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Kim SY, Koh JY, Lee DH, Kim HD, Choi SJ, Ko YY, Lee HS, Lee JS, Choi IA, Lee EY, Jeong HW, Jung MK, Park SH, Park JY, Kim W, Shin EC. Epigenetic scars in regulatory T cells are retained after successful treatment of chronic hepatitis C with direct-acting antivirals. J Hepatol 2024; 81:806-818. [PMID: 38879170 DOI: 10.1016/j.jhep.2024.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 08/09/2024]
Abstract
BACKGROUND & AIMS Chronic HCV infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Herein, we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (Treg) cells from patients with chronic HCV infection before, during, and after DAA treatment. METHODS Patients with chronic genotype 1b HCV infection who achieved sustained virologic response by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of Treg cells were investigated through flow cytometry analysis. Moreover, the transcriptomic and epigenetic landscapes of Treg cells were analyzed using RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin with sequencing) analysis. RESULTS The Treg cell population - especially the activated Treg cell subpopulation - was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA sequencing analysis revealed that viral clearance did not abrogate the inflammatory features of these Treg cells, such as Treg activation and TNF signaling. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of Treg cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that Treg cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance. CONCLUSIONS Overall, our results showed that during chronic HCV infection, the expanded Treg cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the Treg cell population after recovery from chronic HCV infection. IMPACT AND IMPLICATIONS During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of direct-acting antivirals has led to high cure rates. Nevertheless, we have demonstrated that inflammatory features of Treg cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection.
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Affiliation(s)
- So-Young Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - June-Young Koh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; GENOME INSIGHT Inc., Daejeon 34051, Republic of Korea
| | - Dong Hyeon Lee
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul 07061, Republic of Korea
| | - Hyung-Don Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Seong Jin Choi
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Yun Yeong Ko
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea
| | - Ha Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Jeong Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; GENOME INSIGHT Inc., Daejeon 34051, Republic of Korea
| | - In Ah Choi
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea
| | - Eun Young Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hye Won Jeong
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju 28644, Republic of Korea
| | - Min Kyung Jung
- The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul 07061, Republic of Korea.
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea.
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Wang S, Jaggi U, Katsumata M, Ghiasi H. The importance of IFNα2A (Roferon-A) in HSV-1 latency and T cell exhaustion in ocularly infected mice. PLoS Pathog 2024; 20:e1012612. [PMID: 39352890 PMCID: PMC11469491 DOI: 10.1371/journal.ppat.1012612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/11/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
Published studies have generated compelling results indicating that type I IFN modulates function of HSV-1 latency-associated transcript (LAT). One member of type I IFN is IFNα2A also called Roferon-A). IFNα2A has been used in monotherapy or in combination therapy with other drugs to treat viral infections and different kinds of cancer in humans. The goal of this study was to determine whether the absence of IFNα2A affects primary and latent infections in ocularly infected mice. Therefore, we generated a mouse strain lacking IFNα2A expression (IFNα2A-/-). Ocular HSV-1 replication, IFN and immune cell expressions on days 3 and 5 post infection (PI), as well as eye disease, survival, latency-reactivation, and T cell exhaustion were evaluated in ocularly infected IFNα2A-/- and wild type (WT) control mice. Absence of IFNα2A did not affect other members of the IFNα family but it affected IFNβ and IFNγ expressions as well as some immune cells on day 5 PI compared to WT mice. Viral replication in the eye, eye disease, and survival amongst ocularly infected IFNα2A-/- mice were similar to that of WT infected mice. The absence of IFNα2A significantly reduced the levels of latency and T cell exhaustion but not time of reactivation compared with control mice. Our results suggest that blocking IFNα2A expression may be a useful tool in reducing latency and the subsequent side effects associated with higher levels of latency.
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Affiliation(s)
- Shaohui Wang
- Center for Neurobiology & Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Ujjaldeep Jaggi
- Center for Neurobiology & Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Makoto Katsumata
- Rodent genetics core facility, Department of Comparative Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Homayon Ghiasi
- Center for Neurobiology & Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
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Moschouri E, Salemme G, Baserga A, Cerny A, Deibel A, Müllhaupt B, Meier MA, Bernsmeier C, Ongaro M, Negro F, Grosjean M, Clerc O, Künzler-Heule P, Semela D, Hobi G, Stickel F, Mathieu A, Mdawar-Bailly E, Faouzi M, Moradpour D, Fraga M. Real-life experience of chronic hepatitis C treatment in Switzerland: a retrospective analysis. Swiss Med Wkly 2024; 154:3698. [PMID: 38980176 DOI: 10.57187/s.3698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/27/2024] [Indexed: 07/10/2024] Open
Abstract
BACKGROUND AND AIM Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C. We analysed the use of different generations of DAAs over time in Switzerland and investigated factors predictive of treatment failure. METHODS This retrospective study was conducted within the framework of the Swiss Association for the Study of the Liver and the Swiss Hepatitis C Cohort Study; it included all patients with chronic hepatitis C treated with DAAs between January 2015 and December 2019 at eight Swiss referral centres. RESULTS A total of 3088 patients were included; 57.3% were male, and the median age was 54 years. Liver cirrhosis was present in 23.9% of the cohort, 87.8% of whom were compensated. The overall sustained virological response (SVR) rate (defined as undetectable HCV RNA at week 12 after the first course of DAA-based treatment) was 96.2%, with an increase over time. The rate of treatment failure dropped from 8.3% in 2015 to 2.5% in 2019. Multivariable analysis revealed that female sex, the use of the latest generation of pangenotypic DAA regimens, Caucasian origin, and genotype (gt) 1 were associated with SVR, whereas the presence of active hepatocellular carcinoma (HCC), gt 3, and increasing liver stiffness were associated with treatment failure. Notably, the presence of active HCC during treatment increased the risk of DAA failure by a factor of almost thirteen. CONCLUSIONS SVR rates increased over time, and the highest success rates were identified after the introduction of the latest generation of pangenotypic DAA regimens. Active HCC, gt 3 and increasing liver stiffness were associated with DAA failure.
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Affiliation(s)
- Eleni Moschouri
- 1Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne.
| | | | | | | | - Ansgar Deibel
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich.
| | - Beat Müllhaupt
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich.
| | - Marie-Anne Meier
- University Centre for Gastrointestinal and Liver Diseases (Clarunis), University Hospital Basel.
| | - Christine Bernsmeier
- University Centre for Gastrointestinal and Liver Diseases (Clarunis), University Hospital Basel.
| | - Marie Ongaro
- Division of Gastroenterology and Hepatology, University Hospitals Geneva, Geneva, Switzerland.
| | - Francesco Negro
- Division of Gastroenterology and Hepatology, University Hospitals Geneva, Geneva, Switzerland.
| | - Marielle Grosjean
- Divisions of Internal Medicine and Infectious Diseases, Hôpital Neuchâtelois-Pourtalès, Neuchâtel.
| | - Olivier Clerc
- Divisions of Internal Medicine and Infectious Diseases, Hôpital Neuchâtelois-Pourtalès, Neuchâtel.
| | | | - David Semela
- Division of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen.
| | | | - Felix Stickel
- Hirslanden Klinik Beau-Site, Bern, 3Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich.
| | - Adeline Mathieu
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne.
| | - Elise Mdawar-Bailly
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne.
| | - Mohamed Faouzi
- Division of Biostatistics, Center for Primary Care and Public Health (Unisanté), Lausanne;.
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne.
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne.
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Zhang Y, Qiu H, Duan F, An H, Qiao H, Zhang X, Zhang JR, Ding Q, Na J. A Comparative Study of Human Pluripotent Stem Cell-Derived Macrophages in Modeling Viral Infections. Viruses 2024; 16:552. [PMID: 38675895 PMCID: PMC11053470 DOI: 10.3390/v16040552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/03/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
Macrophages play multiple roles in innate immunity including phagocytosing pathogens, modulating the inflammatory response, presenting antigens, and recruiting other immune cells. Tissue-resident macrophages (TRMs) adapt to the local microenvironment and can exhibit different immune responses upon encountering distinct pathogens. In this study, we generated induced macrophages (iMACs) derived from human pluripotent stem cells (hPSCs) to investigate the interactions between the macrophages and various human pathogens, including the hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Streptococcus pneumoniae. iMACs can engulf all three pathogens. A comparison of the RNA-seq data of the iMACs encountering these pathogens revealed that the pathogens activated distinct gene networks related to viral response and inflammation in iMACs. Interestingly, in the presence of both HCV and host cells, iMACs upregulated different sets of genes involved in immune cell migration and chemotaxis. Finally, we constructed an image-based high-content analysis system consisting of iMACs, recombinant GFP-HCV, and hepatic cells to evaluate the effect of a chemical inhibitor on HCV infection. In summary, we developed a human cell-based in vitro model to study the macrophage response to human viral and bacterial infections; the results of the transcriptome analysis indicated that the iMACs were a useful resource for modeling pathogen-macrophage-tissue microenvironment interactions.
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Affiliation(s)
- Yaxuan Zhang
- Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Hui Qiu
- Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Fuyu Duan
- Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
- Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, China
| | - Haoran An
- Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing 100084, China
- Institute of Medical Technology, Peking University Health Science Center, Peking University, Beijing 100084, China
| | - Huimin Qiao
- Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xingwu Zhang
- Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Jing-Ren Zhang
- Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Qiang Ding
- Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Jie Na
- Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan 030001, China
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Ferreira J, Bicho M, Serejo F. Effects of HCV Clearance with Direct-Acting Antivirals (DAAs) on Liver Stiffness, Liver Fibrosis Stage and Metabolic/Cellular Parameters. Viruses 2024; 16:371. [PMID: 38543737 PMCID: PMC10974411 DOI: 10.3390/v16030371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/20/2024] [Accepted: 02/22/2024] [Indexed: 05/23/2024] Open
Abstract
INTRODUCTION Chronic hepatitis C (CHC) is a clinical and pathological syndrome with various causes and is characterized by varying degrees of hepatocellular necrosis and inflammation. It is a significant cause of liver transplantation and liver-related death worldwide. The hepatic manifestations of CHC are typically characterized by slowly progressing liver fibrosis, which is a non-specific and often disproportionate response to tissue damage. A large majority of HCV patients have extrahepatic manifestations with varying degrees of severity. HCV infection is a risk factor for cardiovascular disease and diabetes mellitus, which increases insulin resistance, oxidative stress, and iron overload and causes chronic systemic inflammation. HCV infection is treated using direct-acting antivirals (DAAs) with cure rates of over 95 percent, minimal side effects, and shorter therapeutic courses. Despite the effective elimination of the virus, it seemed pertinent to understand to what extent HCV clearance eliminates or attenuates all the systemic alterations already induced by the virus during infection and chronicity. OBJECTIVES Our study aimed to determine whether eliminating HCV with DAAs alters the severity of liver disease (liver stiffness and liver fibrosis stage by TE) and the metabolic/cellular profile of patients with CHC. MATERIALS AND METHODS A group of 329 CHC patients from a Gastroenterology and Hepatology outpatient department were prospectively studied. Of these, 134 were also studied with DAAs. The liver fibrosis stage was evaluated by transient elastography (TE) using a FibroScan® device, and two groups were established for the analysis of liver stiffness (LS): mild and moderate stiffness (fibrosis F1 and F2; F1/2) and severe stiffness (fibrosis and cirrhosis F3 and F4; F3/4). Metabolic/cellular parameters were evaluated before and after antiviral treatment using standard methods: alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl-transpeptidase (γ-GT), haptoglobin (Hp), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), free iron (Fe), transferrin saturation (TS), total iron binding capacity (TIBC), ferritin (Ft), glycemia, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and platelets count. The results were statistically analyzed using SPSS 24.0 for Windows. RESULTS Comparing the fibrosis stage before and after DAAs treatment, we verify a reduction in LS in 85.7% of patients and an improvement in liver fibrosis stage in 22.2% of them after DAAs treatment. Before DAAs treatment, patients showed a 2.410 risk for higher fibrosis stages (F3/4). Comparing metabolic/cellular parameters before and after DAAs treatment, patients showed lower ALP, AST, ALT, γGT, TG, Fe, TIBC, and Ft values and higher TC, LDL, and Hp values after treatment. As such, HCV elimination reduces iron overload and insulin resistance. On the other hand, it caused dyslipidemia, raising total cholesterol and LDL to levels outside the reference values. The improvement in the liver fibrosis stage by TE was mainly associated with higher baseline platelet count and HDL values and lower insulin resistance. CONCLUSIONS With this study, we were able to contribute to the knowledge of the effects of HCV elimination with DAAs on liver disease and metabolic profile to improve the quality of treatment and follow-up of these patients after HCV elimination.
