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Weigand K, Peschel G, Grimm J, Höring M, Krautbauer S, Liebisch G, Müller M, Buechler C. Serum Phosphatidylcholine Species 32:0 as a Biomarker for Liver Cirrhosis Pre- and Post-Hepatitis C Virus Clearance. Int J Mol Sci 2024; 25:8161. [PMID: 39125730 PMCID: PMC11311844 DOI: 10.3390/ijms25158161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/23/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Phosphatidylcholine (PC) is an essential lipid for liver health and lipoprotein metabolism, but its circulating levels have rarely been studied in patients with cirrhosis. Chronic hepatitis C virus (HCV) infection causes lipid abnormalities and is a major cause of cirrhosis. Effective HCV elimination with direct-acting antivirals (DAAs) is associated with the normalization of serum low-density lipoprotein cholesterol levels. Since PC is abundant in all lipoprotein particles, this study analyzed the association between serum PC species levels and liver cirrhosis before and after HCV eradication. Therefore, 27 PC species were measured by Fourier Transform Mass Spectrometry in the serum of 178 patients with chronic HCV infection at baseline and in 176 of these patients at the end of therapy. The PC species did not correlate with viral load, and the levels of 13 PC species were reduced in patients infected with genotype 3a compared to those affected with genotype 1. Four PC species were slightly elevated 12 weeks after DAA initiation, and genotype-related changes were largely normalized. Patients with HCV and cirrhosis had higher serum levels of PC 30:0 and 32:0 before and at the end of therapy. PC species containing polyunsaturated fatty acids were mostly decreased in cirrhosis. The levels of polyunsaturated, but not saturated, PC species were inversely correlated with the model of the end-stage liver disease score. A receiver operating characteristic curve analysis showed area under the curve values of 0.814 and 0.826 for PC 32:0 and 0.917 and 0.914 for % PC 32:0 (relative to the total PC levels) for the classification of cirrhosis at baseline and at the end of therapy, respectively. In conclusion, the specific upregulation of PC 32:0 in cirrhosis before and after therapy may be of diagnostic value in HCV-related cirrhosis.
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Affiliation(s)
- Kilian Weigand
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (K.W.); (G.P.); (J.G.); (M.M.)
- Department of Gastroenterology, Gemeinschaftsklinikum Mittelrhein, 56073 Koblenz, Germany
| | - Georg Peschel
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (K.W.); (G.P.); (J.G.); (M.M.)
- Department of Internal Medicine, Klinikum Fürstenfeldbruck, 82256 Fürstenfeldbruck, Germany
| | - Jonathan Grimm
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (K.W.); (G.P.); (J.G.); (M.M.)
| | - Marcus Höring
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany; (M.H.); (S.K.); (G.L.)
| | - Sabrina Krautbauer
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany; (M.H.); (S.K.); (G.L.)
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany; (M.H.); (S.K.); (G.L.)
| | - Martina Müller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (K.W.); (G.P.); (J.G.); (M.M.)
| | - Christa Buechler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (K.W.); (G.P.); (J.G.); (M.M.)
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Kozan DW, Farber SA. Is It Ever Wise to Edit Wild-Type Alleles? Engineered CRISPR Alleles Versus Millions of Years of Human Evolution. Arterioscler Thromb Vasc Biol 2024; 44:328-333. [PMID: 38059350 PMCID: PMC10948015 DOI: 10.1161/atvbaha.123.318069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023]
Abstract
The tremendous burden of lipid metabolism diseases, coupled with recent developments in human somatic gene editing, has motivated researchers to propose population-wide somatic gene editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) within the livers of otherwise healthy humans. The best-characterized molecular function of PCSK9 is its ability to regulate plasma LDL (low-density lipoprotein) levels through promoting LDL receptor degradation. Individuals with loss-of-function PCSK9 variants have lower levels of plasma LDL and reduced cardiovascular disease. Gain-of-function variants of PCSK9 are strongly associated with familial hypercholesterolemia. A new therapeutic strategy delivers CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats; CRISPR-associated protein 9) specifically to liver cells to edit the wild-type alleles of PCSK9 with the goal of producing a loss-of-function allele. This direct somatic gene editing approach is being pursued despite the availability of US Food and Drug Administration-approved PCSK9 inhibitors that lower plasma LDL levels. Here, we discuss other characterized functions of PCSK9 including its role in infection and host immunity. We explore important factors that may have contributed to the evolutionary selection of PCSK9 in several vertebrates, including humans. Until such time that more fully understand the multiple biological roles of PCSK9, the ethics of permanently editing the gene locus in healthy, wild-type populations remains highly questionable.
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Affiliation(s)
- Darby W. Kozan
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States
| | - Steven A. Farber
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States
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Peschel G, Krautbauer S, Weigand K, Grimm J, Höring M, Liebisch G, Müller M, Buechler C. Rising Lysophosphatidylcholine Levels Post-Hepatitis C Clearance. Int J Mol Sci 2024; 25:1198. [PMID: 38256273 PMCID: PMC10816147 DOI: 10.3390/ijms25021198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 01/24/2024] Open
Abstract
Hepatitis C virus (HCV) infection alters lysophosphatidylcholine (LPC) metabolism, enhancing viral infectivity and replication. Direct-acting antivirals (DAAs) effectively treat HCV and rapidly normalize serum cholesterol. In serum, LPC species are primarily albumin-bound but are also present in lipoprotein particles. This study aims to assess the impact of HCV eradication on serum LPC species levels in patients infected with HCV. Therefore, 12 different LPC species were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the sera of 178 patients with chronic HCV infections at baseline, and in 176 of these patients after therapy with DAAs. All LPC species increased at 4 and 12 weeks post-initiation of DAA therapy. The serum profiles of the LPC species were similar before and after the viral cure. Patients with HCV and liver cirrhosis exhibited lower serum levels of all LPC species, except LPC 16:1, both before and after DAA treatment. Percentages of LPC 18:1 (relative to the total LPC level) were higher, and % LPC 22:5 and 22:6 were lower in cirrhotic compared to non-cirrhotic patients at baseline and at the end of therapy. LPC species levels inversely correlated with the model of end-stage liver disease score and directly with baseline and post-therapy albumin levels. Receiver operating characteristic curve analysis indicated an area under the curve of 0.773 and 0.720 for % LPC 18:1 (relative to total LPC levels) for classifying fibrosis at baseline and post-therapy, respectively. In summary, HCV elimination was found to increase all LPC species and elevated LPC 18:1 relative to total LPC levels may have pathological significance in HCV-related liver cirrhosis.
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Affiliation(s)
- Georg Peschel
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (G.P.); (K.W.); (J.G.); (M.M.)
- Department of Internal Medicine, Klinikum Fürstenfeldbruck, 82256 Fürstenfeldbruck, Germany
| | - Sabrina Krautbauer
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany; (S.K.); (M.H.); (G.L.)
| | - Kilian Weigand
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (G.P.); (K.W.); (J.G.); (M.M.)
- Department of Gastroenterology, Gemeinschaftsklinikum Mittelrhein, 56073 Koblenz, Germany
| | - Jonathan Grimm
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (G.P.); (K.W.); (J.G.); (M.M.)
| | - Marcus Höring
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany; (S.K.); (M.H.); (G.L.)
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany; (S.K.); (M.H.); (G.L.)
| | - Martina Müller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (G.P.); (K.W.); (J.G.); (M.M.)
| | - Christa Buechler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (G.P.); (K.W.); (J.G.); (M.M.)
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Burnap SA, Ortega-Prieto AM, Jimenez-Guardeño JM, Ali H, Takov K, Fish M, Shankar-Hari M, Giacca M, Malim MH, Mayr M. Cross-Linking Mass Spectrometry Uncovers Interactions Between High-Density Lipoproteins and the SARS-CoV-2 Spike Glycoprotein. Mol Cell Proteomics 2023; 22:100600. [PMID: 37343697 PMCID: PMC10279469 DOI: 10.1016/j.mcpro.2023.100600] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/23/2023] Open
Abstract
High-density lipoprotein (HDL) levels are reduced in patients with coronavirus disease 2019 (COVID-19), and the extent of this reduction is associated with poor clinical outcomes. While lipoproteins are known to play a key role during the life cycle of the hepatitis C virus, their influence on coronavirus (CoV) infections is poorly understood. In this study, we utilize cross-linking mass spectrometry (XL-MS) to determine circulating protein interactors of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoprotein. XL-MS of plasma isolated from patients with COVID-19 uncovered HDL protein interaction networks, dominated by acute-phase serum amyloid proteins, whereby serum amyloid A2 was shown to bind to apolipoprotein (Apo) D. XL-MS on isolated HDL confirmed ApoD to interact with SARS-CoV-2 spike but not SARS-CoV-1 spike. Other direct interactions of SARS-CoV-2 spike upon HDL included ApoA1 and ApoC3. The interaction between ApoD and spike was further validated in cells using immunoprecipitation-MS, which uncovered a novel interaction between both ApoD and spike with membrane-associated progesterone receptor component 1. Mechanistically, XL-MS coupled with data-driven structural modeling determined that ApoD may interact within the receptor-binding domain of the spike. However, ApoD overexpression in multiple cell-based assays had no effect upon viral replication or infectivity. Thus, SARS-CoV-2 spike can bind to apolipoproteins on HDL, but these interactions do not appear to alter infectivity.
