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Elbahrawy A, Atalla H, Mahmoud AA, Eliwa A, Alsawak A, Alboraie M, Madian A, Alashker A, Mostafa S, Alwassief A, Aly HH. Prediction and surveillance of de novo HCC in patients with compensated advanced chronic liver disease after hepatitis C virus eradication with direct antiviral agents. FRONTIERS IN VIROLOGY 2023; 3. [DOI: 10.3389/fviro.2023.1227317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The risk of hepatocellular carcinoma (HCC) diminishes in patients with hepatitis C virus (HCV)-related advanced chronic liver disease after virological cure. However, despite viral clearance, HCV-induced epigenetic alterations, immune dysregulations, and hepatic parenchymal injuries remain, contributing to de novo HCC occurrence. While HCC incidence is low (0.45 – 0.5%) in patients with advanced fibrosis (F3), the presence of liver cirrhosis and clinically significant portal hypertension increases the HCC risk. The cost-effectiveness of lifelong HCC surveillance in patients with compensated advanced chronic liver disease (cACLD) has sparked debate, raising questions about the most reliable noninvasive tests and stratification models for predicting HCC in patients with sustained virological response (SVR). Furthermore, identifying cACLD patients who may not require long-term HCC surveillance after SVR remains crucial. Several HCC risk stratification scores have been suggested for patients with cACLD, and emerging evidence supports individualized care based on personalized risk assessments. This review focuses on revising the pretreatment and posttreatment predictors of HCC, as well as the indications for HCC surveillance in cACLD patients treated with direct-acting antivirals.
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Afzal S, Ali L, Batool A, Afzal M, Kanwal N, Hassan M, Safdar M, Ahmad A, Yang J. Hantavirus: an overview and advancements in therapeutic approaches for infection. Front Microbiol 2023; 14:1233433. [PMID: 37901807 PMCID: PMC10601933 DOI: 10.3389/fmicb.2023.1233433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/25/2023] [Indexed: 10/31/2023] Open
Abstract
Hantaviruses are a significant and emerging global public health threat, impacting more than 200,000 individuals worldwide each year. The single-stranded RNA viruses belong to the Hantaviridae family and are responsible for causing two acute febrile diseases in humans: Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). Currently, there are no licensed treatments or vaccines available globally for HTNV infection. Various candidate drugs have shown efficacy in increasing survival rates during the early stages of HTNV infection. Some of these drugs include lactoferrin, ribavirin, ETAR, favipiravir and vandetanib. Immunotherapy utilizing neutralizing antibodies (NAbs) generated from Hantavirus convalescent patients show efficacy against HTNV. Monoclonal antibodies such as MIB22 and JL16 have demonstrated effectiveness in protecting against HTNV infection. The development of vaccines and antivirals, used independently and/or in combination, is critical for elucidating hantaviral infections and the impact on public health. RNA interference (RNAi) arised as an emerging antiviral therapy, is a highly specific degrades RNA, with post-transcriptional mechanism using eukaryotic cells platform. That has demonstrated efficacy against a wide range of viruses, both in vitro and in vivo. Recent antiviral methods involve using small interfering RNA (siRNA) and other, immune-based therapies to target specific gene segments (S, M, or L) of the Hantavirus. This therapeutic approach enhances viral RNA clearance through the RNA interference process in Vero E6 cells or human lung microvascular endothelial cells. However, the use of siRNAs faces challenges due to their low biological stability and limited in vivo targeting ability. Despite their successful inhibition of Hantavirus replication in host cells, their antiviral efficacy may be hindered. In the current review, we focus on advances in therapeutic strategies, as antiviral medications, immune-based therapies and vaccine candidates aimed at enhancing the body's ability to control the progression of Hantavirus infections, with the potential to reduce the risk of severe disease.
