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Muhammad I, Contes K, Bility MT, Tang Q. Chasing Virus Replication and Infection: PAMP-PRR Interaction Drives Type I Interferon Production, Which in Turn Activates ISG Expression and ISGylation. Viruses 2025; 17:528. [PMID: 40284971 PMCID: PMC12031425 DOI: 10.3390/v17040528] [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: 03/09/2025] [Accepted: 04/02/2025] [Indexed: 04/29/2025] Open
Abstract
The innate immune response, particularly the interferon-mediated pathway, serves as the first line of defense against viral infections. During virus infection, viral pathogen-associated molecular patterns (PAMPs) are recognized by host pattern recognition receptors (PRRs), triggering downstream signaling pathways. This leads to the activation of transcription factors like IRF3, IRF7, and NF-κB, which translocate to the nucleus and induce the production of type I interferons (IFN-α and IFN-β). Once secreted, type I interferons bind to their receptors (IFNARs) on the surfaces of infected and neighboring cells, activating the JAK-STAT pathway. This results in the formation of the ISGF3 complex (composed of STAT1, STAT2, and IRF9), which translocates to the nucleus and drives the expression of interferon-stimulated genes (ISGs). Some ISGs exert antiviral effects by directly or indirectly blocking infection and replication. Among these ISGs, ISG15 plays a crucial role in the ISGylation process, a ubiquitin-like modification that tags viral and host proteins, regulating immune responses and inhibiting viral replication. However, viruses have evolved counteractive strategies to evade ISG15-mediated immunity and ISGylation. This review first outlines the PAMP-PRR-induced pathways leading to the production of cytokines and ISGs, followed by a summary of ISGylation's role in antiviral defense and viral evasion mechanisms targeting ISG15 and ISGYlation.
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Affiliation(s)
| | | | | | - Qiyi Tang
- Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA; (I.M.); (K.C.); (M.T.B.)
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2
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Gibbs VJ, Lin YH, Ghuge AA, Anderson RA, Schiemann AH, Conaglen L, Sansom BJM, da Silva RC, Sattlegger E. GCN2 in Viral Defence and the Subversive Tactics Employed by Viruses. J Mol Biol 2024; 436:168594. [PMID: 38724002 DOI: 10.1016/j.jmb.2024.168594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/01/2024] [Accepted: 05/01/2024] [Indexed: 06/10/2024]
Abstract
The recent SARS-CoV-2 pandemic and associated COVID19 disease illustrates the important role of viral defence mechanisms in ensuring survival and recovery of the host or patient. Viruses absolutely depend on the host's protein synthesis machinery to replicate, meaning that impeding translation is a powerful way to counteract viruses. One major approach used by cells to obstruct protein synthesis is to phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). Mammals possess four different eIF2α-kinases: PKR, HRI, PEK/PERK, and GCN2. While PKR is currently considered the principal eIF2α-kinase involved in viral defence, the other eIF2α-kinases have also been found to play significant roles. Unsurprisingly, viruses have developed mechanisms to counteract the actions of eIF2α-kinases, or even to exploit them to their benefit. While some of these virulence factors are specific to one eIF2α-kinase, such as GCN2, others target all eIF2α-kinases. This review critically evaluates the current knowledge of viral mechanisms targeting the eIF2α-kinase GCN2. A detailed and in-depth understanding of the molecular mechanisms by which viruses evade host defence mechanisms will help to inform the development of powerful anti-viral measures.
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Affiliation(s)
- Victoria J Gibbs
- School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand
| | - Yu H Lin
- School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand
| | - Aditi A Ghuge
- School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand
| | - Reuben A Anderson
- School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand
| | - Anja H Schiemann
- School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand
| | - Layla Conaglen
- School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand
| | - Bianca J M Sansom
- School of Natural Sciences, Massey University, Auckland, New Zealand
| | - Richard C da Silva
- School of Natural Sciences, Massey University, Auckland, New Zealand; Genome Biology and Epigenetics, Department of Biology, Utrecht University, Utrecht, the Netherlands
| | - Evelyn Sattlegger
- School of Food Technology and Natural Sciences, Massey University, Palmerston North, New Zealand; School of Natural Sciences, Massey University, Auckland, New Zealand; Maurice Wilkins Centre for Molecular BioDiscovery, Palmerston North, New Zealand.