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Affiliation(s)
- Joana Ferreira
- Institute for Scientific Research Bento Rocha Cabral, 1250-047 Lisbon, Portugal;
- TERRA, ISAMB, Genetics Laboratory, Lisbon Medical School, University of Lisbon, 1649-028 Lisbon, Portugal;
| | - Manuel Bicho
- Institute for Scientific Research Bento Rocha Cabral, 1250-047 Lisbon, Portugal;
- TERRA, ISAMB, Genetics Laboratory, Lisbon Medical School, University of Lisbon, 1649-028 Lisbon, Portugal;
| | - Fátima Serejo
- TERRA, ISAMB, Genetics Laboratory, Lisbon Medical School, University of Lisbon, 1649-028 Lisbon, Portugal;
- Gastroenterology and Hepatology Department, Hospital de Santa Maria, 1649-028 Lisbon, Portugal
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Karakoese Z, Le-Trilling VTK, Schuhenn J, Francois S, Lu M, Liu J, Trilling M, Hoffmann D, Dittmer U, Sutter K. Targeted mutations in IFNα2 improve its antiviral activity against various viruses. mBio 2023; 14:e0235723. [PMID: 37874130 PMCID: PMC10746204 DOI: 10.1128/mbio.02357-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 10/25/2023] Open
Abstract
IMPORTANCE The potency of interferon (IFN)α to restrict viruses was already discovered in 1957. However, until today, only IFNα2 out of the 12 distinct human IFNα subtypes has been therapeutically used against chronic viral infections. There is convincing evidence that other IFNα subtypes are far more efficient than IFNα2 against many viruses. In order to identify critical antiviral residues within the IFNα subtype sequence, we designed hybrid molecules based on the IFNα2 backbone with individual sequence motifs from the more potent subtypes IFNα6 and IFNα14. In different antiviral assays with HIV or HBV, residues binding to IFNAR1 as well as combinations of residues in the IFNAR1 binding region, the putative tunable anchor, and residues outside these regions were identified to be crucial for the antiviral activity of IFNα. Thus, we designed artificial IFNα molecules, based on the clinically approved IFNα2 backbone, but with highly improved antiviral activity against several viruses.
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Affiliation(s)
- Zehra Karakoese
- University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, Germany
- University Hospital Essen, University of Duisburg-Essen, Institute for Translational HIV Research, Essen, Germany
| | | | - Jonas Schuhenn
- University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, Germany
| | - Sandra Francois
- University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, Germany
| | - Mengji Lu
- University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mirko Trilling
- University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Daniel Hoffmann
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
- Research Group Bioinformatics, Faculty of Biology, University of Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, Germany
- University Hospital Essen, University of Duisburg-Essen, Institute for Translational HIV Research, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
| | - Kathrin Sutter
- University Hospital Essen, University of Duisburg-Essen, Institute for Virology, Essen, Germany
- University Hospital Essen, University of Duisburg-Essen, Institute for Translational HIV Research, Essen, Germany
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China
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7
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Quinn G, Ali RO, Zhang GY, Hill K, Townsend E, Umarova R, Chakraborty M, Ahmad MF, Gewirtz M, Haddad J, Rosenzweig S, Rampertaap S, Schoenfeld M, Yang S, Koh C, Levy E, Kleiner DE, Etzion O, Heller T. Non-selective dampening of the host immune response after hepatitis C clearance and its association with circulating chemokine and endotoxin levels. Liver Int 2023; 43:2701-2712. [PMID: 37752797 DOI: 10.1111/liv.15737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 07/15/2023] [Accepted: 09/04/2023] [Indexed: 09/28/2023]
Abstract
BACKGROUND & AIMS Direct-acting antiviral (DAA) therapy has revolutionized treatment for the hepatitis C virus (HCV). While DAA therapy is common, little is known about the intrahepatic immunological changes after sustained virologic response (SVR). We aim to describe transcriptional alterations of the gut microbiome and the liver after SVR. METHODS Twenty-two HCV patients were evaluated before and 9 months after 12 weeks of sofosbuvir/velpatasvir treatment. All achieved SVR. A liver biopsy, portal blood (direct portal vein cannulation), peripheral blood and stool samples were obtained. RNA-seq and immunofluorescent staining were performed on liver biopsies. RNA-seq and 16S rRNA metagenomics were performed on stool. RESULTS Differential expression within liver transcription showed 514 downregulated genes (FDR q < .05; foldchange > 2) enriched in inflammatory pathways; of note, GO:0060337, type 1 IFN signalling (p = 8e-23) and GO:0042742, defence response to bacterium (p = 8e-3). Interestingly, microbial products increased in the portal blood and liver after SVR. Due to the increase in microbial products, the gut microbiome was investigated. There was no dysbiosis by Shannon diversity index or Bacteroides/Firmicutes ratio. There was a differential increase in genes responsible for bacterial lipopolysaccharide production after SVR. CONCLUSIONS The decrease in the antiviral interferon pathway expression was expected after SVR; however, there was an unanticipated decrease in the transcription of genes involved in recognition and response to bacteria, which was associated with increased levels of microbial products. Finally, the alterations in the function of the gut microbiome are a promising avenue for further investigation of the gut-liver axis, especially in the context of the significant immunological changes noted after SVR.
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Affiliation(s)
- Gabriella Quinn
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Rabab O Ali
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Grace Y Zhang
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Kareen Hill
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Elizabeth Townsend
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Regina Umarova
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Moumita Chakraborty
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Maleeha F Ahmad
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Meital Gewirtz
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - James Haddad
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Sergio Rosenzweig
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Shakuntala Rampertaap
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Megan Schoenfeld
- NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Shanna Yang
- NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Elliot Levy
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ohad Etzion
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Adugna A. Therapeutic strategies and promising vaccine for hepatitis C virus infection. Immun Inflamm Dis 2023; 11:e977. [PMID: 37647422 PMCID: PMC10461427 DOI: 10.1002/iid3.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 07/22/2023] [Accepted: 07/30/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatitis C virus (HCV) infection is still a significant global health problem despite therapeutic advancements. Ribavirin and interferon therapy have been the sole available treatments for HCV infection for a number of years with low efficacy. Thus, currently, a number of therapeutic strategies are being used, including nanoparticles (NPs), micro-RNAs such as small interfering RNA (siRNA), RNAi-based gene silencing and antisense oligonucleotide-based microRNA-122, microRNA-155, and short hairpin RNAs (shRNAs), and immunotherapeutic approaches such as anti-programmed cell death 1(PD-1), monoclonal antibodies (mAb or moAb), and monocyte-derived dendritic cells (Mo-DCs). Furthermore, direct-acting antivirals (DAAs) and host-targeting agents (HTA) were also the current therapeutic approaches with great efficacy. In spite of different clinical trials on HCV vaccine developments, nowadays there is no effective HCV vaccine in opposition to virus due to various challenges including genetic diversity, lack of immunocompetent small animal models, shortage of HCV vaccination testing alternatives, lack of an effective tissue culture method for replicating HCV, and inadequate knowledge regarding to immune responses against HCV infection. Nowadays, mRNA vaccine, recombinant viral vector, peptides vaccine, virus-like particles, DNA vaccine, rational designed vaccine, and recombinant polyantigenic T-cell-based vaccine are novel promising candidates for HCV vaccine based on various clinical trials. This review summarizes the different therapeutic approaches and the advancements of vaccine candidates for HCV infection.
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Affiliation(s)
- Adane Adugna
- Medical Microbiology, Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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9
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Keppler M, Straß S, Geiger S, Fischer T, Späth N, Weinstein T, Schwamborn A, Guezguez J, Guse JH, Laufer S, Burnet M. Imidazoquinolines with improved pharmacokinetic properties induce a high IFNα to TNFα ratio in vitro and in vivo. Front Immunol 2023; 14:1168252. [PMID: 37409123 PMCID: PMC10319141 DOI: 10.3389/fimmu.2023.1168252] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/31/2023] [Indexed: 07/07/2023] Open
Abstract
TLR Agonists have promising activity in preclinical models of viral infection and cancer. However, clinical use is only in topical application. Systemic uses of TLR-ligands such as Resiquimod, have failed due to adverse effects that limited dose and thus, efficacy. This issue could be related to pharmacokinetic properties that include fast elimination leading to low AUC with simultaneously high cmax at relevant doses. The high cmax is associated with a sharp, poorly tolerated cytokine pulse, suggesting that a compound with a higher AUC/cmax-ratio could provide a more sustained and tolerable immune activation. Our approach was to design TLR7/8-agonist Imidazoquinolines intended to partition to endosomes via acid trapping using a macrolide-carrier. This can potentially extend pharmacokinetics and simultaneously direct the compounds to the target compartment. The compounds have hTLR7/8-agonist activity (EC50 of the most active compound in cellular assays: 75-120 nM hTLR7, 2.8-3.1 µM hTLR8) and maximal hTLR7 activation between 40 and 80% of Resiquimod. The lead candidates induce secretion of IFNα from human Leukocytes in the same range as Resiquimod but induce at least 10-fold less TNFα in this system, consistent with a higher specificity for human TLR7. This pattern was reproduced in vivo in a murine system, where small molecules are thought not to activate TLR8. We found that Imidazoquinolines conjugated to a macrolide or, substances carrying an unlinked terminal secondary amine, had longer exposure compared with Resiquimod. The kinetics of pro-inflammatory cytokine release for these substances in vivo were slower and more extended (for comparable AUCs, approximately half-maximal plasma concentrations). Maximal IFNα plasma levels were reached 4 h post application. Resiquimod-treated groups had by then returned to baseline from a peak at 1 h. We propose that the characteristic cytokine profile is likely a consequence of altered pharmacokinetics and, potentially, enhanced endosomal tropism of the novel substances. In particular, our substances are designed to partition to cellular compartments where the target receptor and a distinct combination of signaling molecules relevant to IFNα-release are located. These properties could address the tolerability issues of TLR7/8 ligands and provide insight into approaches to fine-tune the outcomes of TLR7/8 activation by small molecules.
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Affiliation(s)
| | - Simon Straß
- Synovo GmbH, Tübingen, Germany
- Pharmaceutical Chemistry, Institute for Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany
| | | | | | | | | | | | | | | | - Stefan Laufer
- Pharmaceutical Chemistry, Institute for Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany
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10
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Wallis RS, O'Garra A, Sher A, Wack A. Host-directed immunotherapy of viral and bacterial infections: past, present and future. Nat Rev Immunol 2023; 23:121-133. [PMID: 35672482 PMCID: PMC9171745 DOI: 10.1038/s41577-022-00734-z] [Citation(s) in RCA: 113] [Impact Index Per Article: 56.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2022] [Indexed: 02/06/2023]
Abstract
The advent of COVID-19 and the persistent threat of infectious diseases such as tuberculosis, malaria, influenza and HIV/AIDS remind us of the marked impact that infections continue to have on public health. Some of the most effective protective measures are vaccines but these have been difficult to develop for some of these infectious diseases even after decades of research. The development of drugs and immunotherapies acting directly against the pathogen can be equally challenging, and such pathogen-directed therapeutics have the potential disadvantage of selecting for resistance. An alternative approach is provided by host-directed therapies, which interfere with host cellular processes required for pathogen survival or replication, or target the host immune response to infection (immunotherapies) to either augment immunity or ameliorate immunopathology. Here, we provide a historical perspective of host-directed immunotherapeutic interventions for viral and bacterial infections and then focus on SARS-CoV-2 and Mycobacterium tuberculosis, two major human pathogens of the current era, to indicate the key lessons learned and discuss candidate immunotherapeutic approaches, with a focus on drugs currently in clinical trials.
