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1
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Chen J, Qiu P, Zhao T, Jiang H, Tursun K, Ksimu S, Chen X, Wang Q. Measures of insulin resistance and beta cell function before and after treatment of HCV infection. Virol Sin 2024; 39:667-674. [PMID: 38950863 PMCID: PMC11401464 DOI: 10.1016/j.virs.2024.06.007] [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: 12/31/2023] [Accepted: 06/19/2024] [Indexed: 07/03/2024] Open
Abstract
The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on β-cell function particularly in the pre-diabetic population. Here, we evaluated indices of β-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate β-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and β-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of β-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.
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Affiliation(s)
- Jizheng Chen
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China; Guangzhou Laboratory, Guangzhou, 510005, China.
| | - Pan Qiu
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Tingfeng Zhao
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Haowei Jiang
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China
| | - Kebinur Tursun
- The First Affiliated Hospital of Xinjiang Medical University, Urumchi, 830054, China
| | - Sulaiman Ksimu
- The First Affiliated Hospital of Xinjiang Medical University, Urumchi, 830054, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China; Guangzhou Laboratory, Guangzhou, 510005, China.
| | - Qian Wang
- Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China.
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Stoenescu AF, Popescu CP, Florescu SA, Vancea G, Ceausu E, Calistru P. The Prevalence of Depression and Its Potential Link to Liver Fibrosis in Patients Diagnosed With Chronic Hepatitis C Virus Infection Prior to the Initiation of Direct-Acting Antiviral Treatment. Cureus 2024; 16:e62970. [PMID: 38912074 PMCID: PMC11194022 DOI: 10.7759/cureus.62970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 06/25/2024] Open
Abstract
Introduction Chronic hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, including depression. This study aimed to determine the prevalence of depression in treatment-naive HCV patients and explore its potential association with liver fibrosis severity. Methodology A consecutive cohort of 50 treatment-naive HCV patients without coinfections was enrolled over six months. Depression was assessed using the Hamilton Depression Rating Scale (HAM-D), and the liver fibrosis stage was evaluated using Fibroscan elastography. Results The cohort comprised 62% females (n=31) and 38% males (n=19), with ages ranging from 27 to 76 years. HAM-D scores indicated mild depression in 78% (n=39) and moderate depression in 16% (n=8) of patients. Notably, patients with mild depression displayed varying degrees of liver fibrosis (F0, F1, and F2), while all patients with moderate depression had advanced fibrosis (F3). Based on the multiple regression model, fibrosis was a statistically significant independent predictor with an unstandardized regression coefficient (B) of 3.115 (p=0.007). Conclusions Our findings point to a high prevalence of depression in treatment-naive HCV patients. Interestingly, there might be a link between depression severity and the stage of liver fibrosis, with advanced fibrosis potentially associated with more severe depression.
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Affiliation(s)
- Andreea Florentina Stoenescu
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Corneliu Petru Popescu
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Simin Aysel Florescu
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Geta Vancea
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Emanoil Ceausu
- Infectious Diseases, Academy of Medical Sciences, Dr. Victor Babes Hospital of Infectious and Tropical Diseases, Bucharest, ROU
| | - Petre Calistru
- Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, ROU
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Suhail M, Sohrab SS, Kamal M, Azhar EI. Role of hepatitis c virus in hepatocellular carcinoma and neurological disorders: an overview. Front Oncol 2022; 12:913231. [PMID: 35965577 PMCID: PMC9372299 DOI: 10.3389/fonc.2022.913231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
The hepatitis C virus (HCV) causes serious issues, affecting 71 million people globally. The most common manifestations range from chronic hepatitis to liver cirrhosis, leading to hepatocellular carcinoma. Many mechanisms are known to play an important role in HCV-induced HCC. The interaction of viral proteins with host cells results in oxidative stress damage, liver inflammation, and irregularities in signaling pathways. These results in the activation of oncogenes and metabolic disturbances, liver fibrosis, and angiogenesis. Additionally, some non-coding RNAs (ncRNAs) and toll-like receptors have been identified and play a significant role in HCC development. This virus is also associated with impairment of the central nervous system, resulting in acute or sub-acute encephalopathy and inflammatory disorders. Neurological disorders are associated with the inflammatory responses of many cells, including microglia and astrocytes. Additionally, there are many other extrahepatic manifestations, including neurological disorders such as depression and fatigue, in 50% of infected patients. These manifestations include neuro-invasion, immune-mediated damage, neurotransmitter alterations, sensory-motor polyneuropathy, sensitivity loss, weakness of the leg, and cryoglobulinemia, which significantly results in a reduced quality of life. HCV infection may be improved using an appropriate diagnosis and direct antiviral therapy for sustained virological response. However, the success of therapy depends on the symptoms and organ damage, diagnosis, and therapeutic strategies applied. Some published reports have discussed that HCV is associated with both HCC and neurological disorders. Additionally, it has also been observed that individuals with HCC also develop neurological disorders compared with individuals with HCV alone. This review aims to provide an overview of the latest information about the relationship between HCV-induced HCC and their role in neurological disorders. Additionally, we have also discussed the progress made in the diagnosis, physio-pathological mechanisms, and strong antiviral therapies developed for HCV infection and HCC, as well as the latest advancements made in the study of the neurological disorders associated with HCV infection.
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Affiliation(s)
- Mohd Suhail
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sayed Sartaj Sohrab
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- *Correspondence: Sayed Sartaj Sohrab,
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- West China School of Nursing/Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- Enzymoics Novel Global Community Educational Foundation, Hebersham, NSW, Australia
| | - Esam Ibraheem Azhar
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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4
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Significant Decrease in the Prevalence of Anxiety and Depression after Hepatitis C Eradication. J Clin Med 2022; 11:jcm11113044. [PMID: 35683432 PMCID: PMC9181745 DOI: 10.3390/jcm11113044] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/23/2022] [Accepted: 05/26/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic hepatitis C (CHC) is an ongoing epidemiological problem. The hepatitis C virus (HCV) may infect brain tissue, worsening mental health outcomes. The new era of highly effective oral Direct-Acting Agents (DAA) has brought a chance to eradicate the infection by 2030, however, screening campaigns are urgently needed as the majority of the infected are still undiagnosed. The aim of this study was to assess the prevalence of anxiety and depression among HCV patients, and the correlation with health-related quality of life (HRQoL) in the real-world setting, before and after DAA treatment. Data on anxiety, depression, and HRQoL, were collected by using self-reported questionnaires in a single center in Poland. The study group involved 90 respondents, 50% female, with a mean age of 43.8 years. HCV eradication decreased anxiety prevalence from 30.4% to 19.1% and depression from 35.2% to 18.2%. Significant improvement in 3 out of 4 of the WHOQOL-BREF (TheWorld Health Organization Quality of Life-BREF) domains and 8 out of 10 of the HQLQv.2 domains was obtained. Anxiety diminished the somatic domain scores by 3.5 (p < 0.0001), psychological by 2.3 (p = 0.0062), social by 1.75 (p = 0.0008), and environmental by 2.68 points (p = 0.0029). Depression diminished the somatic domain scores by 3.79 (p < 0.001), psychological by 2.23 (p < 0.001), social by 1.84 (p < 0.001), and environmental by 2.42 points (p = 0.004). In the Hepatitis Quality of Life Questionnaire version 2 (HQLQ v.2), the presence of depression and/or anxiety-impaired mental health, physical health, well-being, and vitality. These results indicate the need for an active search for HCV-infective people, especially among patients in psychiatric and psychological care.
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5
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Moretti R, Giuffrè M, Merli N, Caruso P, Di Bella S, Tiribelli C, Crocè LS. Hepatitis C Virus-Related Central and Peripheral Nervous System Disorders. Brain Sci 2021; 11:1569. [PMID: 34942871 PMCID: PMC8699483 DOI: 10.3390/brainsci11121569] [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: 09/30/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood-brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.