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Affiliation(s)
- Sean A Burnap
- Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, UK; King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK.
| | - Ana Maria Ortega-Prieto
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Jose M Jimenez-Guardeño
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Hashim Ali
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK; Division of Virology, Department of Pathology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Kaloyan Takov
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Matthew Fish
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK; Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Manu Shankar-Hari
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK
| | - Mauro Giacca
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Michael H Malim
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Manuel Mayr
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK.
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Cheng PN, Sun HY, Feng IC, Chiu YC, Wang ST, Tan DC, Chiu HC, Chien SC, Young KC. Interdependence of glycemic and lipid modulation in cured chronic hepatitis C patients by direct-acting antiviral agents. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2023; 56:20-30. [PMID: 35842406 DOI: 10.1016/j.jmii.2022.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 05/01/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection causes various liver diseases and metabolic disorders. With direct-acting antiviral agents (DAAs), which effectively eradicate pan-genotypic HCV, hepatic and concomitant metabolic restorations are achieved. The study aims to evaluate the posttherapeutic benefits of lipid and glycemic homeostasis. METHODS Nighty-five chronic hepatitis C patients who achieved sustained virological response (SVR) by using DAAs were enrolled to collect plasma samples and fractionated lipoproteins at baseline, SVR, and during the post-SVR follow-ups for 6 months (pS6m) and 1 year (pS1yr). The lipid and glycemic parameters were analyzed to establish muturally modulatory relationships. RESULTS Plasma cholesterol (Chol) and glucose were elevated at SVR from baseline, whereas plasma Chol remained increased until pS1yr; however, glucose returned to the basal level. The post-SVR responses included a peak elevation of glycated hemoglobin at pS6m, a sustained elevation of triglyceride (Tg), and sustained declines in insulin, homeostasis model assessment (HOMA)-insulin resistance, and HOMA-beta levels until pS1yr. The changes in plasma Chol and high-density-lipoprotein Chol showed positive correlations, as did the plasma Tg with low-density-lipoprotein Tg and very-low-density-lipoprotein Tg per particle load. Very-low-density-lipoprotein was found to be loaded with increased Tg and Chol and underwent efficient Tg catabolism in the form of conversion into low-density-lipoprotein. Additionally, the posttherapeutic dynamics exhibited correlations of high-density-lipoprotein Chol with plasma glucose and HOMA-beta. CONCLUSION Irrespective of the baseline metabolic status, the posttherapeutic interdependent modulation of blood glycemic and lipid metabolic parameters were revealed in chronic hepatitis C patients following clearance of HCV viremia by DAA treatment.
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Affiliation(s)
- Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Yu Sun
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China; Institute of Pathogen Biology and Immunology of College of Biology, Hunan Provincial Key Laboratory of Medical Virology, Hunan University, Changsha, China; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Che Feng
- Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan
| | - Yen-Cheng Chiu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sin-Tian Wang
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Dyoness Charmaine Tan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Chih Chiu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shih-Chih Chien
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Dwivedi M, Dwivedi A, Mukherjee D. An Insight into Hepatitis C Virus: In Search of Promising Drug Targets. Curr Drug Targets 2023; 24:1127-1138. [PMID: 37907492 DOI: 10.2174/0113894501265769231020031857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/13/2023] [Accepted: 09/21/2023] [Indexed: 11/02/2023]
Abstract
Hepatitis C Virus (HCV) is a global health concern, chronically infecting over 70 million people worldwide. HCV is a bloodborne pathogen that primarily affects the liver, and chronic HCV infection can lead to cirrhosis, liver cancer, and liver failure over time. There is an urgent need for more effective approaches to prevent and treat HCV. This review summarizes current knowledge on the virology, transmission, diagnosis, and management of HCV infection. It also provides an in-depth analysis of HCV proteins as promising targets for antiviral drug and vaccine development. Specific HCV proteins discussed as potential drug targets include the NS5B polymerase, NS3/4A protease, entry receptors like CD81, and core proteins. The implications of HCV proteins as diagnostic and prognostic biomarkers are also explored. Current direct-acting antiviral therapies are effective but have cost, genotype specificity, and resistance limitations. This review aims to synthesize essential information on HCV biology and pathogenesis to inform future research on improved preventive, diagnostic, and therapeutic strategies against this global infectious disease threat.
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Affiliation(s)
- Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow- 226028, India
| | - Aditya Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow- 226028, India
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Awadh AA. The Role of Cytosolic Lipid Droplets in Hepatitis C Virus Replication, Assembly, and Release. BIOMED RESEARCH INTERNATIONAL 2023; 2023:5156601. [PMID: 37090186 PMCID: PMC10121354 DOI: 10.1155/2023/5156601] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 03/02/2023] [Accepted: 03/09/2023] [Indexed: 04/25/2023]
Abstract
The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer-the progressive liver damage results from the host's immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host's lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host-virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small-molecule inhibitors of cLD-regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication.
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Affiliation(s)
- Abdullah A. Awadh
- Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah 21423, Saudi Arabia
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8
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Shahriar S, Araf Y, Ahmad R, Kattel P, Sah GS, Rahaman TI, Sadiea RZ, Sultana S, Islam MS, Zheng C, Hossain MG. Insights Into the Coinfections of Human Immunodeficiency Virus-Hepatitis B Virus, Human Immunodeficiency Virus-Hepatitis C Virus, and Hepatitis B Virus-Hepatitis C Virus: Prevalence, Risk Factors, Pathogenesis, Diagnosis, and Treatment. Front Microbiol 2022; 12:780887. [PMID: 35222296 PMCID: PMC8865087 DOI: 10.3389/fmicb.2021.780887] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/21/2021] [Indexed: 12/15/2022] Open
Abstract
Human immunodeficiency virus, hepatitis B virus, and hepatitis C virus are three blood-borne viruses that can cause major global health issues by increasing severe morbidity. There is a high risk of coinfection with these viruses in individuals because of their same transmission routes through blood using shared needles, syringes, other injection equipment, sexual transmission, or even vertical transmission. Coinfection can cause various liver-related illnesses, non-hepatic organ dysfunction, followed by death compared to any of these single infections. The treatment of coinfected patients is complicated due to the side effects of antiviral medication, resulting in drug resistance, hepatotoxicity, and a lack of required responses. On the other hand, coinfected individuals must be treated with multiple drugs simultaneously, such as for HIV either along with HBV or HCV and HBV and HCV. Therefore, diagnosing, treating, and controlling dual infections with HIV, HBV, or HCV is complicated and needs further investigation. This review focuses on the current prevalence, risk factors, and pathogenesis of dual infections with HIV, HBV, and HCV. We also briefly overviewed the diagnosis and treatment of coinfections of these three blood-borne viruses.
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Affiliation(s)
- Sagarika Shahriar
- Biotechnology Program, Department of Mathematics and Natural Sciences, BRAC University, Dhaka, Bangladesh
| | - Yusha Araf
- Department of Genetic Engineering and Biotechnology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Rasel Ahmad
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Pravakar Kattel
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Ganga Sagar Sah
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Tanjim Ishraq Rahaman
- Department of Biotechnology and Genetic Engineering, Faculty of Life Sciences, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Rahila Zannat Sadiea
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Shahnaj Sultana
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Md. Sayeedul Islam
- Department of Biological Sciences, Graduate School of Science, Osaka University, Osaka, Japan
| | - Chunfu Zheng
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
| | - Md. Golzar Hossain
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, Bangladesh
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Chapuy-Regaud S, Allioux C, Capelli N, Migueres M, Lhomme S, Izopet J. Vectorial Release of Human RNA Viruses from Epithelial Cells. Viruses 2022; 14:231. [PMID: 35215825 PMCID: PMC8875463 DOI: 10.3390/v14020231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/07/2022] [Accepted: 01/21/2022] [Indexed: 02/04/2023] Open
Abstract
Epithelial cells are apico-basolateral polarized cells that line all tubular organs and are often targets for infectious agents. This review focuses on the release of human RNA virus particles from both sides of polarized human cells grown on transwells. Most viruses that infect the mucosa leave their host cells mainly via the apical side while basolateral release is linked to virus propagation within the host. Viruses do this by hijacking the cellular factors involved in polarization and trafficking. Thus, understanding epithelial polarization is essential for a clear understanding of virus pathophysiology.