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Affiliation(s)
- Samia Afzal
- CEMB, University of the Punjab, Lahore, Pakistan
| | - Liaqat Ali
- Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
| | - Anum Batool
- Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
| | - Momina Afzal
- CEMB, University of the Punjab, Lahore, Pakistan
| | - Nida Kanwal
- Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
| | | | | | - Atif Ahmad
- CEMB, University of the Punjab, Lahore, Pakistan
| | - Jing Yang
- Wuhan Institute of Biological Products Co., Ltd., Wuhan, Hubei, China
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Siphepho PY, Liu YT, Shabangu CS, Huang JF, Huang CF, Yeh ML, Yu ML, Wang SC. The Impact of Steatosis on Chronic Hepatitis C Progression and Response to Antiviral Treatments. Biomedicines 2021; 9:1491. [PMID: 34680608 PMCID: PMC8533513 DOI: 10.3390/biomedicines9101491] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/12/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as metabolic-associated fatty liver disease (MAFLD), is a common feature in HCV-infected patients, induced by host and/or viral factors. Most chronic HCV-infected (CHC) patients have mild steatosis within the periportal region of the liver with an estimated prevalence of 40% to 86%. Indeed, this is higher than the 19% to 50% prevalence observed in patients with other chronic liver diseases such as chronic hepatitis B (CHB). The histological manifestations of HCV infection are frequently observed in genotype 3 (G-3), where relative to other genotypes, the prevalence and severity of steatosis is also increased. Steatosis may independently influence the treatment efficacy of either interferon-based or interferon-free antiviral regimens. This review aimed to provide updated evidence of the prevalence and risk factors behind HCV-associated steatosis, as well as explore the impact of steatosis on HCV-related outcomes.
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Affiliation(s)
- Phumelele Yvonne Siphepho
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
| | - Yi-Ting Liu
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Ciniso Sylvester Shabangu
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jee-Fu Huang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lung Yu
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
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Paul SS, Biswas G. Repurposed Antiviral Drugs for the Treatment of COVID-19: Syntheses, Mechanism of Infection and Clinical Trials. Mini Rev Med Chem 2021; 21:1123-1143. [PMID: 33355053 DOI: 10.2174/1389557521666201222145842] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 11/22/2022]
Abstract
COVID-19 is a public health emergency of international concern. Although considerable knowledge has been acquired with time about the viral mechanism of infection and mode of replication, yet no specific drugs or vaccines have been discovered against SARS-CoV-2 to date. There are few small molecule antiviral drugs like Remdesivir and Favipiravir, which have shown promising results in different advanced stages of clinical trials. Chloroquinine, Hydroxychloroquine, and Lopinavir- Ritonavir combination, although initially were hypothesized to be effective against SARSCoV- 2, are now discontinued from the solidarity clinical trials. This review provides a brief description of their chemical syntheses along with their mode of action, and clinical trial results available on Google and in different peer-reviewed journals till 24th October 2020.
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Affiliation(s)
| | - Goutam Biswas
- Department of Chemistry, Cooch Behar Panchanan Barma University, Panchanan Nagar, Cooch Behar 736101, India
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Elalfy H, Besheer T, El‐Mesery A, El‐Gilany A, Soliman MA, Alhawarey A, Alegezy M, Elhadidy T, Hewidy AA, Zaghloul H, Neamatallah MAM, Raafat D, El‐Emshaty WM, Abo El Kheir NY, El‐Bendary M. Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19. J Med Virol 2021; 93:3176-3183. [PMID: 33590901 PMCID: PMC8014583 DOI: 10.1002/jmv.26880] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/05/2021] [Accepted: 02/13/2021] [Indexed: 12/11/2022]
Abstract
This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.
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Affiliation(s)
- Hatem Elalfy
- Tropical Medicine and Hepatology Department, Mansoura Faculty of MedicineMansoura UniversityMansouraEgypt
| | - Tarek Besheer
- Department of Tropical Medicine, Faculty of MedicineMansoura UniversityMansouraEgypt
| | - Ahmed El‐Mesery
- Department of Tropical Medicine, Faculty of MedicineMansoura UniversityMansouraEgypt
| | - Abdel‐Hady El‐Gilany
- Department of Public Health and Preventive Medicine, Faculty of MedicineMansoura UniversityMansouraEgypt
| | | | - Ahmed Alhawarey
- Department of Tropical Medicine, Faculty of MedicineMansoura UniversityMansouraEgypt
| | - Mohamed Alegezy
- Tropical Medicine and Hepatology Department, Mansoura Faculty of MedicineMansoura UniversityMansouraEgypt
| | | | - Asem A. Hewidy
- Chest Medicine DepartmentMansoura UniversityMansouraEgypt
| | - Hossam Zaghloul
- Department of Clinical Pathology, Mansoura Faculty of MedicineMansoura UniversityMansouraEgypt
| | | | - Douaa Raafat
- Department of Clinical Pathology, Mansoura Faculty of MedicineMansoura UniversityMansouraEgypt