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Affiliation(s)
- Rita Moretti
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Mauro Giuffrè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Nicola Merli
- Department Neurological Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Paola Caruso
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Stefano Di Bella
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | | | - Lory Saveria Crocè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
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Faccioli J, Nardelli S, Gioia S, Riggio O, Ridola L. Neurological and psychiatric effects of hepatitis C virus infection. World J Gastroenterol 2021; 27:4846-4861. [PMID: 34447230 PMCID: PMC8371503 DOI: 10.3748/wjg.v27.i29.4846] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/07/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is widespread and affects 71 million people worldwide. Although hepatic manifestations are the most frequent, ranging from chronic hepatitis to cirrhosis and hepatocellular carcinoma, it is also associated with several extrahepatic manifestations. Infected patients may present non-specific neurological symptoms, regardless of the presence of liver cirrhosis. Several pathogenetic mechanisms underlying neurological symptoms have been hypothesized: neuroinvasion, immune-mediated damage, neurotransmitter alterations and cryoglobulinemia. Alterations of the central nervous system include cerebral vasculopathy, acute or subacute encephalopathy and inflammatory disorders. HCV infection may be responsible for neuropathies, of which the most frequent form is symmetrical axonal sensory or sensory-motor polyneuropathy which causes loss of leg sensitivity and weakness. Up to 50% of patients with HCV infection may experience cognitive decline and psychological disorders, such as depression and fatigue. HCV associated neurocognitive disorder is independent of the presence of liver cirrhosis and affects different domains than in patients with hepatic encephalopathy. It can be studied using specific tests that mainly explore executive functions, verbal learning and verbal recall. These disorders significantly reduce the quality of life. The new antiviral therapies improve the extrahepatic symptoms of HCV infection and their success depends on the achievement of sustained virological response. However, the effect of therapy may differ depending on the type of organ involved; neurological symptoms can be irreversible if there is organic liver damage. The aim of this review is to provide a critical overview of physiopathological mechanisms, diagnostic and therapeutic strategies of the neurological and psychiatric effects of HCV infection.
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Affiliation(s)
- Jessica Faccioli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Silvia Nardelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
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Choi HG, Soh JS, Lim JS, Sim SY, Lee SW. Association between dementia and hepatitis B and C virus infection. Medicine (Baltimore) 2021; 100:e26476. [PMID: 34398003 PMCID: PMC8294892 DOI: 10.1097/md.0000000000026476] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 05/06/2021] [Accepted: 06/07/2021] [Indexed: 01/04/2023] Open
Abstract
ABSTRACT Several viral infections are known to increase the risk of dementia through brain cell damage and systemic infection. The association between hepatitis B and C virus (HBV and HCV) infections and dementia was evaluated using a national sample cohort from South Korea. Using the national cohort study from the Korean National Health Insurance Service, we extracted data for patients with HBV or HCV infection and for matched control participants. The controls were matched to the patients according to age, sex, income, region of residence, and past medical histories. The incidence of HCV infection was higher in the dementia group (1.0% [113/11,228]) than in the control group (0.8% [364/44,912], P = .043). However, there was no difference in the incidence of HBV infection in the dementia and control groups. The adjusted odds ratio (OR) for HCV infection was 1.25 (95% confidence interval [CI] = 1.01-1.54, P = .043) in the dementia group. According to the subgroup analysis by sex, the adjusted ORs for HCV infection were 1.04 (95% CI = 072-1.49, P = .851) in men and 1.38 (95% CI = 1.06-1.79, P = .016) in women. We concluded that the incidence of HCV infection was higher (with a higher OR) in women with dementia than in matched control participants in South Korea.
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Affiliation(s)
- Hyo Geun Choi
- Department of Otorhinolaryngology-Head & Neck Surgery, Hallym University College of Medicine, Anyang, Republic of Korea
- Hallym Data Science Laboratory, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Jae Seung Soh
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Jae Sung Lim
- Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
| | - Song Yong Sim
- Department of Statistics and Institute of Statistics, Hallym University, Chuncheon, Republic of Korea
| | - Suk Woo Lee
- Department of Obstetrics and Gynecology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea
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8
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Hastings KL, Green MD, Gao B, Ganey PE, Roth RA, Burleson GR. Beyond Metabolism: Role of the Immune System in Hepatic Toxicity. Int J Toxicol 2021; 39:151-164. [PMID: 32174281 DOI: 10.1177/1091581819898399] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The liver is primarily thought of as a metabolic organ; however, the liver is also an important mediator of immunological functions. Key perspectives on this emerging topic were presented in a symposium at the 2018 annual meeting of the American College of Toxicology entitled "Beyond metabolism: Role of the immune system in hepatic toxicity." Viral hepatitis is an important disease of the liver for which insufficient preventive vaccines exist. Host immune responses inadequately clear these viruses and often potentiate immunological inflammation that damages the liver. In addition, the liver is a key innate immune organ against bacterial infection. Hepatocytes and immune cells cooperatively control systemic and local bacterial infections. Conversely, bacterial infection can activate multiple types of immune cells and pathways to cause hepatocyte damage and liver injury. Finally, the immune system and specifically cytokines and drugs can interact in idiosyncratic drug-induced liver injury. This rare disease can result in a disease spectrum that ranges from mild to acute liver failure. The immune system plays a role in this disease spectrum.
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Affiliation(s)
| | | | - Bin Gao
- Laboratory of Liver Diseases, NIH, Bethesda, MD, USA
| | - Patricia E Ganey
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Robert A Roth
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Gary R Burleson
- BRT-Burleson Research Technologies, Inc, Morrisville, NC, USA
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9
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Abo Hagar A, Ashour Y, Negm M, Abdelfatah M, Gad KA, Hashish E. Brain magnetic resonance spectroscopy and cognitive impairment in chronic hepatitis C patients. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2018; 54:43. [PMID: 30613130 PMCID: PMC6302099 DOI: 10.1186/s41983-018-0046-7] [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] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 12/04/2018] [Indexed: 01/18/2023] Open
Abstract
Background Cognitive dysfunction in patients with chronic hepatitis C virus (HCV) infection may appear long before the development of severe liver cirrhosis. These alterations are not ascribed to hepatic encephalopathy; however, early detection is always difficult. Objective The aim of this study was to assess the changes of magnetic resonance spectroscopy (MRS) metabolites among chronic hepatitis C virus patients with and without cognitive impairment. Patients and methods A cross-sectional study was conducted in Suez Canal University Hospital. Forty-six HCV patients was included and divided into two groups: patients with and without cognitive impairment. Assessment of cognitive function was done using mini-mental state examination and Wechsler Memory Scale - Revised. Both groups were subjected to single-voxel MRS to evaluate metabolites in three brain regions: the basal ganglia, hippocampus, and posterior cingulate gyrus. Results The CHO/Cr was significantly higher, and NAA/Cr was significantly lower in group with cognitive impairment in the basal ganglia and posterior cingulate gyrus. Mini-mental state score had negative significant correlation with PCR of HCV. Mini-mental state score had significant negative and positive correlation with CHO/Cr and NAA/Cr, respectively, in the basal ganglia. All values of the Wechsler Memory Scale were statistically higher in the group without cognitive impairment except verbal memory score. Conclusion There were changes at brain metabolites associated with cognitive impairment in chronic hepatitis C patients regarding a decrease of NAA/Cr ratio and an increase of CHO/Cr ratio at the basal ganglia.