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Affiliation(s)
- Sabine Chapuy-Regaud
- Department of Virology, CHU Purpan, F-31059 Toulouse, France; (N.C.); (M.M.); (S.L.); (J.I.)
- INFINITy (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Toulouse III, CHU Purpan, F-31024 Toulouse, France;
| | - Claire Allioux
- INFINITy (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Toulouse III, CHU Purpan, F-31024 Toulouse, France;
| | - Nicolas Capelli
- Department of Virology, CHU Purpan, F-31059 Toulouse, France; (N.C.); (M.M.); (S.L.); (J.I.)
- INFINITy (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Toulouse III, CHU Purpan, F-31024 Toulouse, France;
| | - Marion Migueres
- Department of Virology, CHU Purpan, F-31059 Toulouse, France; (N.C.); (M.M.); (S.L.); (J.I.)
- INFINITy (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Toulouse III, CHU Purpan, F-31024 Toulouse, France;
| | - Sébastien Lhomme
- Department of Virology, CHU Purpan, F-31059 Toulouse, France; (N.C.); (M.M.); (S.L.); (J.I.)
- INFINITy (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Toulouse III, CHU Purpan, F-31024 Toulouse, France;
| | - Jacques Izopet
- Department of Virology, CHU Purpan, F-31059 Toulouse, France; (N.C.); (M.M.); (S.L.); (J.I.)
- INFINITy (Toulouse Institute for Infectious and Inflammatory Diseases), INSERM UMR1291, CNRS UMR5051, Université Toulouse III, CHU Purpan, F-31024 Toulouse, France;
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10
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Grewal T, Buechler C. Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond. Int J Mol Sci 2022; 23:ijms23031070. [PMID: 35162992 PMCID: PMC8834914 DOI: 10.3390/ijms23031070] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/07/2022] [Accepted: 01/17/2022] [Indexed: 02/05/2023] Open
Abstract
Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed.
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Affiliation(s)
- Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia;
| | - Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, 93053 Regensburg, Germany
- Correspondence:
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11
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Zandi M, Hosseini P, Soltani S, Rasooli A, Moghadami M, Nasimzadeh S, Behnezhad F. The role of lipids in the pathophysiology of coronavirus infections. Osong Public Health Res Perspect 2021; 12:278-285. [PMID: 34719219 PMCID: PMC8561023 DOI: 10.24171/j.phrp.2021.0153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/06/2021] [Indexed: 11/23/2022] Open
Abstract
Coronaviruses, which have been known to cause diseases in animals since the 1930s, utilize cellular components during their replication cycle. Lipids play important roles in viral infection, as coronaviruses target cellular lipids and lipid metabolism to modify their host cells to become an optimal environment for viral replication. Therefore, lipids can be considered as potential targets for the development of antiviral agents. This review provides an overview of the roles of cellular lipids in different stages of the life cycle of coronaviruses.
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Affiliation(s)
- Milad Zandi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Parastoo Hosseini
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Saber Soltani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Rasooli
- Department of Biochemistry, Faculty of Sciences, Payame Noor University, Tehran, Iran
| | - Mona Moghadami
- Department of Medical Biotechnology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Sepideh Nasimzadeh
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Farzane Behnezhad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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12
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Gargan S, Stevenson NJ. Unravelling the Immunomodulatory Effects of Viral Ion Channels, towards the Treatment of Disease. Viruses 2021; 13:2165. [PMID: 34834972 PMCID: PMC8618147 DOI: 10.3390/v13112165] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/07/2021] [Accepted: 10/10/2021] [Indexed: 02/07/2023] Open
Abstract
The current COVID-19 pandemic has highlighted the need for the research community to develop a better understanding of viruses, in particular their modes of infection and replicative lifecycles, to aid in the development of novel vaccines and much needed anti-viral therapeutics. Several viruses express proteins capable of forming pores in host cellular membranes, termed "Viroporins". They are a family of small hydrophobic proteins, with at least one amphipathic domain, which characteristically form oligomeric structures with central hydrophilic domains. Consequently, they can facilitate the transport of ions through the hydrophilic core. Viroporins localise to host membranes such as the endoplasmic reticulum and regulate ion homeostasis creating a favourable environment for viral infection. Viroporins also contribute to viral immune evasion via several mechanisms. Given that viroporins are often essential for virion assembly and egress, and as their structural features tend to be evolutionarily conserved, they are attractive targets for anti-viral therapeutics. This review discusses the current knowledge of several viroporins, namely Influenza A virus (IAV) M2, Human Immunodeficiency Virus (HIV)-1 Viral protein U (Vpu), Hepatitis C Virus (HCV) p7, Human Papillomavirus (HPV)-16 E5, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Open Reading Frame (ORF)3a and Polyomavirus agnoprotein. We highlight the intricate but broad immunomodulatory effects of these viroporins and discuss the current antiviral therapies that target them; continually highlighting the need for future investigations to focus on novel therapeutics in the treatment of existing and future emergent viruses.
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Affiliation(s)
- Siobhan Gargan
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland;
| | - Nigel J. Stevenson
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland;
- Viral Immunology Group, Royal College of Surgeons in Ireland-Medical University of Bahrain, Manama 15503, Bahrain
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13
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Adherence to a Fish-Rich Dietary Pattern Is Associated with Chronic Hepatitis C Patients Showing Low Viral Load: Implications for Nutritional Management. Nutrients 2021; 13:nu13103337. [PMID: 34684338 PMCID: PMC8541240 DOI: 10.3390/nu13103337] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 01/04/2023] Open
Abstract
Hepatitis C virus (HCV) infection is influenced by genetic (e.g., APOE polymorphisms) and environmental factors between the virus and the host. HCV modulates the host’s lipid metabolism but dietary components influence lipids and in vitro HCV RNA replication. Few data exist on the role of dietary features or patterns (DPs) in HCV infection. Herein, we aimed to evaluate the nutritional profiles of chronic HCV (CHC) and spontaneous clearance (SC) Mexican patients in the context of APOE alleles and their correlation with HCV-related variables. The fibrosis-related APOEε3 allele prevailed in CHC and SC patients, who had four DPs (“meat and soft drinks”, DP1; “processed animal and fried foods”, DP2; “Mexican-healthy”, DP3; and “fish-rich”, DP4). In CHC subjects, polyunsaturated fatty acid intake (PUFA ≥ 4.9%) was negatively associated, and fiber intake (≥21.5 g/day) was positively associated with a high viral load (p < 0.036). High adherence to fish-rich DP4 was associated with a higher frequency of CHC individuals consuming PUFA ≥ 4.9% (p = 0.004) and low viral load (p = 0.036), but a lower frequency of CHC individuals consuming fiber ≥21.5 g/day (p = 0.038). In SC and CHC individuals, modifying unhealthy DPs and targeting HCV-interacting nutrients, respectively, could be part of a nutritional management strategy to prevent further liver damage.
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14
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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15
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Wang SJ, Huang CF, Yu ML. Elbasvir and grazoprevir for the treatment of hepatitis C. Expert Rev Anti Infect Ther 2021; 19:1071-1081. [PMID: 33428488 DOI: 10.1080/14787210.2021.1874351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Hepatitis C is one of the leading causes of chronic liver disease. The direct-acting-antivirals has revolutionized the chronic hepatitis C treatment. DAAs can achieve a sustained virological response rate >95% in different populations.Area covered: This review summarizes the pharmacokinetics, pharmacodynamics, efficacy, and safety of Elbasvir/Grazoprevir (EBR/GZR).Expert opinion: EBR/GZR is a combination of NS5A and NS3/4A inhibitors. The performance in the EBR/GZR combination's safety and tolerability is appreciated in clinical treatment. EBR/GZR also has a higher barrier to resistance-associated substitutions. Based on clinical trials and real-world experience, elbasvir/grazoprevir is effective in the HCV GT1, 4 infections.
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Affiliation(s)
- Szu-Jen Wang
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, Yuan's General Hospital, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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16
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Ahmed N, Ahmed N, Filip R, Pezacki JP. Nuclear Hormone Receptors and Host-Virus Interactions. NUCLEAR RECEPTORS 2021:315-348. [DOI: 10.1007/978-3-030-78315-0_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Shimotohno K. HCV Assembly and Egress via Modifications in Host Lipid Metabolic Systems. Cold Spring Harb Perspect Med 2021; 11:cshperspect.a036814. [PMID: 32122916 PMCID: PMC7778218 DOI: 10.1101/cshperspect.a036814] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Hepatitis C virus (HCV) proliferates by hijacking the host lipid machinery. In vitro replication systems revealed many aspects of the virus life cycle; in particular, viral utilization of host lipid metabolism during HCV proliferation. HCV interacts with lipid droplets (LDs) before starting the process of virus capsid formation at the lipid-rich endoplasmic reticulum (ER) membrane compartment. HCV buds into the ER via lipoprotein assembly and secretion. Exchangeable apolipoproteins, represented by apolipoprotein E (apoE), play pivotal roles in enhancing HCV-specific infectivity. HCV virions are likely to interact with other lipoproteins circulating in blood vessels and incorporate apolipoproteins as well as lipids. This review focuses on virus assembly and egress by briefly describing the recent advances in this area.