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Affiliation(s)
- Robert S Wallis
- The Aurum Institute, Johannesburg, South Africa.
- Vanderbilt University, Nashville, TN, USA.
- Rutgers University, Newark, NJ, USA.
- Case Western Reserve University, Cleveland, OH, USA.
| | - Anne O'Garra
- Immunoregulation and Infection Laboratory, The Francis Crick Institute, London, UK
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Alan Sher
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Andreas Wack
- Immunoregulation Laboratory, The Francis Crick Institute, London, UK.
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11
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Suslov A, Heim MH, Wieland S. Studying Hepatitis Virus-Host Interactions in Patient Liver Biopsies. Viruses 2022; 14:v14112490. [PMID: 36366588 PMCID: PMC9699472 DOI: 10.3390/v14112490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/12/2022] Open
Abstract
Infectious diseases are a major contributor to human suffering and the associated socioeconomic burden worldwide. A better understanding of human pathogen-host interactions is a prerequisite for the development of treatment strategies aimed at combatting human pathogen-induced diseases. Model systems that faithfully recapitulate the pathogen-host interactions in humans are critical to gain meaningful insight. Unfortunately, such model systems are not yet available for a number of pathogens. The strict tropism of the hepatitis B (HBV) and C (HCV) viruses for the human liver has made it difficult to study their virus-host interactions during the natural history of these infections. In this case, surplus liver biopsy tissue donated by patients provides an opportunity to obtain a snapshot of the phenomenological and molecular aspects of the human liver of chronically HCV or HBV-infected patients. In this review, we will briefly summarize our own efforts over the years to advance our knowledge of the virus-host interactions during the natural history of chronic HCV and HBV infection.
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Affiliation(s)
- Aleksei Suslov
- Department of Biomedicine, University Hospital Basel, University of Basel, CH-4031 Basel, Switzerland
| | - Markus H. Heim
- Department of Biomedicine, University Hospital Basel, University of Basel, CH-4031 Basel, Switzerland
- Division of Gastroenterology and Hepatology, University Hospital Basel, CH-4031 Basel, Switzerland
| | - Stefan Wieland
- Department of Biomedicine, University Hospital Basel, University of Basel, CH-4031 Basel, Switzerland
- Correspondence:
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12
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Bamford CGG, Aranday-Cortes E, Sanchez-Velazquez R, Mullan C, Kohl A, Patel AH, Wilson SJ, McLauchlan J. A Human and Rhesus Macaque Interferon-Stimulated Gene Screen Shows That Over-Expression of ARHGEF3/XPLN Inhibits Replication of Hepatitis C Virus and Other Flavivirids. Viruses 2022; 14:v14081655. [PMID: 36016278 PMCID: PMC9414520 DOI: 10.3390/v14081655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/11/2022] [Accepted: 07/26/2022] [Indexed: 12/30/2022] Open
Abstract
Natural hepatitis C virus (HCV) infection is restricted to humans, whereas other primates such as rhesus macaques are non-permissive for infection. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen of lentivirus-expressed host genes that disrupt replication of HCV subgenomic replicon RNA expressing secreted Gaussia luciferase. A combined total of >800 interferon-stimulated genes (ISGs) were screened. Our findings confirmed established anti-HCV ISGs, such as IRF1, PKR and DDX60. Novel species−specific inhibitors were also identified and independently validated. Using a cell-based system that recapitulates productive HCV infection, we identified that over-expression of the ‘Rho Guanine Nucleotide Exchange Factor 3’ gene (ARHGEF3) from both species inhibits full-length virus replication. Additionally, replication of two mosquito-borne flaviviruses, yellow fever virus (YFV) and Zika virus (ZIKV), were also reduced in cell lines over-expressing ARHGEF3 compared to controls. In conclusion, we ascribe novel antiviral activity to the cellular gene ARHGEF3 that inhibits replication of HCV and other important human viral pathogens belonging to the Flaviviridae, and which is conserved between humans and rhesus macaques.
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Affiliation(s)
- Connor G. G. Bamford
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT7 1NN, UK
| | - Elihu Aranday-Cortes
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
| | - Ricardo Sanchez-Velazquez
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
- BioNTech SE, 55131 Mainz, Germany
| | - Catrina Mullan
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
| | - Alain Kohl
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
| | - Arvind H. Patel
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
| | - Sam J. Wilson
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
| | - John McLauchlan
- MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd, Bearsden, Glasgow G61 1QH, UK; (C.G.G.B.); (E.A.-C.); (R.S.-V.); (C.M.); (A.K.); (A.H.P.); (S.J.W.)
- Correspondence:
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13
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Matthews DW, Coleman S, Razavi H, Izaret J. The Payer License Agreement, or "Netflix model," for hepatitis C virus therapies enables universal treatment access, lowers costs and incentivizes innovation and competition. Liver Int 2022; 42:1503-1516. [PMID: 35289467 PMCID: PMC9314612 DOI: 10.1111/liv.15245] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/18/2022] [Accepted: 03/10/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS High unit prices of treatments limit access. For epidemics like that of hepatitis C virus (HCV), reduced treatment access increases prevalence and incidence, making the infectious disease increasingly difficult to manage. The objective of the current study was to construct and test an alternative pricing model, the Payer License Agreement (PLA), and determine whether it could improve outcomes, cut costs and incentivize innovation versus the current unit-based pricing model. METHODS We built and used computational models of hepatitis C disease progression, treatment, and pricing in historical and future scenarios and quantitatively analyzed their economic and epidemiological impact in three high-income countries. RESULTS This study had three key results regarding HCV treatment. First, if the PLA model had been implemented when interferon-free direct-acting antiviral (DAA) combinations launched, the number of patients treated and cured would have more than doubled in the first three years, while the liver-related deaths (LRDs) would have decreased by around 40%. Second, if the PLA model had been implemented beginning in 2018, the year that several Netflix-like payment models were under implementation, the number of treated and cured patients would nearly double, and the LRDs would decline by more than 55%. Third, implementing the PLA model would result in a decline in total payer costs of more than 25%, with an increase to pharmaceutical manufacturer revenues of 10%. These results were true across the three healthcare landscapes studied, the USA, the UK and Italy, and were robust against variations to critical model parameters through sensitivity analysis. CONCLUSIONS AND RELEVANCE These results suggest that implementation of the PLA model in high-income countries across a variety of health system contexts would improve patient outcomes at lower payer cost with more stable revenue for pharmaceutical manufacturers. Health policy-makers in high-income countries should consider the PLA model for application to more cost-effective management of HCV, and explore its application for other infectious diseases with curative therapies available now or soon.
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Affiliation(s)
- David W. Matthews
- The Boston Consulting GroupBostonMassachusettsUSA,The Bruce Henderson InstituteNew YorkNew YorkUSA
| | | | - Homie Razavi
- The Center for Disease Analysis (CDA)LafayetteColoradoUSA
| | - Jean‐Manuel Izaret
- The Boston Consulting GroupBostonMassachusettsUSA,The Bruce Henderson InstituteNew YorkNew YorkUSA
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14
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Yang X, Jeong K, Yabes JG, Ragni MV. Prevalence and risk factors for hepatocellular carcinoma in individuals with haemophilia in the era of direct-acting antiviral agents: A national inpatient sample study. Haemophilia 2022; 28:769-775. [PMID: 35727998 DOI: 10.1111/hae.14607] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 05/08/2022] [Accepted: 06/01/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis C virus (HCV) infection. Among haemophilic (H) men, HCV is the leading cause of liver disease. Direct-acting antiviral agents (DAA) reduce HCV viral load, but impact on HCC is unknown. METHODS This was a retrospective study of adult H and nonhaemophilic (NH) male discharges, with and without HCC, identified by ICD-10 codes in the National Inpatient Sample (NIS) database, 2016-2018, with DAA availability. Analyses included discharge-level weights to reflect national estimates. Categorical variables were assessed by Rao-Scott chi-square and continuous variables by weighted simple linear regression. HCC correlates were determined by weighted multivariable logistic regression. RESULTS Among 7,674,969 adult male discharges, 3730 H (.04%) were identified in 2016-2018, of whom 10.06% had HCV and 1.07% had HCC, significantly higher than NH (1.22% and .27%, respectively) all P < .001. Annual HCC rates were similar during the 3-year period (2016-2018) in H and NH. Among H, HCC is associated with older age and higher rates of HCV, HBV, NASH, end-stage liver disease, and Charlson comorbidity (CCI), each P < .001. Among HCC, H were younger and more likely HIV+, each P < .001, but less likely alcoholic (P = .018) or hyperlipidaemic (P = .008) compared to NH. In multivariable regression, risk factors for HCC among H included NASH (OR 21.6), HCV (OR 3.96), CCI (OR1.54), all P < .001, while HIV and hyperlipidaemia were protective. CONCLUSION From 2016 to 2018, HCC rates did not change significantly in haemophilia discharges. NASH, HCV, and CCI are significant risks for HCC in haemophilia during the DAA-era.
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Affiliation(s)
- Xi Yang
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.,Hemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania, USA
| | - Kwonho Jeong
- Center for Research on Health Care Data Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jonathan G Yabes
- Center for Research on Health Care Data Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Margaret V Ragni
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.,Hemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania, USA
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15
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Fueyo-González F, McGinty M, Ningoo M, Anderson L, Cantarelli C, Andrea Angeletti, Demir M, Llaudó I, Purroy C, Marjanovic N, Heja D, Sealfon SC, Heeger PS, Cravedi P, Fribourg M. Interferon-β acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation. Immunity 2022; 55:459-474.e7. [PMID: 35148827 PMCID: PMC8917088 DOI: 10.1016/j.immuni.2022.01.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 06/18/2021] [Accepted: 01/13/2022] [Indexed: 12/19/2022]
Abstract
Type I interferons (IFNs) are pleiotropic cytokines with potent antiviral properties that also promote protective T cell and humoral immunity. Paradoxically, type I IFNs, including the widely expressed IFNβ, also have immunosuppressive properties, including promoting persistent viral infections and treating T-cell-driven, remitting-relapsing multiple sclerosis. Although associative evidence suggests that IFNβ mediates these immunosuppressive effects by impacting regulatory T (Treg) cells, mechanistic links remain elusive. Here, we found that IFNβ enhanced graft survival in a Treg-cell-dependent murine transplant model. Genetic conditional deletion models revealed that the extended allograft survival was Treg cell-mediated and required IFNβ signaling on T cells. Using an in silico computational model and analysis of human immune cells, we found that IFNβ directly promoted Treg cell induction via STAT1- and P300-dependent Foxp3 acetylation. These findings identify a mechanistic connection between the immunosuppressive effects of IFNβ and Treg cells, with therapeutic implications for transplantation, autoimmunity, and malignancy.