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3
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Goh L, Kerkar N. Hepatitis C Virus and Molecular Mimicry. Pathogens 2024; 13:527. [PMID: 39057754 PMCID: PMC11280050 DOI: 10.3390/pathogens13070527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/04/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
This review delves into the interactions between hepatitis C virus (HCV) and the host immune system, shedding light on how by using the mechanism of molecular mimicry, the virus strategically evades the immune system, resulting in a cascade of diverse complications. HCV, notorious for its ability to persistently infect hepatocytes, employs molecular mimicry to resemble host proteins, thereby avoiding immune detection and mounting an effective defense. This mimicry also triggers systemic autoimmune responses that lead to various sequelae. The objective of this review is to comprehensively explore the role of HCV-induced molecular mimicry, which not only facilitates viral survival but is also instrumental in developing autoimmune and inflammatory disorders. By mimicking host proteins, HCV triggers an immune response that inadvertently attacks the host, fostering the development of autoimmune and other inflammatory disorders. Understanding the nuanced mechanisms of HCV-mediated molecular mimicry provides crucial insights into the multifaceted sequelae of viral infections on host immune responses. Unravelling these complexities is paramount for advancing therapeutic strategies that not only target the virus directly but also mitigate the secondary autoimmune and inflammatory complications induced by HCV.
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Affiliation(s)
- Lynette Goh
- KK Women’s and Children’s Hospital, Singapore 229899, Singapore
| | - Nanda Kerkar
- Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA 02114, USA;
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Mondelli MU, Ottolini S, Oliviero B, Mantovani S, Cerino A, Mele D, Varchetta S. Hepatitis C Virus and the Host: A Mutual Endurance Leaving Indelible Scars in the Host's Immunity. Int J Mol Sci 2023; 25:268. [PMID: 38203436 PMCID: PMC10779088 DOI: 10.3390/ijms25010268] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatitis C virus (HCV) has spread worldwide, and it is responsible for potentially severe chronic liver disease and primary liver cancer. Chronic infection remains for life if not spontaneously eliminated and viral persistence profoundly impairs the efficiency of the host's immunity. Attempts have been made to develop an effective vaccine, but efficacy trials have met with failure. The availability of highly efficacious direct-acting antivirals (DAA) has created hope for the progressive elimination of chronic HCV infections; however, this approach requires a monumental global effort. HCV elicits a prompt innate immune response in the host, characterized by a robust production of interferon-α (IFN-α), although interference in IFN-α signaling by HCV proteins may curb this effect. The late appearance of largely ineffective neutralizing antibodies and the progressive exhaustion of T cells, particularly CD8 T cells, result in the inability to eradicate the virus in most infected patients. Moreover, an HCV cure resulting from DAA treatment does not completely restore the normal immunologic homeostasis. Here, we discuss the main immunological features of immune responses to HCV and the epigenetic scars that chronic viral persistence leaves behind.
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Affiliation(s)
- Mario U. Mondelli
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Sabrina Ottolini
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Barbara Oliviero
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Stefania Mantovani
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Antonella Cerino
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Dalila Mele
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Stefania Varchetta
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
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Kumari S, Kessel A, Singhal D, Kaur G, Bern D, Lemay-St-Denis C, Singh J, Jain S. Computational identification of a multi-peptide vaccine candidate in E2 glycoprotein against diverse Hepatitis C virus genotypes. J Biomol Struct Dyn 2023; 41:11044-11061. [PMID: 37194293 DOI: 10.1080/07391102.2023.2212777] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 12/11/2022] [Indexed: 05/18/2023]
Abstract
Hepatitis C Virus (HCV) is estimated to affect nearly 180 million people worldwide, culminating in ∼0.7 million yearly casualties. However, a safe vaccine against HCV is not yet available. This study endeavored to identify a multi-genotypic, multi-epitopic, safe, and globally competent HCV vaccine candidate. We employed a consensus epitope prediction strategy to identify multi-epitopic peptides in all known envelope glycoprotein (E2) sequences, belonging to diverse HCV genotypes. The obtained peptides were screened for toxicity, allergenicity, autoimmunity and antigenicity, resulting in two favorable peptides viz., P2 (VYCFTPSPVVVG) and P3 (YRLWHYPCTV). Evolutionary conservation analysis indicated that P2 and P3 are highly conserved, supporting their use as part of a designed multi-genotypic vaccine. Population coverage analysis revealed that P2 and P3 are likely to be presented by >89% Human Leukocyte Antigen (HLA) molecules from six geographical regions. Indeed, molecular docking predicted the physical binding of P2 and P3 to various representative HLAs. We designed a vaccine construct using these peptides and assessed its binding to toll-like receptor 4 (TLR-4) by molecular docking and simulation. Subsequent analysis by energy-based and machine learning tools predicted high binding affinity and pinpointed the key binding residues (i.e. hotspots) in P2 and P3. Also, a favorable immunogenic profile of the construct was predicted by immune simulations. We encourage the scientific community to validate our vaccine construct in vitro and in vivo.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Shweta Kumari