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18
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Pellegrini L, Albecka A, Mallery DL, Kellner MJ, Paul D, Carter AP, James LC, Lancaster MA. SARS-CoV-2 Infects the Brain Choroid Plexus and Disrupts the Blood-CSF Barrier in Human Brain Organoids. Cell Stem Cell 2020; 27:951-961.e5. [PMID: 33113348 PMCID: PMC7553118 DOI: 10.1016/j.stem.2020.10.001] [Citation(s) in RCA: 361] [Impact Index Per Article: 72.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/28/2020] [Accepted: 10/07/2020] [Indexed: 01/06/2023]
Abstract
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, leads to respiratory symptoms that can be fatal. However, neurological symptoms have also been observed in some patients. The cause of these complications is currently unknown. Here, we use human-pluripotent-stem-cell-derived brain organoids to examine SARS-CoV-2 neurotropism. We find expression of viral receptor ACE2 in mature choroid plexus cells expressing abundant lipoproteins, but not in neurons or other cell types. We challenge organoids with SARS-CoV-2 spike pseudovirus and live virus to demonstrate viral tropism for choroid plexus epithelial cells but little to no infection of neurons or glia. We find that infected cells are apolipoprotein- and ACE2-expressing cells of the choroid plexus epithelial barrier. Finally, we show that infection with SARS-CoV-2 damages the choroid plexus epithelium, leading to leakage across this important barrier that normally prevents entry of pathogens, immune cells, and cytokines into cerebrospinal fluid and the brain.
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Affiliation(s)
- Laura Pellegrini
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Anna Albecka
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Donna L Mallery
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Max J Kellner
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - David Paul
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Andrew P Carter
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Leo C James
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Madeline A Lancaster
- MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
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19
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D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
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Affiliation(s)
- Simmone D'souza
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Keith CK Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Trushar R Patel
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge T1K3M4, AB, Canada
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20
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Huang CF, Dai CY, Yeh ML, Huang CI, Lee HC, Lai WT, Liang PC, Lin YH, Hsieh MY, Hou NJ, Lin ZY, Chen SC, Huang JF, Chuang WL, Yu ML. Cure or curd: Modification of lipid profiles and cardio-cerebrovascular events after hepatitis C virus eradication. Kaohsiung J Med Sci 2020; 36:920-928. [PMID: 32643842 DOI: 10.1002/kjm2.12275] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/09/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) eradication deteriorates lipid profiles. Although HCV eradication may reduce the risk of vascular events as a whole, whether deteriorated lipid profiles increases the risk of cardio-cerebral disease in certain patients is elusive. Serial lipid profiles were measured before, during, at and 3 months after the end of direct-acting antivirals (DAAs) therapy, and annually thereafter in chronic hepatitis C patients who achieved a sustained virological response (SVR, undetectable HCV RNA at posttreatment week 12). The primary end-point was the occurrence of the events. A total of 617 patients were included, with a mean follow-up period of 26.8 months (range: 1-65 months). The total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels increased significantly from treatment week 4 to 2 years after treatment. Logistic regression analysis revealed that the factors independently associated with a significant cholesterol increase included age (odds ratio [OR]/95% confidence intervals [CIs]:1.02/1.006-1.039, P = .007) and smoking (OR/CI:3.21/1.14-9.02, P = .027). Five patients developed cardio-cerebral diseases during 1376 person-years follow-up period. Compared to patients without vascular events, a significantly higher proportion of those with vascular events experienced an LDL-C surge >40% (80% vs 19.9%, P = .001). Cox-regression analysis revealed that an LDL-C surge >40% was the only factor predictive of vascular events (HR/CI: 15.44/1.73-138.20, P = .014). Dyslipidemia occurred after HCV eradication, and it was associated with the risk of cardio-cerebrovascular diseases. Attention should also be paid to the extrahepatic consequence beyond liver-related complications in the post-SVR era.
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Affiliation(s)
- Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Liquid Biopsy and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Liquid Biopsy and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Liquid Biopsy and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiang-Chun Lee
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wen-Ter Lai
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Nai-Jen Hou
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Liquid Biopsy and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Liquid Biopsy and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Liquid Biopsy and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.,College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan
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21
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Glaría E, Letelier NA, Valledor AF. Integrating the roles of liver X receptors in inflammation and infection: mechanisms and outcomes. Curr Opin Pharmacol 2020; 53:55-65. [PMID: 32599447 DOI: 10.1016/j.coph.2020.05.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 01/10/2023]
Abstract
Liver X receptors (LXRs) are transcription factors from the nuclear receptor family that can be pharmacologically activated by high-affinity agonists. LXR activation exerts a combination of metabolic and anti-inflammatory actions that result in the modulation of immune responses and in the amelioration of inflammatory disorders. In addition, LXR agonists modulate the metabolism of infected cells and limit the infectivity and/or growth of several pathogens. This review gives an overview of the recent advances in understanding the complexity of the mechanisms through which the LXR pathway controls inflammation and host-cell pathogen interaction.
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Affiliation(s)
- Estibaliz Glaría
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain
| | - Nicole A Letelier
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain
| | - Annabel F Valledor
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain.
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22
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Ghosh S, Chakraborty J, Goswami A, Bhowmik S, Roy S, Ghosh A, Dokania S, Kumari P, Datta S, Chowdhury A, Bhattacharyya SN, Chatterjee R, Banerjee S. A novel microRNA boosts hyper-β-oxidation of fatty acids in liver by impeding CEP350-mediated sequestration of PPARα and thus restricts chronic hepatitis C. RNA Biol 2020; 17:1352-1363. [PMID: 32507013 DOI: 10.1080/15476286.2020.1768353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Imbalance in lipid metabolism induces steatosis in liver during Chronic hepatitis C (CHC). Contribution of microRNAs in regulating lipid homoeostasis and liver disease progression is well established using small RNA-transcriptome data. Owing to the complexity in the development of liver diseases, the existence and functional importance of yet undiscovered regulatory miRNAs in disease pathogenesis was explored in this study using the unmapped sequences of the transcriptome data of HCV-HCC liver tissues following miRDeep2.pl pipeline. MicroRNA-c12 derived from the first intron of LGR5 of chromosome 12 was identified as one of the miRNA like sequences retrieved in this analysis that showed human specific origin. Northern blot hybridization has proved its existence in the hepatic cell line. Enrichment of premiR-c12 in dicer-deficient cells and miR-c12 in Ago2-RISC complex clearly suggested that it followed canonical miRNA biogenesis pathway and accomplished its regulatory function. Expression of this miRNA was quite low in CHC tissues than normal liver implying HCV-proteins might be regulating its biogenesis. Promoter scanning and ChIP analysis further revealed that under expression of p53 and hyper-methylation of STAT3 binding site upon HCV infection restricted its expression in CHC tissues. Centrosomal protein 350 (CEP350), which sequestered PPARα, was identified as one of the targets of miR-c12 using Miranda and validated by luciferase assay/western blot analysis. Furthermore, reduced triglyceride accumulation and enhanced PPARα mediated transcription of β-oxidation genes upon restoration of miR-c12 in liver cells suggested its role in lipid catabolism. Thus this study is reporting miR-c12 for the first time and showed its' protective role during chronic HCV infection.