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Affiliation(s)
| | - Youssri Ashour
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed Negm
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | | | - Khaled A Gad
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Ehab Hashish
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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10
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Mercuri L, Thomson EC, Hughes J, Karayiannis P. Quasispecies Changes with Distinctive Point Mutations in the Hepatitis C Virus Internal Ribosome Entry Site (IRES) Derived from PBMCs and Plasma. Adv Virol 2018; 2018:4835252. [PMID: 30581467 PMCID: PMC6276526 DOI: 10.1155/2018/4835252] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 11/11/2018] [Indexed: 12/12/2022] Open
Abstract
The 5' untranslated region (UTR) of the hepatitis C virus (HCV) genome contains the internal ribosome entry site (IRES), a highly conserved RNA structure essential for cap-independent translation of the viral polyprotein. HCV, apart from the liver, is thought to be associated with lymphocyte subpopulations of peripheral blood mononuclear cells (PBMCs), in lymph nodes and brain tissue. In this study, RT-PCR, cloning, and sequence analysis were employed to investigate the quasispecies nature of the 5'UTR following extraction of viral RNA from PBMCs and plasma of HCV infected individuals. The nucleotide variation between IRES-derived sequences from PBMCs and plasma indicated the existence of polymorphic sites within the IRES. HCV isolates had divergent variants with unique mutations particularly at positions 107, 204, and 243 of the IRES. Most of the PBMC-derived sequences contained an A-A-A variant at these positions. The mutations associated with the IRESes suggested the presence of unique quasispecies populations in PBMCs compared with plasma.
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Affiliation(s)
- Luca Mercuri
- Hepatology Section, Division of Medicine, Faculty of Medicine, Imperial College, London, UK
| | - Emma C. Thomson
- University of Glasgow MRC Centre for Virus Research, Glasgow, UK
| | - Joseph Hughes
- University of Glasgow MRC Centre for Virus Research, Glasgow, UK
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11
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Forton D, Weissenborn K, Bondin M, Cacoub P. Expert opinion on managing chronic HCV in patients with neuropsychiatric manifestations. Antivir Ther 2018; 23:47-55. [PMID: 30451150 DOI: 10.3851/imp3245] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2018] [Indexed: 10/27/2022]
Abstract
Neurological manifestations of HCV infection appear to be under-recognized in clinical practice despite the majority of HCV-infected patients experiencing symptoms such as fatigue, depression and cognitive dysfunction. There is also growing evidence for a link between HCV infection and an increased risk of Parkinson's disease. The mechanism underpinning the association between HCV and these neuropsychiatric syndromes still requires further investigation. Here we review the pre-clinical and clinical evidence for a link between HCV and effects on the central nervous system leading to neuropsychiatric syndromes. Lastly, we describe how improvements in neuropsychiatric manifestations of HCV following treatment have been observed, which is subsequently reflected in an overall improvement in health-related quality of life.
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Affiliation(s)
- Daniel Forton
- Department of Gastroenterology and Hepatology, St George's Hospital London, London, UK
- St George's University of London, London, UK
| | | | | | - Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France
- INSERM, UMR_S 959, Paris, France
- CNRS, FRE3632, F-75005, Paris, France
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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12
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King B, Tarr AW. How have retrovirus pseudotypes contributed to our understanding of viral entry? Future Virol 2017. [DOI: 10.2217/fvl-2017-0062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Study of virus entry into host cells is important for understanding viral tropism and pathogenesis. Studying the entry of in vitro cultured viruses is not always practicable. Study of highly pathogenic viruses, viruses that do not grow in culture, and viruses that rapidly change phenotype in vitro can all benefit from alternative models of entry. Retrovirus particles can be engineered to display the envelope proteins of heterologous enveloped viruses. This approach, broadly termed ‘pseudotyping’, is an important technique for interrogating virus entry. In this perspective we consider how retrovirus pseudotypes have addressed these challenges and improved our understanding of the entry pathways of diverse virus species, including Ebolavirus, human immunodeficiency virus and hepatitis C virus.
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Affiliation(s)
- Barnabas King
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & the University of Nottingham, Nottingham, UK
- School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK
| | - Alexander W Tarr
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & the University of Nottingham, Nottingham, UK
- School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK
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Lin MS, Chen TH, Lin WY, Liu CH, Hsieh YY, Chiu WN, Chang CH, Chen MY, Chung CM, Lin YS. Add-on neurological benefits of antiviral therapy in HCV patients with chronic kidney disease - a nationwide cohort study. BMC Gastroenterol 2017; 17:99. [PMID: 28814273 PMCID: PMC5559858 DOI: 10.1186/s12876-017-0653-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 07/31/2017] [Indexed: 12/18/2022] Open
Abstract
Background Hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) have rarely been studied because they rarely accept interferon-based therapy (IBT) and have been difficult to follow up. We investigated long-term outcomes of IBT on the population. Methods This population-based cohort study used the Taiwan National Health Insurance Research Database as its data source. HCV patients diagnosed with CKD between Jan. 1, 2003, and Dec. 31, 2013, were selected. They were then divided into two groups based on whether they had undergone IBT. All-cause mortality, acute myocardial infarction (AMI), ischemic stroke (IS), hemorrhagic stroke, and new-onset dialysis were evaluated using a Cox proportional hazard regression analysis after propensity score matching. Results We enrolled 9872 HCV patients with CKD: 1684 patients in the treated cohort and 8188 patients in the untreated cohort. The annual incidence of all-cause mortality (19.00 vs. 42.89 events per 1000 person-years; p < 0.001) and the incidences of hemorrhagic stroke (1.21 vs. 4.19 events per 1000 person-years; p = 0.006) were lower in the treated cohort. New-onset dialysis was also lower in the treated cohort (aHR: 0.31; 95% CI: 0.20–0.48; p < 0.001). Conclusion Antiviral therapy might provide protective benefits on all-cause mortality, hemorrhagic stroke, and new-onset dialysis in HCV-infected patients with CKD. Electronic supplementary material The online version of this article (doi:10.1186/s12876-017-0653-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ming-Shyan Lin
- Department of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Tien-Hsing Chen
- Department of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Keelung, Taiwan
| | - Wey-Yil Lin
- Stroke Center and Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chi-Hung Liu
- Stroke Center and Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yung-Yu Hsieh
- Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Wen-Nan Chiu
- Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Chih-Hsiang Chang
- Department of Nephrology, Kidney research center, Chang Gung Memorial Hospital, Chang Gung University, College of medicine, Taoyuan, Taiwan
| | - Mei-Yen Chen
- College of Nursing, Chang Gung University of Science and Technology (CGUST), Taoyuan, Taiwan.,Department of Nursing, Chang Gung University, Taoyuan, Taiwan
| | - Chang-Min Chung
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan County, Taiwan. .,Department of Cardiology, Chiayi Chang Gung Memorial Hospital, 6, Sec. West Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, 61363, Taiwan.
| | - Yu-Sheng Lin
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan County, Taiwan. .,Department of Cardiology, Chiayi Chang Gung Memorial Hospital, 6, Sec. West Chai-Pu Road, Pu-TZ City, Chai Yi Hsien, 61363, Taiwan.
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Adinolfi LE, Nevola R, Rinaldi L, Romano C, Giordano M. Chronic Hepatitis C Virus Infection and Depression. Clin Liver Dis 2017; 21:517-534. [PMID: 28689590 DOI: 10.1016/j.cld.2017.03.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is a systemic disease with hepatic and extrahepatic manifestations, including neuropsychiatric conditions. Depression is a frequent disorder, which has been reported in one-third of patients with HCV infection and has an estimated prevalence of 1.5 to 4.0 times higher than that observed in patients with chronic hepatitis B virus infection or the general population. HCV seems to play a direct and indirect role in the development of depression. Impaired quality of life and increasing health care costs have been reported for patients with HCV infection with depression. Treatment-induced HCV clearance has been associated with improvement of depression and quality of life.