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
| | - Amit Kessel
- Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Divya Singhal
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
| | - Gurpreet Kaur
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India
| | - David Bern
- Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Claudèle Lemay-St-Denis
- Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada
- PROTEO, The Québec Network for Research on Protein, Function, Engineering and Applications, Québec, QC, Canada
- CGCC, Center in Green Chemistry and Catalysis, Montréal, QC, Canada
| | - Jasdeep Singh
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
| | - Sahil Jain
- University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, India
- Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
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Medina C, García AH, Crespo FI, Toro FI, Mayora SJ, De Sanctis JB. A Synopsis of Hepatitis C Virus Treatments and Future Perspectives. Curr Issues Mol Biol 2023; 45:8255-8276. [PMID: 37886964 PMCID: PMC10605161 DOI: 10.3390/cimb45100521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.
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Affiliation(s)
- Christian Medina
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Alexis Hipólito García
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Francis Isamarg Crespo
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Félix Isidro Toro
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Soriuska José Mayora
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Juan Bautista De Sanctis
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, 779 00 Olomouc, Czech Republic
- The Czech Advanced Technology and Research Institute (Catrin), Palacky University, 779 00 Olomouc, Czech Republic
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7
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Colon-Moran W, Baer A, Lamture G, Stapleton JT, Fischer JW, Bhattarai N. A short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity. Gene Ther 2022; 29:616-623. [PMID: 34759330 PMCID: PMC9091046 DOI: 10.1038/s41434-021-00302-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 01/09/2023]
Abstract
Viral vector-mediated gene therapies have the potential to treat many human diseases; however, host immune responses against the vector and/or the transgene pose a safety risk to the patients and can negatively impact product efficacy. Thus, novel strategies to reduce vector immunogenicity are critical for the advancement of these therapies. T cell activation (TCA) is required for the development of immune responses during gene therapy. We hypothesized that modulation of TCA by incorporating a novel viral immunomodulatory factor into a viral vector may reduce unwanted TCA and immune responses during gene therapy. To test this hypothesis, we identified an immunomodulatory domain of the hepatitis C virus (HCV) NS protein 5A (NS5A) protein and studied the effect of viral vectors expressing NS5A peptide on TCA. Lentiviral vector-mediated expression of a short 20-mer peptide derived from the NS5A protein in human T cells was sufficient to inhibit TCA. Synthetic 20-mer NS5A peptide also inhibited TCA in primary human T cells. Mechanistically, the NS5A protein interacted with Lck and inhibited proximal TCR signaling. Importantly, NS5A peptide expression did not cause global T cell signaling dysfunction as distal T cell signaling was not inhibited. Finally, recombinant adeno-associated virus (AAV) vector expressing the 20-mer NS5A peptide reduced both the recall antigen and the TCR-mediated activation of human T cells and did not cause global T cell signaling dysfunction. Together, these data suggest that expression of a 20-mer NS5A peptide by an AAV vector may reduce unwanted TCA and may contribute to lower vector immunogenicity during gene therapy.
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Affiliation(s)
- Winston Colon-Moran
- Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Alan Baer
- Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Gauri Lamture
- Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
- Adicet Bio, Inc., Menlo Park, CA, USA
| | - Jack T Stapleton
- Research Service, Iowa City Veterans Affairs Medical Center, Iowa City, IA, USA
- Departments of Internal Medicine and Microbiology, University of Iowa, Iowa City, IA, USA
| | - Joseph W Fischer
- Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
- AstraZeneca, Gaithersburg, MD, USA
| | - Nirjal Bhattarai
- Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA.