| | - Wafaa M. El‐Emshaty
- Department of Clinical Pathology, Mansoura Faculty of MedicineMansoura UniversityMansouraEgypt
| | - Nermin Y. Abo El Kheir
- Department of Clinical Pathology, Mansoura Faculty of MedicineMansoura UniversityMansouraEgypt
| | - Mahmoud El‐Bendary
- Tropical Medicine and Hepatology Department, Mansoura Faculty of MedicineMansoura UniversityMansouraEgypt
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Khalili JS, Zhu H, Mak NSA, Yan Y, Zhu Y. Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19. J Med Virol 2020; 92:740-746. [PMID: 32227493 PMCID: PMC7228408 DOI: 10.1002/jmv.25798] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/15/2022]
Abstract
Confronting the challenge of the outbreak of COVID-19 should sharpen our focus on global drug access as a key issue in antiviral therapy testing. The testing and adoption of effective therapies for novel coronaviruses are hampered by the challenge of conducting controlled studies during a state of emergency. The access to direct antiviral drugs, such as ribavirin, that have an existing inventory and reliable supply chain may be a priority consideration for therapies developed for the 2019-nCoV infection outbreaks and any strain variants that may emerge. On the basis of the direct antiviral activity of ribavirin against 2019-nCoV in vitro and evidence for potency enhancement strategies developed during the prior SARS and MERS outbreaks, ribavirin may significantly impact our ability to end the lingering outbreaks in China and slow outbreaks in other countries. The apparent COVID-19 pandemic provides an opportunity to follow dosage guidelines for treatment with ribavirin, test new therapeutic concepts, and conduct controlled testing to apply the scientific rigor required to address the controversy around this mainstay of antiviral therapy.
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Affiliation(s)
| | - Hai Zhu
- SystImmune Inc, Redmond, Washington
| | | | | | - Yi Zhu
- SystImmune Inc, Redmond, Washington
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7
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Liu R, Ma H, Shu J, Zhang Q, Han M, Liu Z, Jin X, Zhang F, Wu X. Vaccines and Therapeutics Against Hantaviruses. Front Microbiol 2020; 10:2989. [PMID: 32082263 PMCID: PMC7002362 DOI: 10.3389/fmicb.2019.02989] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 12/10/2019] [Indexed: 12/16/2022] Open
Abstract
Hantaviruses (HVs) are rodent-transmitted viruses that can cause hantavirus cardiopulmonary syndrome (HCPS) in the Americas and hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Together, these viruses have annually caused approximately 200,000 human infections worldwide in recent years, with a case fatality rate of 5–15% for HFRS and up to 40% for HCPS. There is currently no effective treatment available for either HFRS or HCPS. Only whole virus inactivated vaccines against HTNV or SEOV are licensed for use in the Republic of Korea and China, but the protective efficacies of these vaccines are uncertain. To a large extent, the immune correlates of protection against hantavirus are not known. In this review, we summarized the epidemiology, virology, and pathogenesis of four HFRS-causing viruses, HTNV, SEOV, PUUV, and DOBV, and two HCPS-causing viruses, ANDV and SNV, and then discussed the existing knowledge on vaccines and therapeutics against these diseases. We think that this information will shed light on the rational development of new vaccines and treatments.
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Affiliation(s)
- Rongrong Liu
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Hongwei Ma
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Jiayi Shu
- Scientific Research Center, Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education & Health, Shanghai Medical College, Fudan University, Shanghai, China.,Viral Disease and Vaccine Translational Research Unit, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Qiang Zhang
- School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China
| | - Mingwei Han
- Cadet Brigade, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Ziyu Liu
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Xia Jin
- Scientific Research Center, Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education & Health, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fanglin Zhang
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Xingan Wu
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China
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Rinaldi L, Perrella A, Guarino M, De Luca M, Piai G, Coppola N, Pafundi PC, Ciardiello F, Fasano M, Martinelli E, Valente G, Nevola R, Monari C, Miglioresi L, Guerrera B, Berretta M, Sasso FC, Morisco F, Izzi A, Adinolfi LE. Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study. J Transl Med 2019; 17:292. [PMID: 31462268 PMCID: PMC6712712 DOI: 10.1186/s12967-019-2033-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 08/18/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND An unexpected increased HCC recurrence and occurrence rate among HCV patients treated with direct acting antivirals combination has been reported. Aim of the study was the evaluation of early HCC occurrence rate and its risk factors in a HCV infected population, treated with direct-acting-antivirals. METHODS According to the Italian ministerial guidelines for direct-acting-antivirals treatment, 1022 consecutive HCV patients treated with direct-acting-antivirals were enrolled. Patients either with active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Abdominal ultrasound was performed before starting antiviral therapy, and repeated every 6 months. HCC was diagnosed according to the international guidelines. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour were excluded from a further follow-up. RESULTS Nine hundred and eighty-five patients completed the 48 weeks follow-up after the end of treatment. A Sofosbuvir-based regimen was administered in the 74.9% of patients, among whom, the 71.6% underwent a simultaneous Ribavirin administration. A sustained virological response at 12 weeks off treatment was documented in 966 patients (98.2%). During the post treatment follow-up HCC was detected in 35 patients, with a cumulative incidence rate of the 3.55%. At multivariate analysis, four variables resulted independently associated with HCC development, both in a cirrhosis based and a class B Child based model, respectively: cirrhosis/class B Child, therapeutic schedule including Sofosbuvir without Ribavirin, liver stiffness values, male gender and presence of diabetes. A multivariate analysis performed on Child A cirrhotic patients, showed that Sofosbuvir based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than Ribavirin-based schedules with or without Sofosbuvir (p < 0.0001, OR: 5.686, 95% CI 2.455-13.169). CONCLUSIONS Our data suggest that early HCC occurrence appears more frequently related to Sofosbuvir-based therapy without Ribavirin which, indeed, seems to play a protective role on HCC onset. Therefore, a careful follow-up should be mandatory, especially in those regimens including Sofosbuvir without Ribavirin.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
| | - Alessandro Perrella
- Immunological and Neurological Infectious Diseases Unit, Cotugno Hospital, Naples, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy
| | - Massimo De Luca
- Hepatology and Pancreas Unit, Cardarelli Hospital, Naples, Italy
| | - Guido Piai
- Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | - Nicola Coppola
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fortunato Ciardiello
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Morena Fasano
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Erika Martinelli
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giovanna Valente
- Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Caterina Monari
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Lucia Miglioresi
- Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy
| | | | - Massimiliano Berretta
- Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori Aviano, Aviano, PN, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy
| | - Antonio Izzi
- Immunological and Neurological Infectious Diseases Unit, Cotugno Hospital, Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Nakatsuka K, Atsukawa M, Shimizu M, Takahashi H, Kawamoto C. Ribavirin contributes to eradicate hepatitis C virus through polarization of T helper 1/2 cell balance into T helper 1 dominance. World J Hepatol 2015; 7:2590-2596. [PMID: 26557951 PMCID: PMC4635144 DOI: 10.4254/wjh.v7.i25.2590] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 08/22/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
The mechanism of action of ribavirin (RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus (HCV) infection are reviewed. RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper (Th) 1/2 cell balance to Th1 dominance. Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells, which contributes to differentiating naïve Th cells into Th2 cells while reducing their interleukin-10 production. The effects on T-regulatory (Treg) cells were also investigated, and RBV inhibited the differentiation of naïve Th cells into adaptive Treg cells by down-modulating forkhead box-P3. These findings indicate that RBV mainly down-regulates the activity of Th2 cells, resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes. Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications, regimens with RBV will be still be used because of their ability to facilitate the cellular immune response, which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.
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10
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Barjon C, Dahlqvist G, Calmus Y, Conti F. Role of regulatory T-cells during hepatitis C infection: From the acute phase to post-transplantation recurrence. Dig Liver Dis 2015. [PMID: 26216068 DOI: 10.1016/j.dld.2015.06.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C viral infection persists and becomes chronic in a majority of affected individuals. Numerous factors have been described to explain how the virus manages to escape the host immune system. One important escape mechanism is the increase in regulatory T cells induced by the virus. In this review, we will focus on the status of regulatory T cells throughout the natural history of hepatitis C infection and after liver transplantation. The molecular mechanisms involved in increasing the number of regulatory T cells are also discussed, as are data regarding the impact of regulatory T-cells on hepatic fibrosis in the context of hepatitis C viral infection.