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Affiliation(s)
- Francisco Fueyo-González
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Mitchell McGinty
- Carter Immunology Center, University of Virginia, Charlottesville, VA 22903, USA
| | - Mehek Ningoo
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Lisa Anderson
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Chiara Cantarelli
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
| | - Andrea Angeletti
- Division of Nephrology, Dialysis, Transplantation, IRCCS Giannina Gaslini, Genoa, Italy
| | - Markus Demir
- Department of Anesthesiology, University of Cologne, Cologne, Germany
| | - Inés Llaudó
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Carolina Purroy
- Department of Nephrology, Complejo Hospitalario de Navarra, Navarra, Spain
| | - Nada Marjanovic
- Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - David Heja
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Stuart C Sealfon
- Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Peter S Heeger
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Paolo Cravedi
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Miguel Fribourg
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
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16
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Guo C, Reuss D, Coey JD, Sukumar S, Lang B, McLauchlan J, Boulant S, Stanifer ML, Bamford CGG. Conserved Induction of Distinct Antiviral Signalling Kinetics by Primate Interferon Lambda 4 Proteins. Front Immunol 2021; 12:772588. [PMID: 34868037 PMCID: PMC8636442 DOI: 10.3389/fimmu.2021.772588] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/18/2021] [Indexed: 11/23/2022] Open
Abstract
Interferon lambdas (IFNλ) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver, and gastrointestinal tract. Humans have four IFNλs (1–4), where IFNλ1–3 show ~80%–95% homology, and IFNλ4 is the most divergent displaying only ~30% sequence identity. Variants in IFNλ4 in humans are associated with the outcome of infection, such as with hepatitis C virus. However, how IFNλ4 variants impact cytokine signalling in other tissues and how well this is conserved is largely unknown. In this study, we address whether differences in antiviral signalling exist between IFNλ4 variants in human hepatocyte and intestinal cells, comparing them to IFNλ3. We demonstrate that compared to IFNλ3, wild-type human IFNλ4 induces a signalling response with distinct magnitudes and kinetics, which is modified by naturally occurring variants P70S and K154E in both cell types. IFNλ4’s distinct antiviral response was more rapid yet transient compared to IFNλ1 and 3. Additionally, divergent antiviral kinetics were also observed using non-human primate IFNλs and cell lines. Furthermore, an IFNλ4-like receptor-interacting interface failed to alter IFNλ1’s kinetics. Together, our data provide further evidence that major functional differences exist within the IFNλ gene family. These results highlight the possible tissue specialisation of IFNλs and encourage further investigation of the divergent, non-redundant activities of IFNλ4 and other IFNλs.
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Affiliation(s)
- Cuncai Guo
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Dorothee Reuss
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jonathon D Coey
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom
| | - Swathi Sukumar
- Institute of Virology, University of Münster, Münster, Germany
| | - Benjamin Lang
- Exzellenzcluster Science of Intelligence, Technische Universität Berlin, Berlin, Germany
| | - John McLauchlan
- Medical Research Council University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom
| | - Steeve Boulant
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.,Research Group "Cellular Polarity and Viral Infection", German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Megan L Stanifer
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, United States.,Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Connor G G Bamford
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom
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17
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Bhattacharjee C, Singh M, Das D, Chaudhuri S, Mukhopadhyay A. Current therapeutics against HCV. Virusdisease 2021; 32:228-243. [PMID: 34307769 PMCID: PMC8279913 DOI: 10.1007/s13337-021-00697-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C is a positive stranded enveloped RNA virus belonging to the Flaviviridae family. HCV infection leads to severe liver diseases, cirrhosis and hepatocellular carcinoma worldwide. Although treatments have been available for a while, due to its complexity and genetic diversity, only few are reported to be effective against all HCV genotypes. Here, we review the HCV life cycle and its immunogenic potential and various mechanisms via which the virus interferes in the signalling process. A comprehensive overview of current anti-HCV therapeutics, such as, Direct Acting Antiviral (DAA) as well as Host Targeting Agents (HTA), along with their scope, known mechanism of action and limitations are presented. Supplementary Information The online version contains supplementary material available at 10.1007/s13337-021-00697-0.
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Affiliation(s)
- Chayan Bhattacharjee
- Department of Life Science, Presidency University, 86/1 College Street, Kolkata, 700073 India
| | - Maitri Singh
- Department of Life Science, Presidency University, 86/1 College Street, Kolkata, 700073 India
| | - Debisukti Das
- Department of Life Science, Presidency University, 86/1 College Street, Kolkata, 700073 India
| | | | - Aparna Mukhopadhyay
- Department of Life Science, Presidency University, 86/1 College Street, Kolkata, 700073 India
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18
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Nishio A, Bolte FJ, Takeda K, Park N, Yu ZX, Park H, Valdez K, Ghany MG, Rehermann B. Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection. Sci Transl Med 2021; 13:13/587/eaba6322. [PMID: 33790025 DOI: 10.1126/scitranslmed.aba6322] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 02/24/2021] [Indexed: 12/12/2022]
Abstract
Pegylated interferon-α (PEG-IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG-IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG-IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG-IFN-α injection experienced greater liver inflammation, lysis of HBV-infected hepatocytes, and hepatitis B surface antigen (HBsAg) decline than those without. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG-IFN-α pharmacokinetics. Patients with delayed increases in PEG-IFN-α concentrations had greater amounts of PEG-specific immunoglobulin M (IgM) immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG-IFN-α concentration. This was associated with reduced NK cell activation. These results indicate that the immunomodulatory functions of PEG-IFN-α, particularly activation of NK cells, play a pivotal role in the response to treatment and further demonstrate that these functions are affected by PEG-IFN-α pharmacokinetics. Accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of HBV therapeutics. Thus, these findings may contribute to improving the efficacy of pegylated drugs that are now being developed for other chronic diseases and cancer.
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Affiliation(s)
- Akira Nishio
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Fabian J Bolte
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Kazuyo Takeda
- Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Nana Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Zu-Xi Yu
- Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Heiyoung Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Kristin Valdez
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Marc G Ghany
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
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19
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Vijayan K, Wei L, Glennon EKK, Mattocks C, Bourgeois N, Staker B, Kaushansky A. Host-targeted Interventions as an Exciting Opportunity to Combat Malaria. Chem Rev 2021; 121:10452-10468. [PMID: 34197083 DOI: 10.1021/acs.chemrev.1c00062] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Terminal and benign diseases alike in adults, children, pregnant women, and others are successfully treated by pharmacological inhibitors that target human enzymes. Despite extensive global efforts to fight malaria, the disease continues to be a massive worldwide health burden, and new interventional strategies are needed. Current drugs and vector control strategies have contributed to the reduction in malaria deaths over the past 10 years, but progress toward eradication has waned in recent years. Resistance to antimalarial drugs is a substantial and growing problem. Moreover, targeting dormant forms of the malaria parasite Plasmodium vivax is only possible with two approved drugs, which are both contraindicated for individuals with glucose-6-phosphate dehydrogenase deficiency and in pregnant women. Plasmodium parasites are obligate intracellular parasites and thus have specific and absolute requirements of their hosts. Growing evidence has described these host necessities, paving the way for opportunities to pharmacologically target host factors to eliminate Plasmodium infection. Here, we describe progress in malaria research and adjacent fields and discuss key challenges that remain in implementing host-directed therapy against malaria.
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Affiliation(s)
| | - Ling Wei
- Seattle Children's Research Institute, Seattle, Washington 98109, United States
| | | | - Christa Mattocks
- Department of Global Health, University of Washington, Seattle, Washington 98195, United States
| | - Natasha Bourgeois
- Seattle Children's Research Institute, Seattle, Washington 98109, United States.,Department of Global Health, University of Washington, Seattle, Washington 98195, United States
| | - Bart Staker
- Seattle Children's Research Institute, Seattle, Washington 98109, United States
| | - Alexis Kaushansky
- Seattle Children's Research Institute, Seattle, Washington 98109, United States.,Department of Global Health, University of Washington, Seattle, Washington 98195, United States.,Department of Pediatrics, University of Washington, Seattle, Washington 98105, United States.,Brotman Baty Institute for Precision Medicine, Seattle, Washington 98195, United States
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20
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HCV Infection and Chronic Renal Disease. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2021-0010] [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
Abstract
Chronic Hepatitis C virus (HCV) infection is defined as persistence of HCV RNA in the blood for more than six months. HCV is a major cause of chronic liver disease and cirrhosis. It’s serious public health problem, affects about 71 million people worldwide. HCV doesn’t destroy hepatocytes directly. It activates the host's innate and acquired immune system and causes liver injury indirectly. Behind hepatic, HCV can cause extra-hepatic manifestations. One of them is renal disease which can lead to end-stage renal disease, ESRD. The prevalence of HCV infection in patients on hemodialysis is high, ranging from 5% to 60%. HCV infection is a significant cause of morbidity and mortality in patients with ESRD on hemodialysis. In this review, we discuss HCV infection and chronic renal disease as comorbidities, their severity and outcome.
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21
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Li X, Peng T. Strategy, Progress, and Challenges of Drug Repurposing for Efficient Antiviral Discovery. Front Pharmacol 2021; 12:660710. [PMID: 34017257 PMCID: PMC8129523 DOI: 10.3389/fphar.2021.660710] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/16/2021] [Indexed: 12/17/2022] Open
Abstract
Emerging or re-emerging viruses are still major threats to public health. Prophylactic vaccines represent the most effective way to prevent virus infection; however, antivirals are more promising for those viruses against which vaccines are not effective enough or contemporarily unavailable. Because of the slow pace of novel antiviral discovery, the high disuse rates, and the substantial cost, repurposing of the well-characterized therapeutics, either approved or under investigation, is becoming an attractive strategy to identify the new directions to treat virus infections. In this review, we described recent progress in identifying broad-spectrum antivirals through drug repurposing. We defined the two major categories of the repurposed antivirals, direct-acting repurposed antivirals (DARA) and host-targeting repurposed antivirals (HTRA). Under each category, we summarized repurposed antivirals with potential broad-spectrum activity against a variety of viruses and discussed the possible mechanisms of action. Finally, we proposed the potential investigative directions of drug repurposing.
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Affiliation(s)
- Xinlei Li
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, College of Basic Medicine, Guangzhou Medical University, Guangzhou, China
| | - Tao Peng
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, College of Basic Medicine, Guangzhou Medical University, Guangzhou, China
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22
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Rueschenbaum S, Cai C, Schmidt M, Schwarzkopf K, Dittmer U, Zeuzem S, Welsch C, Lange CM. Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity. Front Immunol 2021; 11:581352. [PMID: 33584648 PMCID: PMC7874116 DOI: 10.3389/fimmu.2020.581352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/30/2020] [Indexed: 12/18/2022] Open
Abstract
Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.
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Affiliation(s)
- Sabrina Rueschenbaum
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Chengcong Cai
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Matthias Schmidt
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | | | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stefan Zeuzem
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Christoph Welsch
- Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Christian M Lange
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
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23
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Mohan M, Bhattacharya D. Host-directed Therapy: A New Arsenal to Come. Comb Chem High Throughput Screen 2021; 24:59-70. [PMID: 32723230 DOI: 10.2174/1386207323999200728115857] [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: 01/07/2020] [Revised: 06/04/2020] [Accepted: 06/15/2020] [Indexed: 11/22/2022]
Abstract
The emergence of drug-resistant strains among the variety of pathogens worsens the situation in today's scenario. In such a situation, a very heavy demand for developing the new antibiotics has arisen, but unfortunately, very limited success has been achieved in this arena till now. Infectious diseases usually make their impression in the form of severe pathology. Intracellular pathogens use the host's cell machinery for their survival. They alter the gene expression of several host's pathways and endorse to shut down the cell's innate defense pathway like apoptosis and autophagy. Intracellular pathogens are co-evolved with hosts and have a striking ability to manipulate the host's factors. They also mimic the host molecules and secrete them to prevent the host's proper immune response against them for their survival. Intracellular pathogens in chronic diseases create excessive inflammation. This excessive inflammation manifests in pathology. Host directed therapy could be alternative medicine in this situation; it targets the host factors, and abrogates the replication and persistence of pathogens inside the cell. It also provokes the anti-microbial immune response against the pathogen and reduces the exacerbation by enhancing the healing process to the site of pathology. HDT targets the host's factor involved in a certain pathway that ultimately targets the pathogen life cycle and helps in eradication of the pathogen. In such a scenario, HDT could also play a significant role in the treatment of drugsensitive as well with drug resistance strains because it targets the host's factors, which favors the pathogen survival inside the cell.