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8
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Tariq M, Shoukat AB, Akbar S, Hameed S, Naqvi MZ, Azher A, Saad M, Rizwan M, Nadeem M, Javed A, Ali A, Aziz S. Epidemiology, risk factors, and pathogenesis associated with a superbug: A comprehensive literature review on hepatitis C virus infection. SAGE Open Med 2022; 10:20503121221105957. [PMID: 35795865 PMCID: PMC9252020 DOI: 10.1177/20503121221105957] [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: 10/20/2021] [Accepted: 05/20/2022] [Indexed: 12/20/2022] Open
Abstract
Viral hepatitis is a major public health concern. It is associated with life threatening conditions including liver cirrhosis and hepatocellular carcinoma. Hepatitis C virus infects around 71 million people annually, resultantly 700,000 deaths worldwide. Extrahepatic associated chronic hepatitis C virus accounts for one fourth of total healthcare load. This review included a total of 150 studies that revealed almost 19 million people are infected with hepatitis C virus and 240,000 new cases are being reported each year. This trend is continually rising in developing countries like Pakistan where intravenous drug abuse, street barbers, unsafe blood transfusions, use of unsterilized surgical instruments and recycled syringes plays a major role in virus transmission. Almost 123–180 million people are found to be hepatitis C virus infected or carrier that accounts for 2%–3% of world’s population. The general symptoms of hepatitis C virus infection include fatigue, jaundice, dark urine, anorexia, fever malaise, nausea and constipation varying on severity and chronicity of infection. More than 90% of hepatitis C virus infected patients are treated with direct-acting antiviral agents that prevent progression of liver disease, decreasing the elevation of hepatocellular carcinoma. Standardizing the healthcare techniques, minimizing the street practices, and screening for viral hepatitis on mass levels for early diagnosis and prompt treatment may help in decreasing the burden on already fragmented healthcare system. However, more advanced studies on larger populations focusing on mode of transmission and treatment protocols are warranted to understand and minimize the overall infection and death stigma among masses.
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Affiliation(s)
- Mehlayl Tariq
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Abu Bakar Shoukat
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sedrah Akbar
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Samaia Hameed
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muniba Zainab Naqvi
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ayesha Azher
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Saad
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,BreathMAT Lab, IAD, Pakistan Institute of Nuclear Science and Technology (PINSTECH), Islamabad, Pakistan
| | - Muhammad Rizwan
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Nadeem
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Anum Javed
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Asad Ali
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Punjab, Pakistan
| | - Shahid Aziz
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,BreathMAT Lab, IAD, Pakistan Institute of Nuclear Science and Technology (PINSTECH), Islamabad, Pakistan
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9
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Toll-like Receptor Response to Hepatitis C Virus Infection: A Recent Overview. Int J Mol Sci 2022; 23:ijms23105475. [PMID: 35628287 PMCID: PMC9141274 DOI: 10.3390/ijms23105475] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection remains a major global health burden, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that detect pathogen-associated molecular patterns and activate downstream signaling to induce proinflammatory cytokine and chemokine production. An increasing number of studies have suggested the importance of TLR responses in the outcome of HCV infection. However, the exact role of innate immune responses, including TLR response, in controlling chronic HCV infection remains to be established. A proper understanding of the TLR response in HCV infection is essential for devising new therapeutic approaches against HCV infection. In this review, we discuss the progress made in our understanding of the host innate immune response to HCV infection, with a particular focus on the TLR response. In addition, we discuss the mechanisms adopted by HCV to avoid immune surveillance mediated by TLRs.
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10
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Lee J, Ou JHJ. Hepatitis C virus and intracellular antiviral response. Curr Opin Virol 2022; 52:244-249. [PMID: 34973476 PMCID: PMC8844188 DOI: 10.1016/j.coviro.2021.12.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 12/09/2021] [Indexed: 02/03/2023]
Abstract
To establish successful infection in cells, it is essential for hepatitis C virus (HCV) to overcome intracellular antiviral responses. The host cell mechanism that fights against the virus culminates in the production of interferons (IFNs), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines as well as the induction of autophagy and apoptosis. HCV has developed multiple means to disrupt the host signaling pathways that lead to these antiviral responses. HCV impedes signaling pathways initiated by pattern-recognition receptors (PRRs), usurps and uses the antiviral autophagic response to enhance its replication, alters mitochondrial dynamics and metabolism to prevent cell death and attenuate IFN response, and dysregulates inflammasomal response to cause IFN resistance and immune tolerance. These effects of HCV allow HCV to successful replicate and persist in its host cells.