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Affiliation(s)
- Clément Barjon
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France.
| | - Géraldine Dahlqvist
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France
| | - Yvon Calmus
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France; Department of Hepatology and Gastroenterology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Filomena Conti
- Sorbonne University, UPMC Univ. Paris 6, Inserm UMRS 938, CDR Saint-Antoine, Paris, France; Department of Hepatology and Gastroenterology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
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11
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Wang H, Li L, Zhang Y, Pan SC, Chen AQ, Qian WD. Expression and significance of CD4(+)CD25(+)CD127(-) regulatory T cells in peripheral blood of patients with different phenotypes of Guillain-Barré syndrome. Int J Clin Exp Med 2015; 8:19126-19131. [PMID: 26770543 PMCID: PMC4694443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 10/10/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE This study aims to investigate the changes of immune status and significance in patients with Guillain-Barré syndrome (GBS). METHODS The proportion of CD4(+)CD25(+)CD127(-) regulatory T cells in peripheral blood before immunotherapy for 41 patients with GBS (including 29 classic type and 12 variant type) and 42 normal control patients (healthy volunteers) were evaluated by flow cytometry. And molybdenum three phenol red method was used to detect cerebrospinal fluid protein content of 28 patients with GBS (including 19 with classic type and 9 with variant type). RESULTS Compared with healthy control group, the CD4(+)CD25(+)CD127(-) of GBS group had obvious difference (P<0.05). Of which, the CD4(+)CD25(+)CD127(-) regulatory T cells of the classic GBS group had no significant changes compared with the variant group (P>0.05), as well as the cerebrospinal fluid protein content between classic and variant GBS groups. The decrease of the proportion of CD4(+)CD25(+)CD127(-) regulatory T cells suggested abnormal expression of immune function in GBS patients. CONCLUSION The decrease of GBS regulatory T cell number or function indicated that the immune regulatory T cells mediated imbalance of immune regulation involved in the pathogenesis of GBS.
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Affiliation(s)
- Hao Wang
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College Bengbu 233004, China
| | - Li Li
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College Bengbu 233004, China
| | - Yin Zhang
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College Bengbu 233004, China
| | - Shu-Chao Pan
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College Bengbu 233004, China
| | - An-Qiang Chen
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College Bengbu 233004, China
| | - Wei-Dong Qian
- Department of Neurology, The First Affiliated Hospital of Bengbu Medical College Bengbu 233004, China
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Lipopolysaccharide from Rhodobacter sphaeroides Attenuates Microglia-Mediated Inflammation and Phagocytosis and Directs Regulatory T Cell Response. Int J Inflam 2015; 2015:361326. [PMID: 26457222 PMCID: PMC4589630 DOI: 10.1155/2015/361326] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 08/03/2015] [Accepted: 08/04/2015] [Indexed: 12/22/2022] Open
Abstract
Microglia activation and neuroinflammation are key events during the progression of neurodegenerative disorders. Microglia exhibits toll-like receptors (TLRs), with predominant expression of TLR4, inducing aberrant neuroinflammation and exacerbated neurotoxicity. Studies suggest that microglia initiate infiltration of T cells into the brain that critically influence disease conditions. We report that LPS-Rs, through TLR4 antagonism, significantly inhibit TLR4 mediated inflammatory molecules like IL-1β, IL-6, TNF-α, COX-2, iNOS, and NO. LPS-Rs regulates JNK/p38 MAPKs and p65-NF-κB signaling pathways, which we report as indispensible for LPS induced neuroinflammation. LPS-Rs mitigates microglial phagocytic activity and we are first to report regulatory role of LPS-Rs which blocked microglia mediated inflammation and apoptotic cell death. LPS-Rs significantly inhibits expression of costimulatory molecules CD80, CD86, and CD40. Chemokine receptor, CCR5, and T cell recruitment chemokines, MIP-1α and CCL5, were negatively regulated by LPS-Rs. Furthermore, LPS-Rs significantly inhibited lymphocyte proliferation with skewed regulatory T (Treg) cell response as evidenced by increased FOXP3, IL-10, and TGF-β. Additionally, LPS-Rs serves to induce coordinated immunosuppressive response and confer tolerogenic potential to activated microglia extending neurosupportive microenvironment. TLR4 antagonism can be a strategy providing neuroprotection through regulation of microglia as well as the T cells.