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Affiliation(s)
- Luigi Elio Adinolfi
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy.
| | - Riccardo Nevola
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Luca Rinaldi
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Ciro Romano
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Mauro Giordano
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
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15
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Coto-Llerena M, Koutsoudakis G, Boix L, López-Oliva JM, Caro-Pérez N, Fernández-Carrillo C, González P, Gastaminza P, Bruix J, Forns X, Pérez-Del-Pulgar S. Permissiveness of human hepatocellular carcinoma cell lines for hepatitis C virus entry and replication. Virus Res 2017; 240:35-46. [PMID: 28751105 DOI: 10.1016/j.virusres.2017.07.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 07/20/2017] [Accepted: 07/20/2017] [Indexed: 12/28/2022]
Abstract
Hepatitis C virus (HCV) is a globally prevalent pathogen and is associated with high death rates and morbidity. Since its discovery in 1989, HCV research has been impeded by the lack of a robust infectious cell culture system and thus in vitro studies on diverse genetic backgrounds are hampered because of the limited number of hepatoma cell lines which are able to support different aspects of the HCV life cycle. In the current study, we sought to expand the limited number of permissive cells capable of supporting the diverse phases of the HCV life cycle. Initially, we screened a panel of new hepatoma-derived cell lines, designated BCLC-1, -2, -3, -4, -5, -6, -9 and -10 cells, for their ability to express essential HCV receptors and subsequently to support HCV entry by using the well-characterized HCV pseudoparticle system (HCVpp). Apart from BCLC-9, all BCLC cell lines were permissive for HCVpp infection. Next, BCLC cells were subjected to short- and long-term HCV RNA replication studies using HCV subgenomic replicons. Interestingly, only BCLC-1, -5 and -9 cells, supported short-term HCV RNA replication, but the latter were excluded from further studies since they were refractory for HCV entry. BCLC-1, -5 were able to support long-term HCV replication too; yet BCLC-5 cells supported the highest long-term HCV RNA replication levels. Furthermore, cured BCLC-5 clones from HCV subgenomic replicon, showed increased permissiveness for HCV RNA replication. Strikingly, we were unable to detect endogenous BCLC-5 miR122 expression - an important HCV host factor- and as expected, the exogenous expression of miR122 in BCLC-5 cells increased their permissiveness for HCV RNA replication. However, this cell line was unable to produce HCV infectious particles despite ectopic expression of apolipoprotein E, which in other hepatoma cell lines has been shown to be sufficient to enable the HCV secretion process, suggesting a lack of other host cellular factor(s) and/or the presence of inhibitory factor(s). In conclusion, the establishment of these new permissive cell lines for HCV entry and replication, which possess a different genetic background compared to the well-established models, expands the current repertoire of hepatoma cell lines susceptible to the study of the HCV life cycle and also will aid to further elucidate the cellular determinants that modulate HCV replication, assembly and egress.
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Affiliation(s)
| | | | - Loreto Boix
- Barcelona Clínic Liver Cancer (BCLC) Group, Hospital Clínic, IDIBAPS, CIBERehd, Spain
| | | | | | | | | | - Pablo Gastaminza
- Centro Nacional De Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Campus Cantoblanco, Madrid, Spain
| | - Jordi Bruix
- Barcelona Clínic Liver Cancer (BCLC) Group, Hospital Clínic, IDIBAPS, CIBERehd, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
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16
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Chronic Hepatitis B, C, and D. Microbiol Spectr 2017; 4. [PMID: 27726758 DOI: 10.1128/microbiolspec.dmih2-0025-2015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Chronic hepatitis B, C, and D virus infections contribute significantly to the morbidity and mortality of immunocompromised individuals. To contextualize discussion of these infections in immunocompromised patients, this paper provides an overview of aspects of infection in normal hosts. It then describes differences in disease, diagnostic testing, and therapeutic management observed in immunocompromised patients.
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17
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Ono C, Fukuhara T, Motooka D, Nakamura S, Okuzaki D, Yamamoto S, Tamura T, Mori H, Sato A, Uemura K, Fauzyah Y, Kurihara T, Suda T, Nishio A, Hmwe SS, Okamoto T, Tatsumi T, Takehara T, Chayama K, Wakita T, Koike K, Matsuura Y. Characterization of miR-122-independent propagation of HCV. PLoS Pathog 2017; 13:e1006374. [PMID: 28494029 PMCID: PMC5441651 DOI: 10.1371/journal.ppat.1006374] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 05/23/2017] [Accepted: 04/24/2017] [Indexed: 12/12/2022] Open
Abstract
miR-122, a liver-specific microRNA, is one of the determinants for liver tropism of hepatitis C virus (HCV) infection. Although miR-122 is required for efficient propagation of HCV, we have previously shown that HCV replicates at a low rate in miR-122-deficient cells, suggesting that HCV-RNA is capable of propagating in an miR-122-independent manner. We herein investigated the roles of miR-122 in both the replication of HCV-RNA and the production of infectious particles by using miR-122-knockout Huh7 (Huh7-122KO) cells. A slight increase of intracellular HCV-RNA levels and infectious titers in the culture supernatants was observed in Huh7-122KO cells upon infection with HCV. Moreover, after serial passages of HCV in miR-122-knockout Huh7.5.1 cells, we obtained an adaptive mutant, HCV122KO, possessing G28A substitution in the 5’UTR of the HCV genotype 2a JFH1 genome, and this mutant may help to enhance replication complex formation, a possibility supported by polysome analysis. We also found the introduction of adaptive mutation around miR-122 binding site in the genotype 1b/2a chimeric virus, which originally had an adenine at the nucleotide position 29. HCV122KO exhibited efficient RNA replication in miR-122-knockout cells and non-hepatic cells without exogenous expression of miR-122. Competition assay revealed that the G28A mutant was dominant in the absence of miR-122, but its effects were equivalent to those of the wild type in the presence of miR-122, suggesting that the G28A mutation does not confer an advantage for propagation in miR-122-rich hepatocytes. These observations may explain the clinical finding that the positive rate of G28A mutation was higher in miR-122-deficient PBMCs than in the patient serum, which mainly included the hepatocyte-derived virus from HCV-genotype-2a patients. These results suggest that the emergence of HCV mutants that can propagate in non-hepatic cells in an miR-122-independent manner may participate in the induction of extrahepatic manifestations in chronic hepatitis C patients. A liver-specific microRNA, miR-122, is one of the key determinants of hepatitis C virus (HCV) hepatotropism and is required for efficient propagation of HCV. On the other hand, chronic infection with HCV is often associated with extrahepatic manifestations (EHMs), and a low level of HCV-RNA replication has been detected in some non-hepatic cells. Nonetheless, the detailed mechanisms underlying these phenomena remain unknown. Here, we show that miR-122 is dispensable for low-level replication or infectious particle formation, and a mutant virus adapted to miR-122-knockout cells exhibited efficient but miR-122-independent propagation. The adaptive virus of HCV genotype 2a possessed a G28A substitution in the 5’UTR and facilitated efficient replication complex formation under an miR-122-deficient condition, while it propagated at a level comparable to the wild type HCV in the presence of miR-122. Moreover, various adaptive mutations including C30U were introduced into genotype 1b, which originally had an adenine at the nucleotide position 29. These observations suggest that substitutions that yield miR-122-independent propagation are not induced during propagation in hepatocytes; however, treatment with an miR-122 inhibitor or persistent infection of HCV in non-hepatic cells may induce the emergence of mutant viruses, as evidenced by clinical samples.
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Affiliation(s)
- Chikako Ono
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Takasuke Fukuhara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Daisuke Motooka
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Shota Nakamura
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Daisuke Okuzaki
- DNA-Chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Satomi Yamamoto
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Tomokazu Tamura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Hiroyuki Mori
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Asuka Sato
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Kentaro Uemura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Yuzy Fauzyah
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Takeshi Kurihara
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Takahiro Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Akira Nishio
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Su Su Hmwe
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Toru Okamoto
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazuaki Chayama
- Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- * E-mail:
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18
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Lythgoe KA, Gardner A, Pybus OG, Grove J. Short-Sighted Virus Evolution and a Germline Hypothesis for Chronic Viral Infections. Trends Microbiol 2017; 25:336-348. [PMID: 28377208 PMCID: PMC5405858 DOI: 10.1016/j.tim.2017.03.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/03/2017] [Accepted: 03/03/2017] [Indexed: 12/24/2022]
Abstract
With extremely short generation times and high mutability, many viruses can rapidly evolve and adapt to changing environments. This ability is generally beneficial to viruses as it allows them to evade host immune responses, evolve new behaviours, and exploit ecological niches. However, natural selection typically generates adaptation in response to the immediate selection pressures that a virus experiences in its current host. Consequently, we argue that some viruses, particularly those characterised by long durations of infection and ongoing replication, may be susceptible to short-sighted evolution, whereby a virus' adaptation to its current host will be detrimental to its onward transmission within the host population. Here we outline the concept of short-sighted viral evolution and provide examples of how it may negatively impact viral transmission among hosts. We also propose that viruses that are vulnerable to short-sighted evolution may exhibit strategies that minimise its effects. We speculate on the various mechanisms by which this may be achieved, including viral life history strategies that result in low rates of within-host evolution, or the establishment of a 'germline' lineage of viruses that avoids short-sighted evolution. These concepts provide a new perspective on the way in which some viruses have been able to establish and maintain global pandemics.