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11
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Abstract
Cells respond to viral infections through sensors that detect non-self-molecules, and through effectors, which can have direct antiviral activities or adapt cell physiology to limit viral infection and propagation. Eukaryotic translation initiation factor 2 alpha kinase 2, better known as PKR, acts as both a sensor and an effector in the response to viral infections. After sensing double-stranded RNA molecules in infected cells, PKR self-activates and majorly exerts its antiviral function by blocking the translation machinery and inducing apoptosis. The antiviral potency of PKR is emphasized by the number of strategies developed by viruses to antagonize the PKR pathway. In this review, we present an update on the diversity of such strategies, which range from preventing double-stranded RNA recognition upstream from PKR activation, to activating eIF2B downstream from PKR targets.
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Affiliation(s)
- Teresa Cesaro
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Thomas Michiels
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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12
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Virus-Induced Tumorigenesis and IFN System. BIOLOGY 2021; 10:biology10100994. [PMID: 34681093 PMCID: PMC8533565 DOI: 10.3390/biology10100994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/01/2021] [Accepted: 09/27/2021] [Indexed: 01/11/2023]
Abstract
Oncogenic viruses favor the development of tumors in mammals by persistent infection and specific cellular pathways modifications by deregulating cell proliferation and inhibiting apoptosis. They counteract the cellular antiviral defense through viral proteins as well as specific cellular effectors involved in virus-induced tumorigenesis. Type I interferons (IFNs) are a family of cytokines critical not only for viral interference but also for their broad range of properties that go beyond the antiviral action. In fact, they can inhibit cell proliferation and modulate differentiation, apoptosis, and migration. However, their principal role is to regulate the development and activity of most effector cells of the innate and adaptive immune responses. Various are the mechanisms by which IFNs exert their effects on immune cells. They can act directly, through IFN receptor triggering, or indirectly by the induction of chemokines, the secretion of further cytokines, or by the stimulation of cells useful for the activation of particular immune cells. All the properties of IFNs are crucial in the host defense against viruses and bacteria, as well as in the immune surveillance against tumors. IFNs may be affected by and, in turn, affect signaling pathways to mediate anti-proliferative and antiviral responses in virus-induced tumorigenic context. New data on cellular and viral microRNAs (miRNAs) machinery, as well as cellular communication and microenvironment modification via classical secretion mechanisms and extracellular vesicles-mediated delivery are reported. Recent research is reviewed on the tumorigenesis induced by specific viruses with RNA or DNA genome, belonging to different families (i.e., HPV, HTLV-1, MCPyV, JCPyV, Herpesviruses, HBV, HCV) and the IFN system involvement.
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13
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Prasad V, Greber UF. The endoplasmic reticulum unfolded protein response - homeostasis, cell death and evolution in virus infections. FEMS Microbiol Rev 2021; 45:fuab016. [PMID: 33765123 PMCID: PMC8498563 DOI: 10.1093/femsre/fuab016] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
Viruses elicit cell and organismic stress, and offset homeostasis. They trigger intrinsic, innate and adaptive immune responses, which limit infection. Viruses restore homeostasis by harnessing evolutionary conserved stress responses, such as the endoplasmic reticulum (ER) unfolded protein response (UPRER). The canonical UPRER restores homeostasis based on a cell-autonomous signalling network modulating transcriptional and translational output. The UPRER remedies cell damage, but upon severe and chronic stress leads to cell death. Signals from the UPRER flow along three branches with distinct stress sensors, the inositol requiring enzyme (Ire) 1, protein kinase R (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). This review shows how both enveloped and non-enveloped viruses use the UPRER to control cell stress and metabolic pathways, and thereby enhance infection and progeny formation, or undergo cell death. We highlight how the Ire1 axis bypasses apoptosis, boosts viral transcription and maintains dormant viral genomes during latency and persistence periods concurrent with long term survival of infected cells. These considerations open new options for oncolytic virus therapies against cancer cells where the UPRER is frequently upregulated. We conclude with a discussion of the evolutionary impact that viruses, in particular retroviruses, and anti-viral defense has on the UPRER.