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Affiliation(s)
- Suchandrima Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | - Joyeeta Chakraborty
- Human Genetics Unit, Indian Statistical Institute , Kolkata, Human Genetics Unit, India
| | - Avijit Goswami
- Department of Molecular Genetics, Indian Institute of Chemical Biology , Kolkata, India
| | - Sayantani Bhowmik
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | - Susree Roy
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | - Amit Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | - Sakshi Dokania
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | - Priyanka Kumari
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
| | | | - Raghunath Chatterjee
- Human Genetics Unit, Indian Statistical Institute , Kolkata, Human Genetics Unit, India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research , Kolkata, India
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Gobeil Odai K, O’Dwyer C, Steenbergen R, Shaw TA, Renner TM, Ghorbani P, Rezaaifar M, Han S, Langlois MA, Crawley AM, Russell RS, Pezacki JP, Tyrrell DL, Fullerton MD. In Vitro Hepatitis C Virus Infection and Hepatic Choline Metabolism. Viruses 2020; 12:v12010108. [PMID: 31963173 PMCID: PMC7019665 DOI: 10.3390/v12010108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/13/2020] [Indexed: 01/04/2023] Open
Abstract
Choline is an essential nutrient required for normal neuronal and muscular development, as well as homeostatic regulation of hepatic metabolism. In the liver, choline is incorporated into the main eukaryotic phospholipid, phosphatidylcholine (PC), and can enter one-carbon metabolism via mitochondrial oxidation. Hepatitis C virus (HCV) is a hepatotropic positive-strand RNA virus that similar to other positive-strand RNA viruses and can impact phospholipid metabolism. In the current study we sought to interrogate if HCV modulates markers of choline metabolism following in vitro infection, while subsequently assessing if the inhibition of choline uptake and metabolism upon concurrent HCV infection alters viral replication and infectivity. Additionally, we assessed whether these parameters were consistent between cells cultured in fetal bovine serum (FBS) or human serum (HS), conditions known to differentially affect in vitro HCV infection. We observed that choline transport in FBS- and HS-cultured Huh7.5 cells is facilitated by the intermediate affinity transporter, choline transporter-like family (CTL). HCV infection in FBS, but not HS-cultured cells diminished CTL1 transcript and protein expression at 24 h post-infection, which was associated with lower choline uptake and lower incorporation of choline into PC. No changes in other transporters were observed and at 96 h post-infection, all differences were normalized. Reciprocally, limiting the availability of choline for PC synthesis by use of a choline uptake inhibitor resulted in increased HCV replication at this early stage (24 h post-infection) in both FBS- and HS-cultured cells. Finally, in chronic infection (96 h post-infection), inhibiting choline uptake and metabolism significantly impaired the production of infectious virions. These results suggest that in addition to a known role of choline kinase, the transport of choline, potentially via CTL1, might also represent an important and regulated process during HCV infection.
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Affiliation(s)
- Kaelan Gobeil Odai
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
| | - Conor O’Dwyer
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
| | - Rineke Steenbergen
- Department of Medical Microbiology and Immunology and Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada; (R.S.); (D.L.T.)
| | - Tyler A. Shaw
- Department of Chemistry and Biomolecular Sciences, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada;
| | - Tyler M. Renner
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
| | - Peyman Ghorbani
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
| | - Mojgan Rezaaifar
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
| | - Shauna Han
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
| | - Marc-André Langlois
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
| | - Angela M. Crawley
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Medicine, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada
- Department of Biology, Faculty of Science, Carleton University, Ottawa, ON K1S 5B6, Canada
| | - Rodney S. Russell
- Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada;
| | - John P. Pezacki
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
- Department of Chemistry and Biomolecular Sciences, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada;
| | - D. Lorne Tyrrell
- Department of Medical Microbiology and Immunology and Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada; (R.S.); (D.L.T.)
| | - Morgan D. Fullerton
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (K.G.O.); (C.O.); (T.M.R.); (P.G.); (M.R.); (S.H.); (M.-A.L.); (A.M.C.); (J.P.P.)
- University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
- Correspondence: ; Tel.: +(1)-613-562-5800 (ext. 8310)
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Todorovska B, Joksimovic N, Caloska-Ivanova V, Dimitrova-Genadieva M, Trajkovska M, Curakova E, Kiprijanovska S, Zafirova-Ivanovska B, Serafimoski V. Factors That Influence the Virological Response in Patients with Chronic Hepatitis C Treated with Pegylated Interferon and Ribavirin. ACTA ACUST UNITED AC 2019; 38:25-33. [PMID: 28593897 DOI: 10.1515/prilozi-2017-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The success of the antiviral treatment in patients with chronic hepatitis C depends on the factors related to the virus and the host. The aim of the study is the analysis of the antiviral therapy which is a combination of pegylated interferon and ribavirin, considering various factors that will identify the predictors of the sustained virological response. MATERIAL AND METHODS This retrospective study included 226 patients, divided in two groups. Patients with sustained virological response and patients without sustained virological response were compared in terms of the following factors: genotype, viral load, gender, age, inflammatory and fibrotic changes in the liver, metabolic abnormalities, obesity and fatty liver. RESULTS The rate of the sustained virological response is 83.6%, more frequently in patients with genotype 3, with evidenced statistical significance (90.54%). The factors that significantly contribute to sustained virological response are related to the age (p = 0.0001), genotype (p = 0.002), mode of transmission (p = 0.005), inflammatory changes in the liver (p = 0.028), body mass index (p = 0.022) and insulin resistance (p = 0.039). The high rate of sustained virological response is related to the younger age of the patients which indirectly means short Hepatitis C Virus infection duration, absence of advanced liver disease and lack of significant co-morbid conditions. Single confirmed independent predictors of sustained virological response are the age (OR 0.928, p = 0.0001) and genotype (OR 3.134, p = 0.005). CONCLUSIONS Factors that are related to the virological response are the age, genotype, mode of transmission, inflammatory changes in the liver, body mass index and insulin resistance, but still, independent predictors of sustained virologic response are the age and the genotype.
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Affiliation(s)
- Beti Todorovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Nenad Joksimovic
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Viktorija Caloska-Ivanova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | | | - Meri Trajkovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Elena Curakova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Sanja Kiprijanovska
- Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Skopje
| | - Beti Zafirova-Ivanovska
- Institute of Epidemiology and Biostatistics, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
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25
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Vescovo T, Refolo G, Manuelli MC, Tisone G, Piacentini M, Fimia GM. The Impact of Mevastatin on HCV Replication and Autophagy of Non-Transformed HCV Replicon Hepatocytes Is Influenced by the Extracellular Lipid Uptake. Front Pharmacol 2019; 10:718. [PMID: 31316383 PMCID: PMC6611414 DOI: 10.3389/fphar.2019.00718] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 06/05/2019] [Indexed: 12/22/2022] Open
Abstract
Statins efficiently inhibit cholesterol synthesis by blocking 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase in the mevalonate pathway. However, the effect of statins on intracellular cholesterol is partially counterbalanced by a consequent increased uptake of extracellular lipid sources. Hepatitis C virus (HCV) infection induces intracellular accumulation of cholesterol by promoting both new synthesis and uptake of circulating lipoproteins, which is required for HCV replication and release. Hepatocytes respond to the increase in intracellular cholesterol levels by inducing lipophagy, a selective type of autophagy mediating the degradation of lipid deposits within lysosomes. In a cellular system of HCV replication based on HuH7 hepatoma cells, statin treatment was shown to be sufficient to decrease intracellular cholesterol, which is accompanied by reduced HCV replication and decreased lipophagy, and has no apparent impact on endocytosis-mediated cholesterol uptake. To understand whether these results were influenced by an altered response of cholesterol influx in hepatoma cells, we analyzed the effect of statins in non-transformed murine hepatocytes (MMHD3) harboring subgenomic HCV replicons. Notably, we found that total amount of cholesterol is increased in MMHD3 cells upon mevastatin treatment, which is associated with increased HCV replication and lipophagy. Conversely, mevastatin is able to reduce cholesterol amounts only when cells are grown in the presence of delipidated serum to prevent extracellular lipid uptake. Under this condition, HCV replication is reduced and autophagy flux is severely impaired. Altogether, these results indicate that both de novo synthesis and extracellular uptake have to be targeted in non-transformed hepatocytes in order to decrease intracellular cholesterol levels and consequently limit HCV replication.
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Affiliation(s)
- Tiziana Vescovo
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy
| | - Giulia Refolo
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy
| | | | - Giuseppe Tisone
- Liver Unit, Polyclinic Tor Vergata Foundation, University of Rome Tor Vergata, Rome, Italy
| | - Mauro Piacentini
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy.,Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Gian Maria Fimia
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy.,Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy
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26
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Visfatin serum concentration and hepatic mRNA expression in chronic hepatitis C. Clin Exp Hepatol 2019; 5:147-154. [PMID: 31501791 PMCID: PMC6728865 DOI: 10.5114/ceh.2019.85074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 12/26/2018] [Indexed: 12/15/2022] Open
Abstract
Aim of the study Chronic hepatitis C (CHC) is a viral disease with metabolic disturbances involved in its pathogenesis. Adipokines may influence the inflammatory response and contribute to development of metabolic abnormalities in CHC. Visfatin exerts immunomodulatory and insulin-mimetic effects. The aim was to measure visfatin serum concentrations and its mRNA hepatic expression in non-obese CHC patients and to assess the relationships with metabolic and histological parameters. Material and methods In a group of 63 non-obese CHC patients (29 M/34 F) infected with genotype 1b aged 46.6 ±14.6 years, body mass index (BMI) 24.8 ±3.0 kg/m2, serum visfatin levels and its mRNA hepatic expression were examined and the subsequent associations with metabolic and histopathological features were assessed. Results Serum visfatin levels were significantly higher in CHC patients compared to controls (22.7 ±5.7 vs. 17.8 ±1.5 ng/ml, p < 0.001). There was no difference in serum visfatin and its mRNA hepatic expression regardless of sex, BMI, insulin sensitivity and lipids concentrations. There was no mutual correlation between serum visfatin and visfatin mRNA hepatic expression. Hepatic visfatin mRNA levels but not visfatin serum levels were higher in patients with steatosis (1.35 ±0.75 vs. 0.98 ±0.34, p = 0.009). Conclusions Serum visfatin levels may reflect its involvement in chronic inflammatory processes accompanying HCV infection. Increased visfatin mRNA hepatic expression in patients with steatosis seems to be a compensatory mechanism enabling hepatocytes to survive metabolic abnormalities resulting from virus-related lipid droplet deposition prerequisite to HCV replication.