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Affiliation(s)
| | - Andy Gardner
- School of Biology, University of St Andrews, St Andrews, KY16 9TH, UK
| | - Oliver G Pybus
- Department of Zoology, University of Oxford, Oxford, OX1 3PS, UK
| | - Joe Grove
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, WC1E 6BT, UK
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19
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Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo. J Virol 2017; 91:JVI.01799-16. [PMID: 27928007 DOI: 10.1128/jvi.01799-16] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 11/23/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) causes chronic infections in at least 150 million individuals worldwide. HCV has a narrow host range and robustly infects only humans and chimpanzees. The underlying mechanisms for this narrow host range are incompletely understood. At the level of entry, differences in the amino acid sequences between the human and mouse orthologues of two essential host factors, the tetraspanin CD81 and the tight junction protein occludin (OCLN), explain, at least in part, HCV's limited ability to enter mouse hepatocytes. We have previously shown that adenoviral or transgenic overexpression of human CD81 and OCLN facilitates HCV uptake into mouse hepatocytes in vitro and in vivo In efforts to refine these models, we constructed knock-in mice in which the second extracellular loops of CD81 and OCLN were replaced with the respective human sequences, which contain the determinants that are critical for HCV uptake. We demonstrate that the humanized CD81 and OCLN were expressed at physiological levels in a tissue-appropriate fashion. Mice bearing the humanized alleles formed normal tight junctions and did not exhibit any immunologic abnormalities, indicating that interactions with their physiological ligands were intact. HCV entry factor knock-in mice take up HCV with an efficiency similar to that in mice expressing HCV entry factors transgenically or adenovirally, demonstrating the utility of this model for studying HCV infection in vivo IMPORTANCE: At least 150 million individuals are chronically infected with hepatitis C virus (HCV). Chronic hepatitis C can result in progressive liver disease and liver cancer. New antiviral treatments can cure HCV in the majority of patients, but a vaccine remains elusive. To gain a better understanding of the processes culminating in liver failure and cancer and to prioritize vaccine candidates more efficiently, small-animal models are needed. Here, we describe the characterization of a new mouse model in which the parts of two host factors that are essential for HCV uptake, CD81 and occludin (OCLN), which differ between mice and humans, were humanized. We demonstrate that such minimally humanized mice develop normally, express the modified genes at physiological levels, and support HCV uptake. This model is of considerable utility for studying viral entry in the three-dimensional context of the liver and to test approaches aimed at preventing HCV entry.
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20
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Rajora MA, Zheng G. Targeting SR-BI for Cancer Diagnostics, Imaging and Therapy. Front Pharmacol 2016; 7:326. [PMID: 27729859 PMCID: PMC5037127 DOI: 10.3389/fphar.2016.00326] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 09/06/2016] [Indexed: 01/13/2023] Open
Abstract
Scavenger receptor class B type I (SR-BI) plays an important role in trafficking cholesteryl esters between the core of high density lipoprotein and the liver. Interestingly, this integral membrane protein receptor is also implicated in the metabolism of cholesterol by cancer cells, whereby overexpression of SR-BI has been observed in a number of tumors and cancer cell lines, including breast and prostate cancers. Consequently, SR-BI has recently gained attention as a cancer biomarker and exciting target for the direct cytosolic delivery of therapeutic agents. This brief review highlights these key developments in SR-BI-targeted cancer therapies and imaging probes. Special attention is given to the exploration of high density lipoprotein nanomimetic platforms that take advantage of upregulated SR-BI expression to facilitate targeted drug-delivery and cancer diagnostics, and promising future directions in the development of these agents.
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Affiliation(s)
- Maneesha A Rajora
- Princess Margaret Cancer Centre and Techna Institute, University Health NetworkToronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of TorontoToronto, ON, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre and Techna Institute, University Health NetworkToronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of TorontoToronto, ON, Canada; Department of Medical Biophysics, University of TorontoToronto, ON, Canada
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21
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Yarlott L, Heald E, Forton D. Hepatitis C virus infection, and neurological and psychiatric disorders - A review. J Adv Res 2016; 8:139-148. [PMID: 28149649 PMCID: PMC5272938 DOI: 10.1016/j.jare.2016.09.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/09/2016] [Accepted: 09/09/2016] [Indexed: 02/06/2023] Open
Abstract
An association between hepatitis C virus infection and neuropsychiatric symptoms has been proposed for some years. A variety of studies have been undertaken to assess the nature and severity of these symptoms, which range from fatigue and depression to defects in attention and verbal reasoning. There is evidence of mild neurocognitive impairment in some patients with HCV infection, which is not fully attributable to liver dysfunction or psychosocial factors. Further evidence of a biological cerebral effect has arisen from studies using magnetic resonance spectroscopy; metabolic abnormalities correlate with cognitive dysfunction and resemble the patterns of neuroinflammation that have been described in HIV infection. Recent research has suggested that, in common with HIV infection, HCV may cross the blood brain barrier leading to neuroinflammation. Brain microvascular endothelial cells, astrocytes and microglia may be minor replication sites for HCV. Importantly, patient reported outcomes improve following successful antiviral therapy. Further research is required to elucidate the molecular basis for HCV entry and replication in the brain, and to clarify implications and recommendations for treatment.
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Affiliation(s)
- Lydia Yarlott
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Eleanor Heald
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Daniel Forton
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom; St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
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22
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Mathew S, Faheem M, Ibrahim SM, Iqbal W, Rauff B, Fatima K, Qadri I. Hepatitis C virus and neurological damage. World J Hepatol 2016; 8:545-556. [PMID: 27134702 PMCID: PMC4840160 DOI: 10.4254/wjh.v8.i12.545] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/16/2015] [Accepted: 04/11/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.
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23
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Yang DR, Zhu HZ. Hepatitis C virus and antiviral innate immunity: Who wins at tug-of-war? World J Gastroenterol 2015; 21:3786-3800. [PMID: 25852264 PMCID: PMC4385526 DOI: 10.3748/wjg.v21.i13.3786] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/21/2015] [Accepted: 02/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major human pathogen of chronic hepatitis and related liver diseases. Innate immunity is the first line of defense against invading foreign pathogens, and its activation is dependent on the recognition of these pathogens by several key sensors. The interferon (IFN) system plays an essential role in the restriction of HCV infection via the induction of hundreds of IFN-stimulated genes (ISGs) that inhibit viral replication and spread. However, numerous factors that trigger immune dysregulation, including viral factors and host genetic factors, can help HCV to escape host immune response, facilitating viral persistence. In this review, we aim to summarize recent advances in understanding the innate immune response to HCV infection and the mechanisms of ISGs to suppress viral survival, as well as the immune evasion strategies for chronic HCV infection.