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Affiliation(s)
- Mradul Mohan
- National Institute of Malaria Research, New Delhi, India
| | - Debapriya Bhattacharya
- Center for Biotechnology, School of Pharmaceutical Sciences, SOA Deemed University, Bhubaneswar, Odisha, India
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24
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Mizokami M, Liu LJ, Fujiyama N, Littman M, Yuan J, Sekiya T, Hedskog C, Ng LJ. Real-world safety and effectiveness of ledipasvir/sofosbuvir for the treatment of chronic hepatitis C virus genotype 1 in Japan. J Viral Hepat 2021; 28:129-141. [PMID: 32869924 DOI: 10.1111/jvh.13395] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 08/15/2020] [Accepted: 08/17/2020] [Indexed: 01/06/2023]
Abstract
As patients with chronic hepatitis C virus (HCV) tend to be older and/or have advanced liver disease in Japan, real-world data are needed to evaluate safe and effective treatment options. The study aim was to assess safety and effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in a real-world cohort of Japanese patients with HCV genotype (GT) 1 infection overall and by patient subgroups: elderly, compensated cirrhotic, advanced fibrotic and those with hepatocellular carcinoma (HCC). A large prospective observational study was conducted, enrolling adult patients treated for HCV GT1 infection with LDV/SOF at clinical sites across Japan. Patients were observed for safety outcomes during and 4 weeks after treatment, and for sustained virologic response at 12-weeks post-treatment (SVR12). Incidence rates (IRs) of adverse drug reactions (ADRs) and serious ADRs (SADRs) and SVR12 rates were assessed overall and by subgroups. ADR and SADR IRs were low (2.26 and 0.17 per 100 person-months, respectively) and did not significantly differ in elderly patients or those with presence of compensated cirrhosis, worsening fibrosis or HCC. SVR12 rates were high overall (98.5%) and across subgroups investigated (≥94%), including patients who were elderly (98.2%), treatment-experienced (97.6%), advanced fibrotic (≥95.8%), had existing NS5A resistance-associated substitutions reported pre-treatment (95.0%), compensated cirrhosis (95.7%), HCC (94.0%) and other chronic liver diseases (96.1%). In this large, real-world observational study of Japanese patients with HCV GT1 infection, LDV/SOF treatment resulted in low incidence of adverse events, with high real-world effectiveness, even among patients with potentially higher risks of adverse safety outcomes and treatment failure.
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Affiliation(s)
| | | | | | | | - Jason Yuan
- Gilead Sciences Inc., Foster City, CA, USA
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25
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Fox LE, Locke MC, Lenschow DJ. Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease. Front Immunol 2020; 11:606874. [PMID: 33408718 PMCID: PMC7779635 DOI: 10.3389/fimmu.2020.606874] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/11/2020] [Indexed: 12/15/2022] Open
Abstract
Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In this review, we summarize some of the mechanisms underlying differential expression of and signaling by type I IFNs, and we discuss examples of differential functions of IFNα and IFNβ in models of infectious disease, cancer, and autoimmunity.
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Affiliation(s)
- Lindsey E. Fox
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
| | - Marissa C. Locke
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
| | - Deborah J. Lenschow
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
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26
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Virzì A, Roca Suarez AA, Lupberger J. Interferon revisited: Peering behind the lines of antiviral defense. J Hepatol 2020; 73:496-498. [PMID: 32660730 PMCID: PMC7351677 DOI: 10.1016/j.jhep.2020.05.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 05/19/2020] [Indexed: 12/04/2022]
Affiliation(s)
- Alessia Virzì
- Université de Strasbourg, F-67000, France,Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), Strasbourg, F-67000, France
| | - Armando Andres Roca Suarez
- Université de Strasbourg, F-67000, France,Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), Strasbourg, F-67000, France
| | - Joachim Lupberger
- Université de Strasbourg, F-67000, France; Institut National de la Santé et de la Recherche Médicale, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg (IVH), Strasbourg, F-67000, France.
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27
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Structurally distinct cyclosporin and sanglifehrin analogs CRV431 and NV556 suppress established HCV infection in humanized-liver mice. PLoS One 2020; 15:e0237236. [PMID: 32764799 PMCID: PMC7413547 DOI: 10.1371/journal.pone.0237236] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023] Open
Abstract
We previously reported that the non-immunosuppressive cyclophilin inhibitors (CypIs)—cyclosporin A analog CRV431 and sanglifehrin analog NV556—efficiently inhibit HCV replication in vitro. In this study, we asked whether they can also reduce HCV replication in vivo. We found that a single oral administration of CRV431 and NV556 to HCV-infected humanized-liver mice drastically reduced HCV blood levels. The antiviral effect was observed when CRV431 or NV556 were each individually administered with HCV, 3, 6 weeks or even 3 months post-infection when viral replication is robust. These results were confirmed in chimeric mice implanted with human hepatocytes isolated from three distinct donors. Remarkably, no viral rebound was observed 5 months after a single dose administration of 50 mg/kg of CRV431 or NV556 four weeks post-HCV infection, indicating the possibility of suppression of an established viral infection. Since we recently demonstrated that both CRV431 and NV556 also inhibit the development of liver fibrosis and hepatocellular carcinoma in nonviral-induced non-alcoholic steatohepatitis mouse models, our present data suggest that the two entirely structurally different CypIs—CRV431 and NV556—derived from unrelated natural products, represent attractive partners to current direct-acting agent (DAA) regimens for the treatment of hepatitis C and liver diseases.
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28
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Winston A, Wurcel AG, Gordon C, Goyal N. Viral hepatitis in patients on hemodialysis. Semin Dial 2020; 33:254-262. [PMID: 32394502 DOI: 10.1111/sdi.12882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatitis B and hepatitis C (HCV) prevalence are higher in people on hemodialysis (HD) than the general population. Through implementation of prevention interventions including vaccines, serologic screening, and post-exposure management, transmissions linked to HD have decreased dramatically. In this manuscript, we review epidemiology of viral hepatitis, summarize current screening and vaccine recommendations, and appraise the available data about efforts to decrease incidence within HD facilities, including isolation of people with viral hepatitis within HD units. Also included is a discussion of the highly effective all-oral HCV treatment options and treatment for HCV in people awaiting kidney transplant.
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Affiliation(s)
- Anna Winston
- Tufts University School of Medicine, Boston, Massachusetts
| | - Alysse G Wurcel
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts
| | - Craig Gordon
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Nitender Goyal
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
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29
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Li X, Li J, Feng Y, Cai H, Li YP, Peng T. Long-chain fatty acyl-coenzyme A suppresses hepatitis C virus infection by targeting virion-bound lipoproteins. Antiviral Res 2020; 177:104734. [PMID: 32057770 DOI: 10.1016/j.antiviral.2020.104734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 12/18/2019] [Accepted: 02/03/2020] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and end-stage liver diseases. Mature HCV virions are bound by host-derived lipoproteins. Lack of an HCV vaccine warrants a major role of antiviral treatment in the global elimination of hepatitis C. Although direct-acting antivirals (DAAs) are replacing the interferon-based treatment and have dramatically improved the cure rate, the presence of viral variants resistant to DAAs, HCV genotype/subtype-specific efficacy, and high cost of DAAs argue novel and affordable regimens. In this study, we identified the antiviral effects of long-chain fatty acyl-coenzyme A (LCFA-CoA) against the infections of HCV genotypes 1-6 through targeting mature HCV-bound lipoproteins, suggesting novel mechanism(s) of antiviral different from those used by host-targeting agents or DAAs. We found that the antiviral activity of LCFA-CoA relied on the long-chain saturated fatty acid and the CoA group, and was enhanced when combined with pegylated-interferon or DAAs. Importantly, we demonstrated that LCFA-CoA efficiently inhibited the infection of HCV variants carrying DAA-resistant mutations. The mechanistic study revealed that LCFA-CoA specifically abolished the attachment and binding steps and also inhibited the cell-to-cell viral transmission. LCFA-CoA targeted mature HCV-bound lipoproteins, but not apolipoproteins B or E. In addition, LCFA-CoA could also inhibit the infection of the dengue virus. Our findings suggest that LCFA-CoA could potentially serve as a supplement HCV therapy, particularly for the DAA-resistant HCV variants. Taken together, LCFA-CoA may be further developed to be a novel class of antivirals with mechanism(s), different from host-targeting agents or DAAs, of targeting the components associated with mature HCV virions.
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Affiliation(s)
- Xinlei Li
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Jinqian Li
- Institute of Human Virology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yetong Feng
- Institute of Human Virology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hua Cai
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Yi-Ping Li
- Institute of Human Virology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Tao Peng
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China.
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30
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Han J, Lee HW, Jin Y, Khadka DB, Yang S, Li X, Kim M, Cho WJ. Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment. Eur J Med Chem 2020; 188:112031. [PMID: 31923861 DOI: 10.1016/j.ejmech.2019.112031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 12/20/2019] [Accepted: 12/31/2019] [Indexed: 12/25/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 μM, but no cytotoxicity at 100 μM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a KD of 3.66 μM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinational therapy in the future.
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Affiliation(s)
- Jinhe Han
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Hye Won Lee
- Virus Research Group, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea
| | - Yifeng Jin
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Daulat B Khadka
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Suhui Yang
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Xiaoli Li
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Meehyein Kim
- Virus Research Group, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
| | - Won-Jea Cho
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea.
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31
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Can Direct-Acting Antiviral Treatment Change the Immunologic Risk Profile in Patients Infected with Hepatitis C Virus Who Are on the Cadaveric Waiting List? Transplant Proc 2020; 52:97-101. [PMID: 31901328 DOI: 10.1016/j.transproceed.2019.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/11/2019] [Accepted: 10/06/2019] [Indexed: 12/09/2022]
Abstract
BACKGROUND In patients with hepatitis C virus (HCV) infection, the activation of the immune system by the virus or viral proteins leads to the production of numerous autoantibodies and clinical manifestations. The objectives of this study were to investigate the relationship between HCV and anti-HLA antibodies, as well as the effect of viremia on the antibody response and of direct-acting antivirals (DAAs) on anti-HLA antibody persistence in patients on the waiting list for a cadaveric kidney transplant. METHODS A total of 395 patients from the cadaveric renal transplant waiting list were included in the study. The patients were grouped according to the presence of HCV infection, and patients with HCV positivity were further divided into a spontaneous clearance group and a persistent group. Anti-HLA antibodies were examined before and after treatment of the patients in the persistent group. The One Lambda Luminex method (Thermo Fisher Scientific, Waltham, MA, United States) was used to assess both HLA class I and II alleles and the anti-HLA antibody profile. RESULTS Anti-HLA class I and II antibodies were detected in 48.2% and 55.1%, respectively, of the patients infected with HCV and in 21.8% and 20.4%, respectively, of the patients who were not infected. The level of anti-HLA A3, A11, B72, B52, Cw6, Cw16, DR3, and DQ4 antibodies was significantly higher in the patients infected with HCV. There was no statistically significant difference in class I and II antibody titration between the HCV-infected spontaneous clearance group and the persistent group (class I mean fluorescence intensity [MFI] ± SD: 13,583 ± 6224, 13,450 ± 9540, P = .808; Class II MFI ± SD: 13,000 ± 8673, 8440 ± 8302, P = .317, respectively). There was no significant difference in the class I and class II anti-HLA antibody profile and titration in the persistent group after treatment with DAAs (P > .05). CONCLUSIONS The results of this study demonstrated that hepatitis C DAA treatment did not change the anti-HLA antibody profile and titration.
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Hung HC, Liao HH, Chen SC, Tsao SM, Lee YT. Maintenance interferon therapy in chronic hepatitis C patients who failed initial antiviral therapy: A meta-analysis. Medicine (Baltimore) 2019; 98:e15563. [PMID: 31083223 PMCID: PMC6531240 DOI: 10.1097/md.0000000000015563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVES To evaluate the effect of pegylated interferon maintenance therapy in patients with chronic hepatitis C who failed initial antiviral therapy. METHODS This is a meta-analysis of 6 randomized controlled trials that met the eligibility criteria. In all, 2438 chronic hepatitis C patients who failed to achieve sustained virologic response after initial treatment with pegylated interferon and ribavirin (antiviral therapy nonresponders or relapsers) were enrolled; 1237 patients received maintenance therapy (Maintenance group) and 1201 received no treatment (Observation group). RESULTS The pooled analyses found that patients in the Maintenance group had a significantly higher rate of normal alanine aminotransferase than did patients in the Observation group (pooled odds ratio [OR] 4.436, 95% confidence interval [CI] 1.225-16.064, P = .023), but there was no significant difference between the 2 groups in the incidence of hepatocellular carcinoma (pooled OR 0.872, 95% CI 0.501-1.519, P = .630), or the mortality rate (pooled OR 1.564, 95% CI 0.807-3.032, P = .185). CONCLUSIONS Interferon-based maintenance therapy in patients with chronic hepatitis C who failed initial antiviral therapy improved liver inflammation as indicated by blood chemistry (alanine aminotransferase).
