lipogenesis is reported to be involved in hepatocarcinogenesis. In current study, de novo lipogenesis and its association with patient survival rate were investigated in human HCC samples induced by hepatitis B virus (HBV), hepatitis C virus (HCV), or nonviral factors. Hepatic mRNA and protein levels of lipogenic transcription factors and lipid synthesis enzymes were examined by realtime‐PCR (RT‐PCR) and western blot. Association of gene expression and patient survival was analyzed using The Cancer Genome Atlas (TCGA) data. Lipogenic pathway regulators such as AKT2, SREBP1c, PPARγ, and lipogenic enzymes such as ACC and FAS were increased in human HCC when compared with control livers. Notably, a more robust increase in de novo lipogenesis was observed in HCV‐HCC when compared to HBV‐HCC and nonviral HCC. High FAS and ACC expression correlated with poor overall survival (OS) in HCV‐HCC. High expression of lipogenesis gene panel significantly correlated with poor OS in HCV‐HCC, but not in HBV‐HCC or nonviral HCC. In sum, de novo lipogenesis is stimulated dramatically in human HCC especially in HCV‐HCC.

• HCV‐HCC
• de novo lipogenesis
• human hepatocellular carcinoma

Many RNA viruses create specialized membranes for genome replication by manipulating host lipid metabolism and trafficking, but in most cases, we do not know the molecular mechanisms responsible or how specific lipids may impact the associated membrane and viral process. For example, hepatitis C virus (HCV) causes a specific, large-fold increase in the steady-state abundance of intracellular desmosterol, an immediate precursor of cholesterol, resulting in increased fluidity of the membrane where HCV RNA replication occurs. Here, we establish the mechanism responsible for HCV's effect on intracellular desmosterol, whereby the HCV NS3-4A protease controls activity of 24-dehydrocholesterol reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol. Our cumulative evidence for the proposed mechanism includes immunofluorescence microscopy experiments showing co-occurrence of DHCR24 and HCV NS3-4A protease; formation of an additional, faster-migrating DHCR24 species (DHCR24*) in cells harboring a HCV subgenomic replicon RNA or ectopically expressing NS3-4A; and biochemical evidence that NS3-4A cleaves DHCR24 to produce DHCR24* in vitro and in vivo. We further demonstrate that NS3-4A cleaves DHCR24 between residues Cys⁹¹ and Thr⁹² and show that this reduces the intracellular conversion of desmosterol to cholesterol. Together, these studies demonstrate that NS3-4A directly cleaves DHCR24 and that this results in the enrichment of desmosterol in the membranes where NS3-4A and DHCR24 co-occur. Overall, this suggests a model in which HCV directly regulates the lipid environment for RNA replication through direct effects on the host lipid metabolism.

• RNA replication
• cholesterol metabolism
• desmosterol
• hepatitis C virus (HCV)
• host–pathogen interaction
• lipid environment
• membrane lipid
• membrane remodeling
• post-translational modification (PTM)
• viral protease
• viral replication

(1) Background: Direct-acting antiviral therapy for chronic hepatitis C virus (HCV) infection is associated with high sustained virologic response (SVR) and overcomes negative predictive factors, including steatosis, in patients without human immunodeficiency virus (HIV) coinfection. The impact of steatosis on SVR in patients with HIV–HCV coinfection is unknown. (2) Methods: A retrospective analysis of patients treated with direct-acting antivirals was performed. Demographic, laboratory and direct-acting antiviral regimen data were prospectively collected. Metabolic syndrome and its components—diabetes mellitus, hypertension, dyslipidemia and obesity—were assessed. Hepatic steatosis (≥5%) was defined by liver biopsy or controlled attenuation parameter (CAP) measurement during vibration-controlled transient elastography (VCTE). (3) Results: A total of 151 HIV–HCV-coinfected patients on combined antiretroviral therapy and direct-acting antiviral therapy were included in this analysis. Prevalence of steatosis by liver biopsy (n = 34) or CAP (≥263 db/m) during VCTE (n = 92) was 27% and was independently associated with obesity (OR 3.11; 95% CI 1.43–6.82; p = 0.004) and the metabolic syndrome (OR 1.08; 95% CI 1.01–0.15; p = 0.01). The overall SVR rate (n = 148) was 95% and was not impacted by the presence of steatosis (p = 0.42). (4) Conclusions: Hepatic steatosis is common in HIV–HCV coinfection, correlates with obesity and the metabolic syndrome and does not impact SVR.

• direct-acting antiviral (DAA) therapy
• hepatic steatosis
• hepatitis C virus (HCV)
• human immunodeficiency virus (HIV)
• sustained virologic response (SVR)

• Direct acting antiviral therapy
• Hepatic steatosis
• Hepatitis C virus