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Rosso C, Caviglia GP, Ciruolo M, Ciancio A, Younes R, Olivero A, Giordanino C, Troshina G, Abate ML, Rizzetto M, Pellicano R, Saracco GM, Bugianesi E, Smedile A. Clinical outcomes in chronic hepatitis C long-term responders to pre-direct antiviral agents: a single-center retrospective study. Minerva Med 2019; 110:401-409. [PMID: 31081312 DOI: 10.23736/s0026-4806.19.06108-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Obesity, type 2 diabetes (T2D), dyslipidemia, arterial hypertension as well as hepatic steatosis (HS) are common conditions that can affect clinical outcomes of patients with chronic hepatitis C (CHC) who achieved sustained virologic response (SVR). The aim of this study was to assess the impact of metabolic cofactors on the occurrence of clinical events during follow-up (FU) in a group of CHC long-term responders (LTRs) to interferon- (IFN) based therapy. METHODS A total of 5172 medical records of CHC patients enrolled from 1990 to 2011 were examined; 1034 of 5172 (20%) patients were treated with IFN-based therapy and 382 of 1034 (37%) of them achieved SVR. A total of 188 (49%) LTRs underwent liver biopsy before antiviral treatment. Data on liver and cardiometabolic events such as cirrhosis and its complications, hepatocellular carcinoma, coronary artery disease, arterial hypertension, impaired fasting glucose (IFG)/type 2 diabetes (T2D) and dyslipidemia, were collected over time. RESULTS The mean age of the whole cohort was 46±12 years and 114/188 (61%) patients were males. HS was found in 82 of 188 (43.6%) patients and most of them were infected by HCV genotype 3a. The prevalence of obesity, IFG/T2D, dyslipidemia and arterial hypertension was 4.3%, 6.9%, 37.2%, and 5.9%, and was similarly distributed among patients with and without HS. Cirrhosis was histologically diagnosed in 18 of 188 (9.6%) patients. After a median follow-up of 11 years (range 3-21 years), the cumulative incidence of cardiovascular events, IFG/T2D and dyslipidemia was higher in CHC-LTRs who had HS at baseline compared to those without HS (1.2%, 2.3%, and 3.0% vs. 0.4%, 0.8%, and 2.5%, respectively). At multivariable Cox regression analysis, HS was significantly associated to the development of cardiovascular events and IFG/T2D (HR=5.2, 95% CI: 1.3-20.7, P=0.019, and HR=2.6, 95% CI: 1.1-6.2, P=0.027, respectively). CONCLUSIONS In CHC-LTRs, HS at baseline may predispose to the development of cardiovascular events and T2D during follow-up emphasizing the importance of an accurate counseling in order to prevent extra-hepatic complications.
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Affiliation(s)
- Chiara Rosso
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy -
| | - Gian Paolo Caviglia
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Michela Ciruolo
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alessia Ciancio
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Ramy Younes
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonella Olivero
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Giordanino
- Department of Gastro-Hepatology, Città della Salute e della Scienza University Hospital, Turin, Italy
| | - Giulia Troshina
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Maria Lorena Abate
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Mario Rizzetto
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Rinaldo Pellicano
- Department of Gastro-Hepatology, Città della Salute e della Scienza University Hospital, Turin, Italy
| | - Giorgio M Saracco
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonina Smedile
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
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Abstract
Hepatitis C virus represents a global pathogen of human health significance. In the space of less than three decades, we have witnessed the discovery of the virus, a growing understanding of the structure and biology of the viral-encoded proteins and their interaction with the host cell and the sequencing of the viral genome. Most importantly, we have moved from early therapeutic strategies aimed at crude boosting of host anti-viral immunity, limited by side effects and with poor response rates, to therapies that directly exploit our understanding of viral biology. In this review, we discuss the significance of the virus, its' discovery and outline the advances in the molecular characterisation of the virus, before setting these within the context of contemporary and emerging therapeutic strategies as well as viral resistance mechanisms.
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29
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Batista MN, Sanches PRDS, Carneiro BM, Braga ACS, Campos GRF, Cilli EM, Rahal P. GA-Hecate antiviral properties on HCV whole cycle represent a new antiviral class and open the door for the development of broad spectrum antivirals. Sci Rep 2018; 8:14329. [PMID: 30254334 PMCID: PMC6156508 DOI: 10.1038/s41598-018-32176-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/02/2018] [Indexed: 12/14/2022] Open
Abstract
In recent years, synthetic peptides have been considered promising targets for drug development that possess low side-effects, are cost-effective and are susceptible to rational design. Hecate was initially described as a potent bacterial inhibitor and subsequently as an anticancer drug with functions related to its lipid interaction property. Viruses, such as hepatitis C virus (HCV), have a lipid-dependent life cycle and could be affected by Hecate in many ways. Here, we assessed modifications on Hecate’s N-terminus region and its effects on HCV and hepatotoxicity. Gallic acid-conjugated Hecate was the most efficient Hecate-derivative, presenting high potential as an antiviral and inhibiting between 50 to 99% of all major steps within the HCV infectious cycle. However, the most promising aspect was GA-Hecate’s mechanism of action, which was associated with a balanced lipid interaction with the viral envelope and lipid droplets, as well as dsRNA intercalation, allowing for the possibility to affect other ssRNA viruses and those with a lipid-dependent cycle.
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Affiliation(s)
- Mariana Nogueira Batista
- Institute of Bioscience, Language and Exact Science, UNESP - São Paulo State University, São José do Rio Preto, SP, Brazil
| | | | - Bruno Moreira Carneiro
- Institute of Bioscience, Language and Exact Science, UNESP - São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Ana Cláudia Silva Braga
- Institute of Bioscience, Language and Exact Science, UNESP - São Paulo State University, São José do Rio Preto, SP, Brazil
| | | | - Eduardo Maffud Cilli
- Institute of Chemistry, UNESP - São Paulo State University, Araraquara, SP, Brazil.
| | - Paula Rahal
- Institute of Bioscience, Language and Exact Science, UNESP - São Paulo State University, São José do Rio Preto, SP, Brazil.
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30
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Batsaikhan B, Huang CI, Yeh ML, Huang CF, Hou NJ, Lin ZY, Chen SC, Huang JF, Yu ML, Chuang WL, Lee JC, Dai CY. The effect of antiviral therapy on serum lipid profiles in chronic hepatitis C. Oncotarget 2018; 9:21313-21321. [PMID: 29765541 PMCID: PMC5940400 DOI: 10.18632/oncotarget.25092] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 03/22/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Low lipid profile is associated with hepatitis C virus (HCV) infection. Chronic HCV infection is the main cause of liver injury and serum lipid levels during antiviral treatment. We aimed to evaluate the effect of antiviral treatment on the change of lipid profiles during HCV treatment. METHODS Total 863 patients who complete the interferon-based therapy in Kaohsiung Medical University Hospital were included in this study. The lipid profile measured and evaluated in baseline and after 6 months of the treatment. RESULTS Sustained virological response (SVR) was achieved in 81.2% of all patients. The baseline triglycerides (TG) levels in the SVR group and non SVR groups were similar. The TG levels at 6 months after cessation of the treatment was significantly elevated in SVR group (102.9±57.0 mg/dL, p=0.0001) but did not elevated in non SVR group (94.5±45.6 mg/dL, p=0.690) compared with baseline TG levels. After adjusting patients by four indexes for fibrosis (FIB4) in cut-off point 3.25, serum TG levels significantly increased in low FIB4 group (103.2±57.9 mg/dL, p=0.0001) but not in high FIB4 group (98.1±49.6 mg/dL, p=0.095) after 6 months end of the treatment. Serum TG level was increased greater in patients who had low FIB4 score and patients who achieved SVR (baseline 89.1±34.8 mg/dL; 6 months after treatment 104.3±59.3 mg/dL, paired T test p=0.0001). CONCLUSION The clearance of the HCV RNA is the main determinant of the increase of lipids after PegIFN/RBV treatment. However advanced fibrosis also has an effect in increase of lipids after the treatment.