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Affiliation(s)
- Hung-Chang Hung
- Division of Gastroenterology, Department of Internal Medicine, Nantou Hospital, Ministry of Health and Welfare, Nantou
- Department of Healthcare Administration, Central Taiwan University of Science and Technology
| | - Hsien-Hua Liao
- School of Medicine, Chung Shan Medical University
- Department of Plastic Surgery
| | - Shiuan-Chih Chen
- School of Medicine, Chung Shan Medical University
- Department of Family and Community Medicine
| | - Shih-Ming Tsao
- School of Medicine, Chung Shan Medical University
- Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
| | - Yuan-Ti Lee
- School of Medicine, Chung Shan Medical University
- Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
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Lazear HM, Schoggins JW, Diamond MS. Shared and Distinct Functions of Type I and Type III Interferons. Immunity 2019; 50:907-923. [PMID: 30995506 PMCID: PMC6839410 DOI: 10.1016/j.immuni.2019.03.025] [Citation(s) in RCA: 755] [Impact Index Per Article: 125.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 12/12/2022]
Abstract
Type I interferons (IFNs) (IFN-α, IFN-β) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease.
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Affiliation(s)
- Helen M Lazear
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - John W Schoggins
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Michael S Diamond
- Departments of Medicine, Pathology & Immunology, and Molecular Microbiology, and The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA.
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Tsai FJ, Cheng CF, Chen CJ, Lin CY, Wu YF, Li TM, Chuang PH, Wu YC, Lai CH, Liu X, Tsang H, Lin TH, Liao CC, Huang SM, Li JP, Lin JC, Lin CC, Liang WM, Lin YJ. Effects of Chinese herbal medicine therapy on survival and hepatic outcomes in patients with hepatitis C virus infection in Taiwan. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 57:30-38. [PMID: 30668320 DOI: 10.1016/j.phymed.2018.09.237] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/25/2018] [Accepted: 09/29/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Chinese herbal medicine (CHM) is a complementary natural medicine that is used widely for the treatment of hepatic diseases. The aim of this study was to investigate the effects of the long-term use of CHM for the treatment of liver diseases, as prescribed by TCM doctors, on overall mortality and hepatic outcomes in patients with HCV. PATIENTS AND METHODS We identified 98788 patients with HCV. Of these, 829 and 829 patients who were users and non-users of CHM, respectively, were matched for age, gender, CCI, and comorbidities prior to CHM treatment. The chi-squared test, Cox proportional hazard model, Kaplan--Meier method, and log-rank test were used for comparisons. RESULTS CHM users had a lower risk of overall mortality than non-users after adjustment for comorbidities by using a multivariate Cox proportional hazard model (p-value < 0.001; HR: 0.12, 95% CI: 0.06-0.26). In addition,the CHM users had a lower risk of liver cirrhosis than non-users after adjustment for comorbidities (p-value = 0.028; HR: 0.29, 95% CI: 0.09-0.88). The 12-year cumulative incidences of overall mortality and liver cirrhosis were lower in the CHM group (p-value < 0.05 for both, log rank test). The CHM co-prescription for Dan-Shen, Bie-Jia, Jia-Wei-Xiao-Yao-San => E-Shu was found to occur most often associated for the specific treatment of HCV infection. CONCLUSION CHM as adjunctive therapy may reduce the overall mortality and the risk of liver cirrhosis in patients with HCV. The comprehensive list of the herbal medicines that may be used for the treatment of patients with HCV may be useful in future scientific investigations or for future therapeutic interventions to prevent negative hepatic outcomes in patients with HCV.
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Affiliation(s)
- Fuu-Jen Tsai
- School of Chinese Medicine, China Medical University, Taichung, Taiwan; Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Asia University, Taichung, Taiwan
| | - Chi-Fung Cheng
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan
| | - Chao-Jung Chen
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Chih-Ying Lin
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan
| | - Yi-Fang Wu
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Te-Mao Li
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Hepato-gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yang-Chang Wu
- Graduate Institute of Natural Products and Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Ho Lai
- Department of Microbiology and Immunology, Molecular Infectious Disease Research Center, Chang Gung University and Memorial Hospital, Taoyuan, Taiwan
| | - Xiang Liu
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Hsinyi Tsang
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Ting-Hsu Lin
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chiu-Chu Liao
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Shao-Mei Huang
- Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Ju-Pi Li
- School of Chinese Medicine, China Medical University, Taichung, Taiwan; Rheumatism Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Jung-Chun Lin
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Chih-Chien Lin
- Department of Cosmetic Science, Providence University, Taichung, Taiwan
| | - Wen-Miin Liang
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan.
| | - Ying-Ju Lin
- School of Chinese Medicine, China Medical University, Taichung, Taiwan; Genetic Center, Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
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Luna JM, Saeed M, Rice CM. Taming a beast: lessons from the domestication of hepatitis C virus. Curr Opin Virol 2019; 35:27-34. [PMID: 30875640 PMCID: PMC6556422 DOI: 10.1016/j.coviro.2019.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/05/2019] [Accepted: 02/12/2019] [Indexed: 12/13/2022]
Abstract
"What I cannot create, I do not understand." Richard Feynman may have championed reasoning from first principles in his famous blackboard missive, but he could just as well have been referring to the plight of a molecular virologist. What cannot be grown in a controlled laboratory setting, we cannot fully understand. The story of the laboratory domestication of hepatitis C virus (HCV) is now a classic example of virologists applying all manner of inventive skill to create cell-based models of infection in order to clarify prospective drug targets. In this review, we highlight key successes and failures that were instructive in achieving cell-based models for HCV studies and drug development. We also emphasize the lessons learned from the ∼40 year saga that may be applicable to viruses yet unknown and uncultured.
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Affiliation(s)
- Joseph M Luna
- The Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States
| | - Mohsan Saeed
- The Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States
| | - Charles M Rice
- The Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States.
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Kalra P, Brandl J, Gaub T, Niederalt C, Lippert J, Sahle S, Küpfer L, Kummer U. Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach. PLoS One 2019; 14:e0209587. [PMID: 30759154 PMCID: PMC6374012 DOI: 10.1371/journal.pone.0209587] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 12/08/2018] [Indexed: 12/26/2022] Open
Abstract
The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design.
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Affiliation(s)
- Priyata Kalra
- Department of Modelling of Biological Processes, COS/BioQuant, Heidelberg University, Im Neuenheimer Feld 267, Heidelberg, Germany
| | - Julian Brandl
- Department of Modelling of Biological Processes, COS/BioQuant, Heidelberg University, Im Neuenheimer Feld 267, Heidelberg, Germany
- Now at Department of Systems Biology, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Thomas Gaub
- Clinical Sciences, Bayer Pharma, Kaiser-Wilhelm-Allee 1, Leverkusen, Germany
| | - Christoph Niederalt
- Clinical Sciences, Bayer Pharma, Kaiser-Wilhelm-Allee 1, Leverkusen, Germany
| | - Jörg Lippert
- Clinical Sciences, Bayer Pharma, Kaiser-Wilhelm-Allee 1, Leverkusen, Germany
| | - Sven Sahle
- Department of Modelling of Biological Processes, COS/BioQuant, Heidelberg University, Im Neuenheimer Feld 267, Heidelberg, Germany
| | - Lars Küpfer
- Clinical Sciences, Bayer Pharma, Kaiser-Wilhelm-Allee 1, Leverkusen, Germany
| | - Ursula Kummer
- Department of Modelling of Biological Processes, COS/BioQuant, Heidelberg University, Im Neuenheimer Feld 267, Heidelberg, Germany
- * E-mail:
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Sghaier I, Brochot E, Loueslati BY, Almawi WY. Hepatitis C virus protein interaction network for HCV clearance and association of DAA to HCC occurrence via data mining approach: A systematic review and critical analysis. Rev Med Virol 2019; 29:e2033. [PMID: 30614131 DOI: 10.1002/rmv.2033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 12/23/2022]
Abstract
HCV has been associated with a pro-inflammatory state, which predisposes to hepatocellular carcinoma (HCC). However, the different molecular mechanisms underlying the effect of HCV infection on HCC progression remain unclear. Although HCV infection illustrates the potential role of host genetics in the outcome of infectious diseases, there is no clear overview of some single nucleotide polymorphisms (SNPs) influencing spontaneous or treatment-induced HCV eradication. We studied the possible role of HCV infection in the processes of HCC initiation and performed a systematic analysis using data mining approaches to identify host polymorphisms associated with treatment response and HCC development using topological analysis of protein-proteins interactions (PPI) networks. On the basis of our analysis performed, we identified key hub proteins related to HCV-treatment response infection and to HCC development. Host genetic polymorphisms, such as inosine triphosphatase (ITPA), interferon, lambda 3 (IFNL3), Q5 interferon, lambda 4 (IFNL4), toll-like receptors (TLRs) and interferon-stimulated gene 15 (ISG-15), were identified as key genes for treatment prediction and HCC evolution. By comparing unique genes for HCV-treatment response and genes particular to HCV-HCC development, we found a common PPI network that may participate in more extensive signalling processes during anti-HCV treatment, which can play important roles in modulating the immune response to the occurrence of HCC. Data mining is an effective tool for identifying potential regulatory pathways involved in treatment response and HCC development. Our study may contribute to a better understanding of HCV immunopathogenesis and highlights the complex role of host genetics in HCV clearance.
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Affiliation(s)
- Ikram Sghaier
- University of Tunis El Manar, Biology department, Tunish, Tunisia
| | - Etienne Brochot
- Department of Virology, Amiens University Medical Centre, Amiens, France.,Virology Research Unit, EA 4294, Jules Verne University of Picardie, Amiens, France
| | - Besma Y Loueslati
- Faculty of Sciences of Tunis, department of Biology, Laboratory of Mycology, Pathologies and Biomarkers, Tunis, Tunisia
| | - Wassim Y Almawi
- University of Tunis El Manar, Biology department, Tunish, Tunisia.,School of Medicine, Nazarbayev University, Astana, Kazakhstan
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Wu X, Dao Thi VL. Embryonic or Induced Pluripotent Stem Cell-Derived Hepatocellular Systems for HCV Culture. Methods Mol Biol 2019; 1911:121-135. [PMID: 30593622 DOI: 10.1007/978-1-4939-8976-8_8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human-induced pluripotent stem cell-derived hepatocyte-like cells (iHeps) constitute a powerful tool for modeling hepatotropic pathogen infections in cell culture. Meanwhile, CRISPR-Cas9 technology enables precise editing of stem cell genomes to generate patient-specific disease models and thus development of personalized experimental systems. Here we present a detailed stepwise protocol for the differentiation of stem cells to hepatocyte-like cells for HCV studies in cell culture. We also outline the use of an inducible iCRISPR platform for the rapid and efficient modification of host factors of interest to better understand their function during HCV infection.
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Affiliation(s)
- Xianfang Wu
- Laboratory of Virology and Infectious Diseases, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, USA.
| | - Viet Loan Dao Thi
- Center for Integrative Infectious Disease Research, University Hospital Heidelberg, Heidelberg, Germany. .,Laboratory of Virology and Infectious Diseases, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, USA.
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Rehermann B, Thimme R. Insights From Antiviral Therapy Into Immune Responses to Hepatitis B and C Virus Infection. Gastroenterology 2019; 156:369-383. [PMID: 30267712 PMCID: PMC6340757 DOI: 10.1053/j.gastro.2018.08.061] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/05/2018] [Accepted: 08/21/2018] [Indexed: 12/17/2022]
Abstract
There are 257 million persons worldwide with chronic hepatitis B virus (HBV) infection, a leading causes of liver cancer. Almost all adults with acute HBV infection have a rapid immune response to the virus, resulting in life-long immunity, but there is no cure for individuals with chronic HBV infection, which they acquire during early life. The mechanisms that drive the progression of HBV through distinct clinical phases to end-stage liver disease are poorly understood. Likewise, it is not clear whether and how immune responses can be modulated to allow control and/or clearance of intrahepatic HBV DNA. We review the innate and adaptive immune responses to acute and chronic HBV infections and responses to antiviral therapy. Comparisons with hepatitis C virus infection provide insights into the reversibility of innate inflammatory responses and the potential for successful therapy to recover virus-specific memory immune responses.