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Dong J, Wei J, Zhong L, Yang Q, Tuo J, Zhou P, Fang J, Cai W, Sun X, Zhou J. Ribavirin enhances myeloid-derived suppressor cell differentiation through CXCL9/10 downregulation. Immunopharmacol Immunotoxicol 2014; 36:412-9. [PMID: 25255161 DOI: 10.3109/08923973.2014.963602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Elevation of myeloid-derived suppressor cells (MDSCs) was observed in some viral infectious diseases. In this study, we studied whether ribavirin, a widely used clinical antiviral drug, could impact the differentiation of human MDSCs in vitro. Flow cytometric analysis showed that ribavirin treatment (5-20 µg/ml) significantly enhanced the differentiation of monocytic MDSCs in a dose-dependent manner. The ribavirin-generated MDSCs were immune-suppressive toward autologous T cells. The mRNA expression of some cytokines was further examined by quantitative reverse transcription polymerase chain reaction. We observed a significant down-regulation of chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 mRNA in ribavirin-generated MDSCs, when compared with control. Peripheral blood mononuclear cells from clinical chronic hepatitis C patients subjected to ribavirin therapy also displayed a similar suppression in CXCL9/10 mRNA expression. Administration of recombinant CXCL9/10 proteins clearly counteracted the effect of ribavirin on MDSCs. In summary, this study showed that ribavirin enhanced human MDSCs differentiation in vitro, which may be attribute to the down-regulation of CXCL9/10 expression.
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Affiliation(s)
- Jingyin Dong
- School of Medicine, Zhejiang University City College , Hangzhou, Zhejiang , PR China
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The murine model for Hantaan virus-induced lethal disease shows two distinct paths in viral evolutionary trajectory with and without ribavirin treatment. J Virol 2013; 87:10997-1007. [PMID: 23903835 DOI: 10.1128/jvi.01394-13] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
In vitro, ribavirin acts as a lethal mutagen in Hantaan virus (HTNV)-infected Vero E6 cells, resulting in an increased mutation load and viral population extinction. In this study, we asked whether ribavirin treatment in the lethal, suckling mouse model of HTNV infection would act similarly. The HTNV genomic RNA (vRNA) copy number and infectious virus were measured in lungs of untreated and ribavirin-treated mice. In untreated, HTNV-infected mice, the vRNA copy number increased for 10 days postinfection (dpi) and thereafter remained constant through 26 dpi. Surprisingly, in ribavirin-treated, HTNV-infected mice, vRNA levels were similar to those in untreated mice between 10 and 26 dpi. Infectious virus levels, however, were different: in ribavirin-treated mice, the amount of infectious HTNV was significantly decreased relative to that in untreated mice, suggesting that ribavirin reduced the specific infectivity of the virus (amount of infectious virus produced per vRNA copy). Mutational analysis revealed a ribavirin-associated elevation in mutation frequency in HTNV vRNA similar to that previously reported in vitro. Codon-based analyses of rates of nonsynonymous (dN) and synonymous (dS) substitutions in the S segment revealed a positive selection for codons within the HTNV N protein gene in the ribavirin-treated vRNA population. In contrast, the vRNA population in untreated, HTNV-infected mice showed a lower level of diversity, reflecting purifying selection for the wild-type genome. In summary, these experiments show two different evolutionary paths that Hantavirus may take during infection in a lethal murine model of disease, as well as the importance of the in vivo host environment in the evolution of the virus, which was not apparent in our prior in vitro model system.
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Guo Z, Wen Z, Qin A, Zhou Y, Liao Z, Liu Z, Liang Y, Ren T, Xu L. Antisense oligonucleotide treatment enhances the recovery of acute lung injury through IL-10-secreting M2-like macrophage-induced expansion of CD4+ regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2013; 190:4337-48. [PMID: 23514739 DOI: 10.4049/jimmunol.1203233] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
MicroRNAs (miRNAs) have been shown as an important regulator in the pathologies of acute lung injury (ALI). However, the potential effect of miRNA-based therapeutic studies in ALI remains poorly understood. We assessed the effect of antisense oligonucleotides (ASOs) against miR-155 on the development of ALI using a murine ALI model. We found that miR-155 ASO treatment could enhance the recovery of ALI as evidenced by accelerated body weight back, reduced level of bronchoalveolar lavage (BAL) protein and proinflammatory cytokines, and reduced number of BAL cells. Adoptive cell transfer assay in RAG1(-/-) mice showed that CD4(+)CD25(+) regulatory T cells (Tregs) mediated the enhanced recovery of ALI. Mechanistic evidence showed that enhanced expansion of Tregs in vivo, dominantly induced by IL-10-secreting M2-like macrophages, was critical for their elevated proportion in miR-155 ASO-treated ALI mice. Finally, we report that C/EBPβ, a target molecule of miR-155, was upregulated and associated with IL-10 secretion and M2-like phenotype of macrophages. These data provided a previously unknown mechanism for miRNA-based therapy against ALI, which could ultimately aid the understanding of recovery of ALI and the development of new therapeutic strategies against clinical inflammatory lung disease.
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Affiliation(s)
- Zhongliang Guo
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
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