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24
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Fletcher NF, Humphreys E, Jennings E, Osburn W, Lissauer S, Wilson GK, van IJzendoorn SCD, Baumert TF, Balfe P, Afford S, McKeating JA. Hepatitis C virus infection of cholangiocarcinoma cell lines. J Gen Virol 2015; 96:1380-1388. [PMID: 25701818 PMCID: PMC4635488 DOI: 10.1099/vir.0.000090] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 02/07/2015] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) infects the liver and hepatocytes are the major cell type supporting viral replication. Hepatocytes and cholangiocytes derive from a common hepatic progenitor cell that proliferates during inflammatory conditions, raising the possibility that cholangiocytes may support HCV replication and contribute to the hepatic reservoir. We screened cholangiocytes along with a panel of cholangiocarcinoma-derived cell lines for their ability to support HCV entry and replication. While primary cholangiocytes were refractory to infection and lacked expression of several entry factors, two cholangiocarcinoma lines, CC-LP-1 and Sk-ChA-1, supported efficient HCV entry; furthermore, Sk-ChA-1 cells supported full virus replication. In vivo cholangiocarcinomas expressed all of the essential HCV entry factors; however, cholangiocytes adjacent to the tumour and in normal tissue showed a similar pattern of receptor expression to ex vivo isolated cholangiocytes, lacking SR-BI expression, explaining their inability to support infection. This study provides the first report that HCV can infect cholangiocarcinoma cells and suggests that these heterogeneous tumours may provide a reservoir for HCV replication in vivo.
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Affiliation(s)
- Nicola F Fletcher
- Centre for Human Virology, Viral Hepatitis Laboratory, University of Birmingham, Birmingham B15 2TT, UK
| | | | - Elliott Jennings
- Centre for Human Virology, Viral Hepatitis Laboratory, University of Birmingham, Birmingham B15 2TT, UK
| | - William Osburn
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Samantha Lissauer
- Centre for Human Virology, Viral Hepatitis Laboratory, University of Birmingham, Birmingham B15 2TT, UK
| | - Garrick K Wilson
- Centre for Human Virology, Viral Hepatitis Laboratory, University of Birmingham, Birmingham B15 2TT, UK
| | - Sven C D van IJzendoorn
- Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen 9713AV, The Netherlands
| | - Thomas F Baumert
- Inserm U1110, University of Strasbourg 3 Rue Koeberlé, F-67000 Strasbourg, France
| | - Peter Balfe
- Centre for Human Virology, Viral Hepatitis Laboratory, University of Birmingham, Birmingham B15 2TT, UK
| | - Simon Afford
- Centre for Liver Research, University of Birmingham, Birmingham B15 2TT, UK
| | - Jane A McKeating
- Centre for Liver Research, University of Birmingham, Birmingham B15 2TT, UK.,Centre for Human Virology, Viral Hepatitis Laboratory, University of Birmingham, Birmingham B15 2TT, UK
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Thames AD, Castellon SA, Singer EJ, Nagarajan R, Sarma MK, Smith J, Thaler NS, Truong JH, Schonfeld D, Thomas MA, Hinkin CH. Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2015; 2:e59. [PMID: 25610883 PMCID: PMC4299885 DOI: 10.1212/nxi.0000000000000059] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 11/21/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV+ individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls. METHOD Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV+ participants (n = 29) and all controls underwent MRI. RESULTS Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV- controls. HCV+ participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV- controls (all p values < 0.05). HCV+ participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV+ patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance. CONCLUSIONS Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions.
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Affiliation(s)
- April D Thames
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Steven A Castellon
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Elyse J Singer
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Rajakumar Nagarajan
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Manoj K Sarma
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Jason Smith
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Nicholas S Thaler
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Jonathan Hien Truong
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Daniel Schonfeld
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - M Albert Thomas
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Charles H Hinkin
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
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Sheridan DA, Bridge SH, Crossey MME, Felmlee DJ, Thomas HC, Neely RDG, Taylor-Robinson SD, Bassendine MF. Depressive symptoms in chronic hepatitis C are associated with plasma apolipoprotein E deficiency. Metab Brain Dis 2014; 29:625-34. [PMID: 24615429 DOI: 10.1007/s11011-014-9520-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Accepted: 02/26/2014] [Indexed: 12/20/2022]
Abstract
Neuro-psychiatric and cognitive disorders are frequent in patients with chronic hepatitis C (CHC) virus (HCV) infection which adversely impact quality of life, antiviral treatment adherence and outcome. HCV has neurotrophic properties and affects lipid metabolism, essential for cognitive function. We evaluated the relationship of lipid profiles with depression and anxiety symptoms and the effects of 12-weeks of therapy with fluvastatin and omega-3 ethyl esters (n-3 PUFA) in a randomised pilot study of CHC prior non-responders. Participants (n = 60) had fasting lipid profiles and assessment of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS) questionnaire at each study visit. At screening 26/60 (43 %) had HADS-A score ≥8 and 13/60 (22 %) had HADS-D scores ≥8. Depressed patients had significantly lower apolipoprotein-E concentrations (30 mg/l vs 39 mg/l, P = 0.029) than those without depression and a tendency toward lower total cholesterol (3.8 vs 4.4 mmol/l, P = 0.053). 3 patients discontinued lipid-modifying treatment because of worsening depression. However, there was a small but significant improvement in anxiety symptoms after 12-weeks of high-dose (2-4 g daily) n-3 PUFA. In conclusion, depression in CHC is associated with plasma apoE deficiency. We postulate that apoE deficiency disrupts blood brain barrier integrity to promote HCV infection of the CNS. High-dose n-PUFAs may alleviate anxiety in some CHC patients but the use of lipid lowering therapy must be balanced against risks of worsening depression.
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Affiliation(s)
- David A Sheridan
- Institute of Cellular Medicine (Hepatology), Newcastle University, William Leech Building, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK,
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Lohmann V, Bartenschlager R. On the History of Hepatitis C Virus Cell Culture Systems. J Med Chem 2013; 57:1627-42. [DOI: 10.1021/jm401401n] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Volker Lohmann
- Department of Infectious
Diseases, Molecular Virology, Heidelberg University, Heidelberg, 69120, Germany
| | - Ralf Bartenschlager
- Department of Infectious
Diseases, Molecular Virology, Heidelberg University, Heidelberg, 69120, Germany
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Abstract
Hepatitis C virus (HCV) exhibits a narrow host range and a specific tissue tropism. Studies on HCV life cycle have been progressed by the developments of in vitro replication and infection systems and an HCV laboratory strain (HCVcc) capable of propagating in human hepatoma cell line, Huh7 cells. Mice expressing four human entry receptor candidates for HCV permit entry of HCVcc, therefore tissue tropism of HCV was believed to be rely on the expression of the entry receptors. However, HCV infection is often associated with extra-hepatic manifestations and the determinants for cell tropism of HCV remain elusive. Recently, we have shown that several nonhepatic cell lines permit HCV-RNA replication through an expression of a liver-specific microRNA, miR-122, upon infection with HCVcc, while no infectious particle was produced. In the nonhepatic cells, only small numbers of lipid droplets and low levels of VLDL-associated proteins were observed in compared with Huh7 cells, suggesting that expression of miR-122 and functional lipid metabolism participates in the replication and assembly of HCVcc, respectively In this review, we would like to discuss about involvement of miR-122 and functional lipid metabolism in the determination of HCV cell tropism.
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29
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Abstract
Hepatitis C virus (HCV) exhibits a narrow host range and a specific tissue tropism. Mice expressing major entry receptors for HCV permit viral entry, and therefore the species tropism of HCV infection is considered to be reliant on the expression of the entry receptors. However, HCV receptor candidates are expressed and replication of HCV-RNA can be detected in several nonhepatic cell lines, suggesting that nonhepatic cells are also susceptible to HCV infection. Recently it was shown that the exogenous expression of a liver-specific microRNA, miR-122, facilitated the efficient replication of HCV not only in hepatic cell lines, including Hep3B and HepG2 cells, but also in nonhepatic cell lines, including Hec1B and HEK-293T cells, suggesting that miR-122 is required for the efficient replication of HCV in cultured cells. However, no infectious particle was detected in the nonhepatic cell lines, in spite of the efficient replication of HCV-RNA. In the nonhepatic cells, only small numbers of lipid droplets and low levels of very-low-density lipoprotein-associated proteins were observed compared with findings in the hepatic cell lines, suggesting that functional lipid metabolism participates in the assembly of HCV. Taken together, these findings indicate that miR-122 and functional lipid metabolism are involved in the tissue tropism of HCV infection. In this review, we would like to focus on the role of miR-122 and lipid metabolism in the cell tropism of HCV.