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Affiliation(s)
- Batbold Batsaikhan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Ching-I Huang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Nei-Jen Hou
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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Morozov VA, Lagaye S. Hepatitis C virus: Morphogenesis, infection and therapy. World J Hepatol 2018; 10:186-212. [PMID: 29527256 PMCID: PMC5838439 DOI: 10.4254/wjh.v10.i2.186] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/11/2018] [Accepted: 02/07/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of liver diseases including liver cirrhosis and hepatocellular carcinoma. Approximately 3% of the world population is infected with HCV. Thus, HCV infection is considered a public healthy challenge. It is worth mentioning, that the HCV prevalence is dependent on the countries with infection rates around 20% in high endemic countries. The review summarizes recent data on HCV molecular biology, the physiopathology of infection (immune-mediated liver damage, liver fibrosis and lipid metabolism), virus diagnostic and treatment. In addition, currently available in vitro, ex vivo and animal models to study the virus life cycle, virus pathogenesis and therapy are described. Understanding of both host and viral factors may in the future lead to creation of new approaches in generation of an efficient therapeutic vaccine.
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Affiliation(s)
- Vladimir Alexei Morozov
- Center for HIV and Retrovirology, Department of Infectious Diseases, Robert Koch Institute, Berlin 13353, Germany
| | - Sylvie Lagaye
- Department of Immunology, Institut Pasteur, INSERM U1223, Paris 75015, France
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Hu L, Li J, Cai H, Yao W, Xiao J, Li YP, Qiu X, Xia H, Peng T. Avasimibe: A novel hepatitis C virus inhibitor that targets the assembly of infectious viral particles. Antiviral Res 2017; 148:5-14. [PMID: 29074218 DOI: 10.1016/j.antiviral.2017.10.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/15/2017] [Accepted: 10/20/2017] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals (DAAs), which target hepatitis C virus (HCV) proteins, have exhibited impressive efficacy in the management of chronic hepatitis C. However, the concerns regarding high costs, drug resistance mutations and subsequent unexpected side effects still call for the development of host-targeting agents (HTAs) that target host factors involved in the viral life cycle and exhibit pan-genotypic antiviral activity. Given the close relationship between lipid metabolism and the HCV life cycle, we investigated the anti-HCV activity of a series of lipid-lowering drugs that have been approved by government administrations or proven safety in clinical trials. Our results showed that avasimibe, an inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), exhibited marked pan-genotypic inhibitory activity and superior inhibition against HCV when combined with DAAs. Moreover, avasimibe significantly impaired the assembly of infectious HCV virions. Mechanistic studies demonstrated that avasimibe induced downregulation of microsomal triglyceride transfer protein expression, resulting in reduced apolipoprotein E and apolipoprotein B secretion. Therefore, the pan-genotypic antiviral activity and clinically proven safety endow avasimibe exceptional potential as a candidate for combination therapy with DAAs. In addition, the discovery of the antiviral properties of ACAT inhibitors also suggests that inhibiting the synthesis of cholesteryl esters might be an additional target for the therapeutic intervention for chronic HCV infection.
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Affiliation(s)
- Longbo Hu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jinqian Li
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hua Cai
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China
| | - Wenxia Yao
- The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Jing Xiao
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yi-Ping Li
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiu Qiu
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Huimin Xia
- Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China; Department of Neonatal Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Tao Peng
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China.
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Gomaa HE, Mahmoud M, Saad NE, Saad-Hussein A, Ismail S, Thabet EH, Farouk H, Kandil D, Heiba A, Hafez W. Impact of Apo E gene polymorphism on HCV therapy related outcome in a cohort of HCV Egyptian patients. J Genet Eng Biotechnol 2017; 16:47-51. [PMID: 30647703 PMCID: PMC6296613 DOI: 10.1016/j.jgeb.2017.10.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 09/18/2017] [Accepted: 10/05/2017] [Indexed: 02/07/2023]
Abstract
The functional apolipoprotein E (Apo E) gene polymorphism could be used as a determinant of outcome of HCV infection. This study aimed to demonstrate the impact of Apo E genotype on the response to HCV combined therapy. MATERIAL AND METHODS The study has been implemented on 125 individuals with persistent HCV infection and 120 cases with sustained virologic response (SVR). All participants were genotyped for ApoE gene polymorphism by a real-time quantitative PCR (qPCR). RESULTS Statistically significant differences were demonstrated regarding the Apo E genotypes between the two groups (P-value < .001) where the frequency of E3E3 was significantly higher among the chronic HCV-patients while E3E4 and E4E4 genotypes frequencies were higher among the SVR-subjects group and E3E3 genotype was associated with increased risk of chronicity (OR 4.7; 95% CI 1.9-12.1, P-value < .001). Moreover, There were statically significant differences regarding E3 and E4 alleles frequencies, where E3 allele display a higher frequency among the chronic HCV-patient group while the SVR-subjects group showed higher frequency of E4 allele and the carriers of E3 allele have 1.4 times more risk to develop chronicity than those with E4 allele (OR 1.4; 95% CI 1.0-2.0, P-value < .05). Meanwhile the protective E2 allele was absent in all infected participants. CONCLUSION This study supports the hypothesis of the protective impact of Apo E4 allele that favors viral clearance of HCV infection and its recovery after combined therapy, while the Apo E3 allele is considered as a particular risk factor for the chronicity in HCV patients and resistance to therapy. Whereas the Apo E2 allele confers a resistance to HCV infection at a time of exposure.
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Affiliation(s)
- Howayda E Gomaa
- Clinical Pathology Department, National Research Centre, El-Behoos Street, Giza, Egypt
| | - Mohamed Mahmoud
- Internal Medicine Department, National Research Centre, Egypt
| | - Nevine E Saad
- Clinical Pathology Department, National Research Centre, El-Behoos Street, Giza, Egypt
| | - Amal Saad-Hussein
- Environmental and Occupational Medicine Department, National Research Centre, Egypt
| | - Somaia Ismail
- Medical Molecular Genetics Department, National Research Centre, Egypt
| | - Eman H Thabet
- Clinical Pathology Department, National Research Centre, El-Behoos Street, Giza, Egypt
| | - Hebatallah Farouk
- Clinical Pathology Department, National Research Centre, El-Behoos Street, Giza, Egypt
| | - Dina Kandil
- Clinical Pathology Department, National Research Centre, El-Behoos Street, Giza, Egypt
| | - Ahmed Heiba
- Internal Medicine Department, National Research Centre, Egypt
| | - Wael Hafez
- Internal Medicine Department, National Research Centre, Egypt
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Barriocanal M, Fortes P. Long Non-coding RNAs in Hepatitis C Virus-Infected Cells. Front Microbiol 2017; 8:1833. [PMID: 29033906 PMCID: PMC5625025 DOI: 10.3389/fmicb.2017.01833] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/06/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) often leads to a chronic infection in the liver that may progress to steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Several viral and cellular factors are required for a productive infection and for the development of liver disease. Some of these are long non-coding RNAs (lncRNAs) deregulated in infected cells. After HCV infection, the sequence and the structure of the viral RNA genome are sensed to activate interferon (IFN) synthesis and signaling pathways. These antiviral pathways regulate transcription of several cellular lncRNAs. Some of these are also deregulated in response to viral replication. Certain viral proteins and/or viral replication can activate transcription factors such as MYC, SP1, NRF2, or HIF1α that modulate the expression of additional cellular lncRNAs. Interestingly, several lncRNAs deregulated in HCV-infected cells described so far play proviral or antiviral functions by acting as positive or negative regulators of the IFN system, while others help in the development of liver cirrhosis and HCC. The study of the structure and mechanism of action of these lncRNAs may aid in the development of novel strategies to treat infectious and immune pathologies and liver diseases such as cirrhosis and HCC.