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Affiliation(s)
- Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
| | - Robert Thimme
- Klinik für Innere Medizin II, University Hospital Freiburg, Faculty of Medicine, Hugstetter Straße 55, 79106 Freiburg, Germany
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Manjula S, Sivanandam M, Kumaradhas P. Probing the "fingers" domain binding pocket of Hepatitis C virus NS5B RdRp and D559G resistance mutation via molecular docking, molecular dynamics simulation and binding free energy calculations. J Biomol Struct Dyn 2018; 37:2440-2456. [PMID: 30047829 DOI: 10.1080/07391102.2018.1491419] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The NS5B RdRp polymerase is a prominent enzyme for the replication of Hepatitis C virus (HCV). During the HCV replication, the template RNA binding takes place in the "fingers" sub-domain of NS5B. The "fingers" domain is a new emerging allosteric site for the HCV drug development. The inhibitors of the "fingers" sub-domain adopt a new antiviral mechanism called RNA intervention. The details of essential amino acid residues, binding mode of the ligand, and the active site intermolecular interactions of RNA intervention reflect that this mechanism is ambiguous in the experimental study. To elucidate these details, we performed molecular docking analysis of the fingers domain inhibitor quercetagetin (QGN) with NS5B polymerase. The detailed analysis of QGN-NS5B intermolecular interactions was carried out and found that QGN interacts with the binding pocket amino acid residues Ala97, Ala140, Ile160, Phe162, Gly283, Gly557, and Asp559; and also forms π⋯π stacking interaction with Phe162 and hydrogen bonding interaction with Gly283. These are found to be the essential interactions for the RNA intervention mechanism. Among the strong hydrogen bonding interactions, the QGN⋯Ala140 is a newly identified important hydrogen bonding interaction by the present work and this interaction was not resolved by the previously reported crystal structure. Since D559G mutation at the fingers domain was reported for reducing the inhibition percentage of QGN to sevenfold, we carried out molecular dynamics (MD) simulation for wild and D559G mutated complexes to study the stability of protein conformation and intermolecular interactions. At the end of 50 ns MD simulation, the π⋯π stacking interaction of Phe162 with QGN found in the wild-type complex is altered into T-shaped π stacking interaction, which reduces the inhibition strength. The origin of the D559G resistance mutation was studied using combined MD simulation, binding free energy calculations and principal component analysis. The results were compared with the wild-type complex. The mutation D559G reduces the binding affinity of the QGN molecule to the fingers domain. The free energy decomposition analysis of each residue of wild-type and mutated complexes revealed that the loss of non-polar energy contribution is the origin of the resistance. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Saravanan Manjula
- a Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics , Periyar University , Salem , India
| | - Magudeeswaran Sivanandam
- a Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics , Periyar University , Salem , India
| | - Poomani Kumaradhas
- a Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics , Periyar University , Salem , India
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Johansson A, Nyberg WA, Sjöstrand M, Moruzzi N, Bergman P, Khademi M, Andersson M, Piehl F, Berggren PO, Covacu R, Jagodic M, Espinosa A. miR-31 regulates energy metabolism and is suppressed in T cells from patients with Sjögren's syndrome. Eur J Immunol 2018; 49:313-322. [PMID: 30307034 DOI: 10.1002/eji.201747416] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 09/24/2018] [Accepted: 10/09/2018] [Indexed: 01/14/2023]
Abstract
Systemic autoimmune diseases are characterized by the overexpression of type I IFN stimulated genes, and accumulating evidence indicate a role for type I IFNs in these diseases. However, the underlying mechanisms for this are still poorly understood. To explore the role of type I IFN regulated miRNAs in systemic autoimmune disease, we characterized cellular expression of miRNAs during both acute and chronic type I IFN responses. We identified a T cell-specific reduction of miR-31-5p levels, both after intramuscular injection of IFNβ and in patients with Sjögren's syndrome (SjS). To interrogate the role of miR-31-51p in T cells we transfected human CD4+ T cells with a miR-31-5p inhibitor and performed metabolic measurements. This identified an increase in basal levels of glucose metabolism after inhibition of miR-31-5p. Furthermore, treatment with IFN-α also increased the basal levels of human CD4+ T-cell metabolism. In all, our results suggest that reduced levels of miR-31-5p in T cells of SjS patients support autoimmune T-cell responses during chronic type I IFN exposure.
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Affiliation(s)
- Alina Johansson
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
| | - William A Nyberg
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
| | - Maria Sjöstrand
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
| | - Noah Moruzzi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Petra Bergman
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Mohsen Khademi
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Magnus Andersson
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Division of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Fredrik Piehl
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Division of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ruxandra Covacu
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Maja Jagodic
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Alexander Espinosa
- Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine Karolinska University Hospital, Stockholm, Sweden
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Pradat P, Virlogeux V, Trépo E. Epidemiology and Elimination of HCV-Related Liver Disease. Viruses 2018; 10:E545. [PMID: 30301201 PMCID: PMC6213504 DOI: 10.3390/v10100545] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/01/2018] [Accepted: 10/03/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection, defined by active carriage of HCV RNA, affects nearly 1.0% of the worldwide population. The main risk factors include unsafe injection drug use and iatrogenic infections. Chronic HCV infection can promote liver damage, cirrhosis and hepatocellular carcinoma (HCC) in affected individuals. The advent of new second-generation, direct-acting antiviral (DAA) agents allow a virological cure in more than 90% of treated patients, and therefore prevent HCV-related complications. Recently, concerns have been raised regarding the safety of DAA-regimens in cirrhotic patients with respect to the occurrence and the recurrence of HCC. Here, we review the current available data on HCV epidemiology, the beneficial effects of therapy, and discuss the recent controversy with respect to the potential link with liver cancer. We also highlight the challenges that have to be overcome to achieve the ambitious World Health Organization objective of HCV eradication by 2030.
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Affiliation(s)
- Pierre Pradat
- Centre for Clinical Research, Groupement Hospitalier Nord, Hospices Civils de Lyon, 69004 Lyon, France.
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.
- Lyon University, Lyon, France.
| | - Victor Virlogeux
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.
- Lyon University, Lyon, France.
- Department of Hepatology, Croix-Rousse Hospital, Hospices Civils de Lyon, 69004 Lyon, France.
| | - Eric Trépo
- Liver Unit, Department of Gastroenterology and Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, 1070 Bruxelles, Belgium.
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Bruxelles, Belgium.
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Andrade E, Rocha D, Fontana-Maurell M, Costa E, Ribeiro M, de Godoy DT, Ferreira AGP, Tanuri A, Alvarez P, Brindeiro R. One-step real-time PCR assay for detection and quantification of RNA HCV to monitor patients under treatment in Brazil. Braz J Infect Dis 2018; 22:418-423. [PMID: 30243981 PMCID: PMC9427815 DOI: 10.1016/j.bjid.2018.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/25/2018] [Accepted: 08/16/2018] [Indexed: 12/24/2022] Open
Abstract
The Brazilian Public Health Service provides freely αPEG-IFN to treat patients infected with HCV. The primary goal of HCV therapy is the long-term elimination of HCV from the blood to reduce the risk of HCV associated complications and death. Patient viremia affects the treatment duration and response, thus influencing clinical decisions. We developed a high-throughput method to perform the quantification of RNA hepatitis C virus (HCV) virus load in plasma samples to monitor patients under treatment. The method is based on a duplex detection, in a one-step real-time RT-PCR assay and it has been validated according to the rules established by the official Brazilian regulatory agency (ANVISA). This new method was compared to a commercial kit (Cobas/Taqman HCV Test v2.0 - Roche), showing virus load results with significant correlation between them (p = 0,012) using commercial and clinical panels. In addition, 611 samples from patients treated with peguilated alfa-interferon (αPEG-IFN) from different regions of Brazil were analyzed. Our one-step real-time RT-PCR assay demonstrated good performance in viral load measurement and in treatment course monitoring, with acceptable sensitivity and specificity values.
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Affiliation(s)
- Elisabete Andrade
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil; Federal University of Rio de Janeiro - UFRJ, Brazil
| | - Daniele Rocha
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil
| | - Marcela Fontana-Maurell
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil
| | - Elaine Costa
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil
| | - Marisa Ribeiro
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil
| | - Daniela Tupy de Godoy
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil
| | - Antonio G P Ferreira
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil
| | | | - Patrícia Alvarez
- Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/ Fiocruz, Rio de Janeiro, Brazil.
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Salvadori M, Tsalouchos A. Hepatitis C and renal transplantation in era of new antiviral agents. World J Transplant 2018; 8:84-96. [PMID: 30148074 PMCID: PMC6107518 DOI: 10.5500/wjt.v8.i4.84] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/17/2018] [Accepted: 05/30/2018] [Indexed: 02/05/2023] Open
Abstract
Data from World Health Organization estimates that the hepatitis C virus (HCV) prevalence is 3% and approximately 71 million persons are infected worldwide. HCV infection is particularly frequent among patients affected by renal diseases and among those in dialysis treatment. In addition to produce a higher rate of any cause of death, HCV in renal patients and in renal transplanted patients produce a deterioration of liver disease and is a recognized cause of transplant glomerulopathy, new onset diabetes mellitus and lymphoproliferative disorders. Treatment of HCV infection with interferon alpha and/or ribavirin had a poor efficacy. The treatment was toxic, expensive and with limited efficacy. In the post-transplant period was also cause of severe humoral rejection. In this review we have highlighted the new direct antiviral agents that have revolutionized the treatment of HCV both in the general population and in the renal patients. Patients on dialysis or with low glomerular filtration rate were particularly resistant to the old therapies, while the direct antiviral agents allowed achieving a sustained viral response in 90%-100% of patients with a short period of treatment. This fact to date allows HCV patients to enter the waiting list for transplantation easier than before. These new agents may be also used in renal transplant patients HCV-positive without relevant clinical risks and achieving a sustained viral response in almost all patients. New drug appears in the pipeline with increased profile of efficacy and safety. These drugs are now the object of several phases II, III clinical trials.
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Affiliation(s)
- Maurizio Salvadori
- Department of Transplantation Renal Unit, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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45
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Zitzmann C, Kaderali L. Mathematical Analysis of Viral Replication Dynamics and Antiviral Treatment Strategies: From Basic Models to Age-Based Multi-Scale Modeling. Front Microbiol 2018; 9:1546. [PMID: 30050523 PMCID: PMC6050366 DOI: 10.3389/fmicb.2018.01546] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/21/2018] [Indexed: 12/14/2022] Open
Abstract
Viral infectious diseases are a global health concern, as is evident by recent outbreaks of the middle east respiratory syndrome, Ebola virus disease, and re-emerging zika, dengue, and chikungunya fevers. Viral epidemics are a socio-economic burden that causes short- and long-term costs for disease diagnosis and treatment as well as a loss in productivity by absenteeism. These outbreaks and their socio-economic costs underline the necessity for a precise analysis of virus-host interactions, which would help to understand disease mechanisms and to develop therapeutic interventions. The combination of quantitative measurements and dynamic mathematical modeling has increased our understanding of the within-host infection dynamics and has led to important insights into viral pathogenesis, transmission, and disease progression. Furthermore, virus-host models helped to identify drug targets, to predict the treatment duration to achieve cure, and to reduce treatment costs. In this article, we review important achievements made by mathematical modeling of viral kinetics on the extracellular, intracellular, and multi-scale level for Human Immunodeficiency Virus, Hepatitis C Virus, Influenza A Virus, Ebola Virus, Dengue Virus, and Zika Virus. Herein, we focus on basic mathematical models on the population scale (so-called target cell-limited models), detailed models regarding the most important steps in the viral life cycle, and the combination of both. For this purpose, we review how mathematical modeling of viral dynamics helped to understand the virus-host interactions and disease progression or clearance. Additionally, we review different types and effects of therapeutic strategies and how mathematical modeling has been used to predict new treatment regimens.