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Abstract
Due to the obligatory intracellular lifestyle of viruses, cell culture systems for efficient viral propagation are crucial to obtain a detailed understanding of the virus-host cell interaction. For hepatitis C virus (HCV) the development of permissive and authentic culture models continues to be a challenging task. The first efforts to culture HCV had limited success and range back to before the virus was molecularly cloned in 1989. Since then several major breakthroughs have gradually overcome limitations in culturing the virus and sequentially permitted analysis of viral RNA replication, cell entry, and ultimately the complete replication cycle in cultured cells in 2005. Until today, basic and applied HCV research greatly benefit from these tremendous efforts which spurred multiple complementary cell-based model systems for distinct steps of the HCV replication cycle. When used in combination they now permit deep insights into the fascinating biology of HCV and its interplay with the host cell. In fact, drug development has been much facilitated and our understanding of the molecular determinants of HCV replication has grown in parallel to these advances. Building on this groundwork and further refining our cellular models to better mimic the architecture, polarization and differentiation of natural hepatocytes should reveal novel unique aspects of HCV replication. Ultimately, models to culture primary HCV isolates across all genotypes may teach us important new lessons about viral functional adaptations that have evolved in exchange with its human host and that may explain the variable natural course of hepatitis C.
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Affiliation(s)
- Eike Steinmann
- Helmholtz Centre for Infection Research, Hannover, Germany
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32
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Shulla A, Randall G. Hepatitis C virus-host interactions, replication, and viral assembly. Curr Opin Virol 2012; 2:725-32. [PMID: 23083892 DOI: 10.1016/j.coviro.2012.09.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 09/21/2012] [Accepted: 09/25/2012] [Indexed: 12/12/2022]
Abstract
As a relatively simple virus, hepatitis C virus (HCV) depends extensively on its host to infect, replicate and disseminate. HCV has evolved host interactions that result in a restricted tropism, both in terms of cell type and species. Efforts into identifying and validating HCV-host interactions have been hampered by a limited number of infectious virus clones and cell lines that support HCV infection. Despite these limitations, consensus HCV-host interactions have emerged that help define the entry, replication, assembly, and tropism of HCV. This has had important implications in expanding our in vitro and in vivo systems to study HCV replication and pathogenesis. Additionally, a number of these host factors are being targeted for therapeutic development. In this review, we focus on medically relevant pro-viral host factors, their role in HCV biology, and their importance in expanding our model systems.
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Affiliation(s)
- Ana Shulla
- Department of Microbiology, The University of Chicago, Chicago, IL 60637, United States
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33
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McCarthy M, Ortega MR. Neurological complications of hepatitis C infection. Curr Neurol Neurosci Rep 2012; 12:642-54. [PMID: 22991069 DOI: 10.1007/s11910-012-0311-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Though well-known as a cause of liver disease, Hepatitis C virus infection is emerging as a cause of a variety of peripheral and central nervous system disorders. The virus causes chronic persistent infection with complex immune responses in the majority of individuals. Viral infection may have the potential to generate neurological illness through direct infection of neural cells or through immune-mediated mechanisms, including enhancement of autoimmune responses. Moreover, the mainstay of antiviral treatment of hepatitis C infection, interferon-alpha, is itself associated with neurological morbidity. Thus neurologists are increasingly faced with diagnosing or even predicting a wide spectrum of neurological complications of hepatitis C infection and/or its treatment.
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Affiliation(s)
- Micheline McCarthy
- Neurology (127), Bruce Carter Veterans Affairs Medical Center, 1201 NW 16th Street, Miami, FL 33125, USA.
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34
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Reconstitution of the entire hepatitis C virus life cycle in nonhepatic cells. J Virol 2012; 86:11919-25. [PMID: 22896615 DOI: 10.1128/jvi.01066-12] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C virus (HCV) is a human hepatotropic virus, but the relevant host factors restricting HCV infection to hepatocytes are only partially understood. We demonstrate that exogenous expression of defined host factors reconstituted the entire HCV life cycle in human nonhepatic 293T cells. This study shows robust HCV entry, RNA replication, and production of infectious virus in human nonhepatic cells and highlights key host factors required for liver tropism of HCV.
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Expression of microRNA miR-122 facilitates an efficient replication in nonhepatic cells upon infection with hepatitis C virus. J Virol 2012; 86:7918-33. [PMID: 22593164 DOI: 10.1128/jvi.00567-12] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the most common etiologic agents of chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. In addition, HCV infection is often associated with extrahepatic manifestations (EHM), including mixed cryoglobulinemia and non-Hodgkin's lymphoma. However, the mechanisms of cell tropism of HCV and HCV-induced EHM remain elusive, because in vitro propagation of HCV has been limited in the combination of cell culture-adapted HCV (HCVcc) and several hepatic cell lines. Recently, a liver-specific microRNA called miR-122 was shown to facilitate the efficient propagation of HCVcc in several hepatic cell lines. In this study, we evaluated the importance of miR-122 on the replication of HCV in nonhepatic cells. Among the nonhepatic cell lines expressing functional HCV entry receptors, Hec1B cells derived from human uterus exhibited a low level of replication of the HCV genome upon infection with HCVcc. Exogenous expression of miR-122 in several cells facilitates efficient viral replication but not production of infectious particles, probably due to the lack of hepatocytic lipid metabolism. Furthermore, expression of mutant miR-122 carrying a substitution in a seed domain was required for efficient replication of mutant HCVcc carrying complementary substitutions in miR-122-binding sites, suggesting that specific interaction between miR-122 and HCV RNA is essential for the enhancement of viral replication. In conclusion, although miR-122 facilitates efficient viral replication in nonhepatic cells, factors other than miR-122, which are most likely specific to hepatocytes, are required for HCV assembly.
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Abstract
Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus of the family Flaviviridae that primarily infects hepatocytes, causing acute and chronic liver disease. HCV is also associated with a variety of extrahepatic symptoms including central nervous system (CNS) abnormalities, cognitive dysfunction, fatigue and depression. These symptoms do not correlate with the severity of liver disease and are independent of hepatic encephalopathy. HCV RNA has been associated with CNS tissue, and reports of viral sequence diversity between brain and liver tissue suggest independent viral evolution in the CNS and liver. This review will explore the data supporting HCV infection of the CNS and how this fits into our current understanding of HCV pathogenesis.
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Affiliation(s)
- N F Fletcher
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK.
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Thimme R, Binder M, Bartenschlager R. Failure of innate and adaptive immune responses in controlling hepatitis C virus infection. FEMS Microbiol Rev 2012; 36:663-83. [PMID: 22142141 DOI: 10.1111/j.1574-6976.2011.00319.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 11/07/2011] [Accepted: 11/25/2011] [Indexed: 12/24/2022] Open
Affiliation(s)
- Robert Thimme
- Department of Medicine II, University Medical Center Freiburg, Freiburg, Germany
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38
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Sugden PB, Cameron B, Bull R, White PA, Lloyd AR. Occult infection with hepatitis C virus: friend or foe? Immunol Cell Biol 2012; 90:763-73. [PMID: 22546735 DOI: 10.1038/icb.2012.20] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) infection is a global pandemic associated with a growing disease burden due to cirrhosis and the consequent morbidity and mortality. Transmission is largely via blood-to-blood contact. Following primary infection, a minority of individuals clear the infection predominantly via cellular immune mechanisms, whereas the majority become chronically infected. Recent data suggest that a third outcome may also be possible, termed 'occult' infection in which subjects who are known, or suspected to have previously been infected with HCV, no longer have viral RNA in their serum at levels detectable by sensitive commercial assays, but do have virus detected by ultra-sensitive techniques. Occult infection has also been detected in peripheral blood mononuclear cells, which may indicate an extra-hepatic reservoir of the virus. Although the clinical significance of occult infection remains unknown, most authors have raised concerns of recrudescent infection. Here we critically review the published literature, suggest further avenues of investigation and propose that occult infection may be beneficial to the host by maintaining immunological memory to protect against reinfection.