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Affiliation(s)
| | - Puri Fortes
- Department of Gene Therapy and Hepatology, Navarra Institute for Health Research (IdiSNA), Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain
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Entry and Release of Hepatitis C Virus in Polarized Human Hepatocytes. J Virol 2017; 91:JVI.00478-17. [PMID: 28659476 DOI: 10.1128/jvi.00478-17] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 06/22/2017] [Indexed: 12/23/2022] Open
Abstract
Hepatitis C virus (HCV) primarily infects hepatocytes, which are highly polarized cells. The relevance of cell polarity in the HCV life cycle has been addressed only in distantly related models and remains poorly understood. Although polarized epithelial cells have a rather simple morphology with a basolateral and an apical domain, hepatocytes exhibit complex polarization structures. However, it has been reported that some selected polarized HepG2 cell clones can exhibit a honeycomb pattern of distribution of the tight-junction proteins typical of columnar polarized epithelia, which can be used as a simple model to study the role of cell polarization in viral infection of hepatocytes. To obtain similar clones, HepG2 cells expressing CD81 (HepG2-CD81) were used, and clones were isolated by limiting dilutions. Two clones exhibiting a simple columnar polarization capacity when grown on a semipermeable support were isolated and characterized. To test the polarity of HCV entry and release, our polarized HepG2-CD81 clones were infected with cell culture-derived HCV. Our data indicate that HCV binds equally to both sides of the cells, but productive infection occurs mainly when the virus is added at the basolateral domain. Furthermore, we also observed that HCV virions are released from the basolateral domain of the cells. Finally, when polarized cells were treated with oleic acid and U0126, a MEK inhibitor, to promote lipoprotein secretion, a higher proportion of infectious viral particles of lower density were secreted. This cell culture system provides an excellent model to investigate the influence of cell polarization on the HCV life cycle.IMPORTANCE Hepatitis C is a major health burden, with approximately 170 million persons infected worldwide. Hepatitis C virus (HCV) primarily infects hepatocytes, which are highly polarized cells with a complex organization. The relevance of cell polarity in the HCV life cycle has been addressed in distantly related models and remains unclear. Hepatocyte organization is complex, with multiple apical and basolateral surfaces. A simple culture model of HepG2 cells expressing CD81 that are able to polarize with unique apical and basolateral domains was developed to study HCV infection. With this model, we demonstrated that HCV enters and exits hepatocytes by the basolateral domain. Furthermore, lower-density viral particles were produced under conditions that promote lipoprotein secretion. This cell culture system provides a useful model to study the influence of cell polarization on HCV infection.
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36
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Masson JJ, Billings HW, Palmer CS. Metabolic reprogramming during hepatitis B disease progression offers novel diagnostic and therapeutic opportunities. Antivir Chem Chemother 2017; 25:53-57. [PMID: 28768434 PMCID: PMC5890528 DOI: 10.1177/2040206617701372] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Metabolic remodeling occurs in immune cells during an infection. Host cells must upregulate energy production for growth, proliferation, and effector functions to limit the damage imposed by pathogens. One example, the hepatitis B virus, induces hepatic injury in human hepatocytes through dysregulation of aerobic glycolysis and lipid metabolism. Increased glycolytic metabolism mediated by elevated expression of Glut1, glucose influx, and lactate secretion is associated with this Warburg phenotype, a classic metabolic signature also observed in cancer cells. This article brings into focus the tight interaction between HBV infection and metabolic dysfunction and how these processes facilitate the progression of end-stage liver diseases, such as hepatocellular carcinoma. We also provide evidence and models by which other viruses such as HIV and Zika disrupt their host metabolic machinery. The emergence of the immunometabolism field provides novel opportunities to take advantage of intermediary metabolites and key metabolic pathways for diagnostic and therapeutic purposes.
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Affiliation(s)
- Jesse Jr Masson
- 1 Centre for Biomedical Research, Burnet Institute, Melbourne, Australia
| | - Hugh Ww Billings
- 1 Centre for Biomedical Research, Burnet Institute, Melbourne, Australia
| | - Clovis S Palmer
- 1 Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.,2 Department of Infectious Diseases, Monash University, Melbourne, Australia.,3 Department of Microbiology and Immunology, University of, Melbourne, Melbourne, Australia
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Crouchet E, Baumert TF, Schuster C. Hepatitis C virus-apolipoprotein interactions: molecular mechanisms and clinical impact. Expert Rev Proteomics 2017; 14:593-606. [PMID: 28625086 PMCID: PMC6138823 DOI: 10.1080/14789450.2017.1344102] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular carcinoma and liver failure. Moreover, chronic HCV infection is associated with liver steatosis and metabolic disorders. With 130-150 million people chronically infected in the world, HCV infection represents a major public health problem. One hallmark on the virus is its close link with hepatic lipid and lipoprotein metabolism. Areas covered: HCV is associated with lipoprotein components such as apolipoproteins. These interactions play a key role in the viral life cycle, viral persistence and pathogenesis of liver disease. This review introduces first the role of apolipoproteins in lipoprotein metabolism, then highlights the molecular mechanisms of HCV-lipoprotein interactions and finally discusses their clinical impact. Expert commentary: While the study of virus-host interactions has resulted in a improvement of the understanding of the viral life cycle and the development of highly efficient therapies, major challenges remain: access to therapy is limited and an urgently needed HCV vaccine remains still elusive. Furthermore, the pathogenesis of disease biology is still only partially understood. The investigation of HCV-lipoproteins interactions offers new perspectives for novel therapeutic approaches, contribute to HCV vaccine design and understand virus-induced liver disease and cancer.
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Affiliation(s)
- Emilie Crouchet
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
| | - Thomas F. Baumert
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Catherine Schuster
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
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Abstract
PURPOSE OF REVIEW Direct-acting antiviral agents (DAAs) have markedly improved the prognosis of hepatitis C virus (HCV)-genotype 3 (GT3), a highly prevalent infection worldwide. However, in patients with hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), GT3 infection presents a treatment challenge compared with other genotypes. The dependence of the HCV life cycle on host lipid metabolism suggests the possible utility of targeting host cellular factors for combination anti-HCV therapy. We discuss current and emergent DAA regimens for HCV-GT3 treatment. We then summarize recent research findings on the reliance of HCV entry, replication, and virion assembly on host lipid metabolism. RECENT FINDINGS Current HCV treatment guidelines recommend the use of daclatasvir plus sofosbuvir (DCV/SOF) or sofosbuvir plus velpatasvir (SOF/VEL) for the management of GT3 based upon clinical efficacy [≥88% overall sustained virological response (SVR)] and tolerability. Potential future DAA options, such as SOF/VEL co-formulated with GS-9857, also look promising in treating cirrhotic GT3 patients. However, HCV resistance to DAAs will likely continue to impact the therapeutic efficacy of interferon-free treatment regimens. Disruption of HCV entry by targeting required host cellular receptors shows potential in minimizing HCV resistance and broadening therapeutic options for certain subpopulations of GT3 patients. The use of cholesterol biosynthesis and transport inhibitors may also improve health outcomes for GT3 patients when used synergistically with DAAs. Due to the morbidity and mortality associated with HCV-GT3 infection compared to other genotypes, efforts should be made to address current limitations in the therapeutic prevention and management of HCV-GT3 infection.
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Triyatni M, Berger EA, Saunier B. Assembly and release of infectious hepatitis C virus involving unusual organization of the secretory pathway. World J Hepatol 2016; 8:796-814. [PMID: 27429716 PMCID: PMC4937168 DOI: 10.4254/wjh.v8.i19.796] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 04/30/2016] [Accepted: 06/03/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine if calnexin (CANX), RAB1 and alpha-tubulin were involved in the production of hepatitis C virus (HCV) particles by baby hamster kidney-West Nile virus (BHK-WNV) cells.
METHODS: Using a siRNA-based approach complemented with immuno-fluorescence confocal microscope and Western blot studies, we examined the roles of CANX, RAB1 and alpha-tubulin in the production of HCV particles by permissive BHK-WNV cells expressing HCV structural proteins or the full-length genome of HCV genotype 1a. Immuno-fluorescence studies in producer cells were performed with monoclonal antibodies against HCV structural proteins, as well as immunoglobulin from the serum of a patient recently cured from an HCV infection of same genotype. The cellular compartment stained by the serum immunoglobulin was also observed in thin section transmission electron microscopy. These findings were compared with the JFH-1 strain/Huh-7.5 cell model.
RESULTS: We found that CANX was necessary for the production of HCV particles by BHK-WNV cells. This process involved the recruitment of a subset of HCV proteins, detected by immunoglobulin of an HCV-cured patient, in a compartment of rearranged membranes bypassing the endoplasmic reticulum-Golgi intermediary compartment and surrounded by mitochondria. It also involved the maturation of N-linked glycans on HCV envelope proteins, which was required for assembly and/or secretion of HCV particles. The formation of this specialized compartment required RAB1; upon expression of HCV structural genes, this compartment developed large vesicles with viral particles. RAB1 and alpha-tubulin were required for the release of HCV particles. These cellular factors were also involved in the production of HCVcc in the JFH-1 strain/Huh-7.5 cell system, which involves HCV RNA replication. The secretion of HCV particles by BHK-WNV cells presents similarities with a pathway involving caspase-1; a caspase-1 inhibitor was found to suppress the production of HCV particles from a full-length genome.
CONCLUSION: Prior activity of the WNV subgenomic replicon in BHK-21 cells promoted re-wiring of host factors for the assembly and release of infectious HCV in a caspase-1-dependent mechanism.
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