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Affiliation(s)
- Carolin Zitzmann
- Institute of Bioinformatics and Center for Functional Genomics of Microbes, University Medicine Greifswald, Greifswald, Germany
| | - Lars Kaderali
- Institute of Bioinformatics and Center for Functional Genomics of Microbes, University Medicine Greifswald, Greifswald, Germany
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Lanini S, Scognamiglio P, Mecozzi A, Lombardozzi L, Vullo V, Angelico M, Gasbarrini A, Taliani G, Attili AF, Perno CF, De Santis A, Puro V, Cerqua F, D’Offizi G, Pellicelli A, Armignacco O, Mennini FS, Siciliano M, Girardi E, Panella V, Ippolito G. Impact of new DAA therapy on real clinical practice: a multicenter region-wide cohort study. BMC Infect Dis 2018; 18:223. [PMID: 29769038 PMCID: PMC5956792 DOI: 10.1186/s12879-018-3125-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 04/30/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Management of chronic hepatitis C (CHC) has significantly accelerated in the last few years. Currently, second generation direct acting antivirals (DAAs) promise clearance of infection in most of patients. Here we present the results of the first analysis carried out on data of Lazio clinical network for DAAs. METHODS The study was designed as a multicenter cohort: a) to assess the evolution of treatment during the first 24 months of the activity of the Clinical Network; b) to report overall efficacy of treatments; c) to analyze potential factors associated with lack of virological response at 12 weeks after therapy (SVR12); d) to evaluate the variation of ALT at baseline and 12 weeks after therapy in those who achieved SVR12 in comparison to those who did not. Analyses of efficacy were carried out with multilevel mixed effect logistic regression model. ALT temporal variation was assessed by mixed effect model mixed models with random intercept at patient's level and random slope at the level of the time; i.e. either before or after therapy. RESULTS Between 30 December 2014 and 31 December 2016 5279 patients started a DAA treatment; of those, 5127 (in 14 clinical centers) had completed the 12-week follow-up. Overall proportion of SVR12 was 93.41% (N = 4780) with no heterogeneity between the 14 clinical centers. Interruption as the consequence of severe side effect was very low (only 23 patients). Unadjusted analysis indicates that proportion of SVR12 significantly changes according to patient's baseline characteristics, however after adjusting for potential confounders only adherence to current guidelines, stage of liver diseases, gender, transplant and HIV status were independently associated with the response to therapy. Analysis of ALT temporal variation showed that ALT level normalized in most, but not, all patients who achieved SVR12. CONCLUSION Our study confirmed the extraordinary efficacy of DAAs outside clinical trials. The advantage of DAAs was particularly significant for those patients who were previously considered as difficult-to-treat and did not have treatment options before DAAs era. Intervention based on network of select centers and prioritization of patients according to diseases severity was successful. Further studies are needed to establish whether clearance of HCV after DAAs therapy can arrest or even revert liver fibrosis in non-cirrhotic patients and/or improve life quality and expectancy in those who achieve SVR12 with cirrhosis.
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Affiliation(s)
- Simone Lanini
- National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
- Servizio Regionale per la Sorveglianza delle Malattie infettive (SeRESMI), Rome, Italy
| | - Paola Scognamiglio
- National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
- Servizio Regionale per la Sorveglianza delle Malattie infettive (SeRESMI), Rome, Italy
| | - Alessandra Mecozzi
- Regione Lazio Direzione Regionale Salute e Politiche Sociali, Rome, Italy
| | | | - Vincenzo Vullo
- Dipartimento di Sanità Pubblica e Malattie Infettive Sapienza Università di Roma, Rome, Italy
| | - Mario Angelico
- Unità di Epatologia e Trapianti, Fondazione Policlinico Tor Vergata, Rome, Italy
| | - Antonio Gasbarrini
- Gastroenterologia, Fondazione Policlinico Gemelli, Universita’ Cattolica del Sacro Cuore, Rome, Italy
| | - Gloria Taliani
- Dipartimento di Medicina Clinica Sapienza, Università di Roma, Rome, Italy
| | | | - Carlo Federico Perno
- Department of Experimental Medicine and Surgery, University of Roma Tor Vergata, Rome, Italy
| | - Adriano De Santis
- Dipartimento di Medicina Clinica Sapienza, Università di Roma, Rome, Italy
| | - Vincenzo Puro
- National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
- Servizio Regionale per la Sorveglianza delle Malattie infettive (SeRESMI), Rome, Italy
| | | | - Gianpiero D’Offizi
- UOC Malattie Infettive Epatologia Dipartimento Interaziendale Trapianti National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Adriano Pellicelli
- UOC Malattie del Fegato Dipartimento Interaziendale Trapianti AO San Camillo Forlanini Roma, Rome, Italy
| | | | - Francesco Saverio Mennini
- EEHTA CEIS, Università di Roma “Tor Vergata” e Institute of Leadership and Management in Health, Kingston University, London, UK
| | - Massimo Siciliano
- Gastroenterologia, Fondazione Policlinico Gemelli, Universita’ Cattolica del Sacro Cuore, Rome, Italy
| | - Enrico Girardi
- National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Vincenzo Panella
- Servizio Regionale per la Sorveglianza delle Malattie infettive (SeRESMI), Rome, Italy
| | - Giuseppe Ippolito
- National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy
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Boldanova T, Suslov A, Heim MH, Necsulea A. Transcriptional response to hepatitis C virus infection and interferon-alpha treatment in the human liver. EMBO Mol Med 2018; 9:816-834. [PMID: 28360091 PMCID: PMC5452008 DOI: 10.15252/emmm.201607006] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) is widely used to investigate host-virus interactions. Cellular responses to HCV infection have been extensively studied in vitro However, in human liver, interferon (IFN)-stimulated gene expression can mask direct transcriptional responses to infection. To better characterize the direct effects of HCV infection in vivo, we analyze the transcriptomes of HCV-infected patients lacking an activated endogenous IFN system. We show that expression changes observed in these patients predominantly reflect immune cell infiltrates rather than cell-intrinsic pathways. We also investigate the transcriptomes of patients with endogenous IFN activation, which paradoxically cannot eradicate viral infection. We find that most IFN-stimulated genes are induced by both recombinant IFN therapy and the endogenous IFN system, but with lower induction levels in the latter, indicating that the innate immune response in chronic hepatitis C is too weak to clear the virus. We show that coding and non-coding transcripts have different expression dynamics following IFN treatment. Several microRNA primary transcripts, including that of miR-122, are significantly down-regulated in response to IFN treatment, suggesting a new mechanism for IFN-induced expression fine-tuning.
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Affiliation(s)
- Tujana Boldanova
- Department of Biomedicine, University of Basel, Basel, Switzerland.,Division of Gastroenterology and Hepatology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Aleksei Suslov
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Markus H Heim
- Department of Biomedicine, University of Basel, Basel, Switzerland .,Division of Gastroenterology and Hepatology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Anamaria Necsulea
- Laboratory of Developmental Genomics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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48
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Beldar S, Manimekalai MSS, Cho NJ, Baek K, Grüber G, Yoon HS. Self-association and conformational variation of NS5A domain 1 of hepatitis C virus. J Gen Virol 2018; 99:194-208. [PMID: 29300159 DOI: 10.1099/jgv.0.001000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Direct-acting antivirals (DAAs) targeting the non-structural 5A (NS5A) protein of the hepatitis C virus (HCV) are crucial drugs that have shown exceptional clinical success in patients. However, their mode of action (MoA) remains unclear, and drug-resistant HCV strains are rapidly emerging. It is critical to characterize the behaviour of the NS5A protein in solution, which can facilitate the development of new classes of inhibitors or improve the efficacy of the currently available DAAs. Using biophysical methods, including dynamic light scattering, size exclusion chromatography and chemical cross-linking experiments, we showed that the NS5A domain 1 from genotypes 1b and 1a of the HCV intrinsically self-associated and existed as a heterogeneous mixture in solution. Interestingly, the NS5A domain 1 from genotypes 1b and 1a exhibited different dynamic equilibria of monomers to higher-order structures. Using small-angle X-ray scattering, we studied the structural dynamics of the various states of the NS5A domain 1 in solution. We also tested the effect of daclatasvir (DCV), the most prominent DAA, on self-association of the wild and DCV-resistant mutant (Y93H) NS5A domain 1 proteins, and demonstrated that DCV induced the formation of large and irreversible protein aggregates that eventually precipitated out. This study highlights the conformational variability of the NS5A domain 1 of HCV, which may be an intrinsic structural behaviour of the HCV NS5A domain 1 in solution.
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Affiliation(s)
- Serap Beldar
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | | | - Nam-Joon Cho
- School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore
| | - Kwanghee Baek
- Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do, 446-701, Republic of Korea
| | - Gerhard Grüber
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Ho Sup Yoon
- Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do, 446-701, Republic of Korea.,School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
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Protective effect of coffee consumption on all-cause mortality of French HIV-HCV co-infected patients. J Hepatol 2017; 67:1157-1167. [PMID: 28942916 DOI: 10.1016/j.jhep.2017.08.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 06/29/2017] [Accepted: 08/02/2017] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Coffee has anti-inflammatory and hepato-protective properties. In the general population, drinking ≥3cups of coffee/day has been associated with a 14% reduction in the risk of all-cause mortality. The aim of this study was to investigate the relationship between coffee consumption and the risk of all-cause mortality in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS ANRS CO13 HEPAVIH is an ongoing French nationwide prospective cohort of patients co-infected with HIV-HCV collecting both medical and psychosocial/behavioural data (annual self-administered questionnaires). We used a Cox proportional hazards model to estimate the effect of elevated coffee consumption (≥3cups/day) at baseline on all-cause mortality during the cohort's five-year follow-up. RESULTS Over a median [interquartile range] follow-up of 5.0 [3.9-5.9] years, 77 deaths occurred among 1,028 eligible patients (mortality rate 1.64/100 person-years; 95% confidence interval [CI] 1.31-2.05). Leading causes of death were HCV-related diseases (n=33, 43%), cancers unrelated to AIDS/HCV (n=9, 12%), and AIDS (n=8, 10%). At the first available visit, 26.6% of patients reported elevated coffee consumption. Elevated coffee consumption at baseline was associated with a 50% reduced risk of all-cause mortality (hazard ratio 0.5; CI 0.3-0.9; p=0.032), after adjustment for gender and psychosocial, behavioral and clinical time-varying factors. CONCLUSIONS Drinking three or more cups of coffee per day halves all-cause mortality risk in patients co-infected with HIV-HCV. The benefits of coffee extracts and supplementing dietary intake with other anti-inflammatory compounds need to be evaluated in this population. LAY SUMMARY Coffee has anti-inflammatory and hepato-protective properties but its effect on mortality risk has never been investigated in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). This study shows that elevated coffee consumption (≥3cups/day) halves all-cause mortality risk in patients co-infected with HIV-HCV. The benefits of coffee extracts and supplementing dietary intake with other anti-inflammatory compounds need to be evaluated in this population.
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Abstract
More than 2 million Americans are infected with hepatitis C virus (HCV), and only about half are aware that they are infected. Primarily blood-borne, risk factors for the virus include injection or intranasal drug use, unregulated tattoos, incarceration, and blood transfusion before 1992. In addition, 75% of those with the virus were born between 1945 and 1965, thus making the baby-boomer cohort a population of screening interest. Because acute and early chronic HCV are often asymptomatic, screening of at-risk individuals is of utmost importance. Left untreated, HCV can go on to produce significant hepatic and extrahepatic manifestations.
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Affiliation(s)
- Dee Ann Bragg
- Via Christi Family Medicine Residency, University of Kansas School of Medicine (KUSM)-Wichita, 1121 South Clifton Street, Wichita, KS 67218, USA.
| | - Ashley Crowl
- University of Kansas School of Pharmacy, 1121 South Clifton Street, Wichita, KS 67218, USA
| | - Emily Manlove
- University of Kansas School of Medicine (KUSM)-Wichita, 1010 North Kansas Street, Wichita, KS 67214, USA
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