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Affiliation(s)
- Peter B Sugden
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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39
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Meredith LW, Wilson GK, Fletcher NF, McKeating JA. Hepatitis C virus entry: beyond receptors. Rev Med Virol 2012; 22:182-93. [PMID: 22392805 DOI: 10.1002/rmv.723] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 09/30/2011] [Accepted: 10/09/2011] [Indexed: 12/11/2022]
Abstract
HCV is a blood-borne pathogen that affects approximately 3% of the global population and leads to progressive liver disease. Recent advances have identified an essential role for host cell molecules: tetraspanin CD81, scavenger receptor B1 and the tight junction proteins claudin-1 and occludin in HCV entry, suggesting a complex multi-step process. The conserved nature of this receptor-dependent step in the viral life cycle offers an attractive target for therapeutic intervention. Evidence is emerging that additional factors other than classical receptors, such as inflammatory mediators regulate the ability of hepatocytes to support HCV entry, and as such may provide potential avenues for drug design and development. In this review, we summarise the recent literature on HCV entry mechanisms with a view to realising the future potential of therapeutically targeting this process.
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Affiliation(s)
- Luke W Meredith
- Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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40
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Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, Stamataki Z, Meredith LW, Rowe IA, Luo G, Lopez–ramirez MIGUELA, Baumert TF, Weksler B, Couraud PO, Kim KS, Romero IA, Jopling C, Morgello S, Balfe P, Mckeating JA. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology 2012; 142:634-643.e6. [PMID: 22138189 PMCID: PMC3801216 DOI: 10.1053/j.gastro.2011.11.028] [Citation(s) in RCA: 187] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2011] [Revised: 10/18/2011] [Accepted: 11/15/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS. METHODS We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culture-derived HCV were used to study the ability of endothelial cells to support viral entry and replication. RESULTS Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis. CONCLUSIONS Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.
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Affiliation(s)
- Nicola F. Fletcher
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Garrick K. Wilson
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Jacinta Murray
- School of Pharmacy, University of Nottingham, Nottingham, England
| | - Ke Hu
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Andrew Lewis
- School of Pharmacy, University of Nottingham, Nottingham, England
| | - Gary M. Reynolds
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Zania Stamataki
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Luke W. Meredith
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Ian A. Rowe
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Guangxiang Luo
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
| | | | - Thomas F. Baumert
- Université de Strasbourg and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | | | - Pierre-Olivier Couraud
- Institut Cochin, CNRS UMR 8104, INSERM Unité 567, Université Paris Descartes, Paris, France
| | - Kwang Sik Kim
- Division of Infectious Diseases, The Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Ignacio A. Romero
- Department of Life Sciences, The Open University, Milton Keynes, England
| | | | - Susan Morgello
- Department of Pathology, Mount Sinai School of Medicine, New York, New York
| | - Peter Balfe
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Jane A. Mckeating
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
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42
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Ploss A, Evans MJ. Hepatitis C virus host cell entry. Curr Opin Virol 2012; 2:14-9. [PMID: 22440961 DOI: 10.1016/j.coviro.2011.12.007] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 11/17/2011] [Accepted: 12/15/2011] [Indexed: 12/12/2022]
Abstract
The hepatitis C virus (HCV) is a major medical problem with at least 130 million infected individuals worldwide. Over the last decade multiple host factors required for HCV cell entry have been identified, but a detailed understanding of their mechanistic interplay remains elusive. Nonetheless, recent advances in defining species-specific barriers of HCV transmission have allowed the identification of a minimal set of entry factors that are required for HCV infection of rodent cells and has culminated in an animal model that recapitulates HCV entry in vivo. A detailed understanding of the viral uptake pathway is imperative to define new drug targets allowing for more effective intervention against this devastating disease.
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Affiliation(s)
- Alexander Ploss
- Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
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In vitro systems for the study of hepatitis C virus infection. Int J Hepatol 2012; 2012:292591. [PMID: 23056952 PMCID: PMC3465938 DOI: 10.1155/2012/292591] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 07/03/2012] [Accepted: 07/17/2012] [Indexed: 12/22/2022] Open
Abstract
The study of a virus is made possible by the availability of culture systems in which the viral lifecycle can be realized. Such systems support robust virus entry, replication, assembly, and secretion of nascent virions. Furthermore, culture models provide a platform in which therapeutic interventions can be devised or monitored. Hepatitis C virus (HCV) has a restricted tropism to human and chimpanzees; thus investigations of HCV biology have been hindered for many years due to a lack of small animal models. Nevertheless, significant efforts have been directed at developing cell culture models to elucidate the viral lifecycle in vitro. HCV primarily infects liver parenchymal cells commonly known as hepatocytes. The liver is a highly specialized and complex organ and the development of in vitro systems that reflects this complexity has proven difficult. Consequently, host cell receptor molecules that potentiate HCV infection were identified over a decade after the virus was discovered. A summary of the various HCV in vitro culture models, their advantages, and disadvantages are described.
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Abstract
CD81, a member of the tetraspanin integral membrane protein family, has been identified as an essential receptor for HCV (hepatitis C virus). The present review highlights recent published data on the role that CD81 plays in HCV entry, including the importance of actin-dependent lateral diffusion of CD81 within the cell membrane, CD81 endocytosis and the CD81-Claudin-1 receptor complex in HCV internalization. Additional functions for CD81 in the viral life cycle and the role of HCV-CD81 interactions in HCV-induced B-cell and CNS (central nervous system) abnormalities are discussed.
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Lindenbach BD. New cell culture models of hepatitis C virus entry, replication, and virus production. Gastroenterology 2010; 139:1090-3. [PMID: 20797436 DOI: 10.1053/j.gastro.2010.08.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Wong-Staal F, Syder AJ, McKelvy JF. Targeting HCV entry for development of therapeutics. Viruses 2010; 2:1718-1733. [PMID: 21994703 PMCID: PMC3185726 DOI: 10.3390/v2081718] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Revised: 08/05/2010] [Accepted: 08/16/2010] [Indexed: 01/11/2023] Open
Abstract
Recent progress in defining the molecular mechanisms of Hepatitis C Virus (HCV) entry affords the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors would limit the expansion of the infected cell reservoir, and would complement the many replication inhibitors now under development. The current model for the pathway of entry involves the initial docking of the virus onto the cell surface through interactions of virion envelope and associated low density lipoproteins (LDL) with cell surface glycosaminoglycans and lipoprotein receptors, followed by more specific utilization with other hepatocyte membrane proteins: Scavenger Receptor Class B type 1 (SR-BI), CD81, Claudin 1 (CLDN1) and Occludin (OCLN). The use of blockers of these interactions, e.g. specific antibodies, suggests that inhibition of any one step in the entry pathway can inhibit infection. Despite this knowledge base, the tools for compound screening, HCV pseudoparticles (HCVpp) and cell culture virus (HCVcc), and the ability to adapt them to industrial use are only recently available and as a result drug discovery initiatives are in their infancy. Several therapies aiming at modulating the virus envelope to prevent host cell binding are in early clinical testing. The first test case for blocking a cellular co-receptor is an SR-BI modulator. ITX 5061, an orally active small molecule, targets SR-BI and has shown potent antiviral activity against HCVpp and HCVcc. ITX 5061 has exhibited good safety in previous clinical studies, and is being evaluated in the clinic in chronic HCV patients and patients undergoing liver transplantation. Entry inhibitors promise to be valuable players in the future development of curative therapy against HCV.
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Affiliation(s)
- Flossie Wong-Staal
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-858-824-1114; Fax: +1-858-824-1112
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