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Affiliation(s)
- Vibhu Prasad
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
| | - Urs F Greber
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
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14
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Markiewicz L, Drazkowska K, Sikorski PJ. Tricks and threats of RNA viruses - towards understanding the fate of viral RNA. RNA Biol 2021; 18:669-687. [PMID: 33618611 PMCID: PMC8078519 DOI: 10.1080/15476286.2021.1875680] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/22/2020] [Accepted: 01/09/2021] [Indexed: 12/24/2022] Open
Abstract
Human innate cellular defence pathways have evolved to sense and eliminate pathogens, of which, viruses are considered one of the most dangerous. Their relatively simple structure makes the identification of viral invasion a difficult task for cells. In the course of evolution, viral nucleic acids have become one of the strongest and most reliable early identifiers of infection. When considering RNA virus recognition, RNA sensing is the central mechanism in human innate immunity, and effectiveness of this sensing is crucial for triggering an appropriate antiviral response. Although human cells are armed with a variety of highly specialized receptors designed to respond only to pathogenic viral RNA, RNA viruses have developed an array of mechanisms to avoid being recognized by human interferon-mediated cellular defence systems. The repertoire of viral evasion strategies is extremely wide, ranging from masking pathogenic RNA through end modification, to utilizing sophisticated techniques to deceive host cellular RNA degrading enzymes, and hijacking the most basic metabolic pathways in host cells. In this review, we aim to dissect human RNA sensing mechanisms crucial for antiviral immune defences, as well as the strategies adopted by RNA viruses to avoid detection and degradation by host cells. We believe that understanding the fate of viral RNA upon infection, and detailing the molecular mechanisms behind virus-host interactions, may be helpful for developing more effective antiviral strategies; which are urgently needed to prevent the far-reaching consequences of widespread, highly pathogenic viral infections.
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15
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Poma AM, Hammerstad SS, Genoni A, Basolo A, Dahl-Jorgensen K, Toniolo A. Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Autoimmune Thyroid Disease. Microorganisms 2021; 9:microorganisms9040876. [PMID: 33921891 PMCID: PMC8073039 DOI: 10.3390/microorganisms9040876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 11/16/2022] Open
Abstract
Background: Hashimoto’s thyroiditis and Graves’ disease are autoimmune thyroid disorders (AITD) of unknown origin. Enterovirus (EV) infection of thyroid cells has been implicated as a possible initiator of cell damage and of organ-specific autoimmunity. We asked whether persistent infection of human epithelial cells with EV strains obtained from thyroid tissue of AITD patients could be associated with transcriptional changes capable of fostering immunopathology. Methods: EV isolates obtained from thyroid tissue of AITD cases were used to infect the AV3 epithelial cell line. AV3 cells incubated with a virus-free medium from thyroid tissue of subjects without evidence of thyroid autoimmunity were used as uninfected controls. Transcripts of immune-related genes were compared in infected vs. uninfected cells. Results: The EV genome and antigens were detected only in the cells exposed to AITD-derived virus isolates, not in control cells. Persistent EV infection, while suppressing transcription of several type I IFN and cytokine determinants, was associated with enhanced transcription of NFKB1/RELA, IFNAR1, JAK1/STAT1, i.e., the determinants that play key immunologic roles. Infection also led to upregulation of the CCL2 chemokine and the IL-18 pro-inflammatory interleukin. Conclusion: As in the case of EV strains obtained from autoimmune diabetes, results show that the EV strains that are present in the thyroid of AITD cases do repress IFN and cytokine pathways. JAK1/STAT1 upregulation supports activation of TLR pathways and aberrant T cell signaling. In the early phases of AITD, our results highlight the potential benefit of interventions aimed at blocking the viral infection and easing the inflammatory response.
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Affiliation(s)
- Anello Marcello Poma
- Department of Surgical, Medical, Molecular Pathology and Clinical Area, University of Pisa, 56126 Pisa, Italy
- Correspondence: ; Tel.: +39-050-993260
| | - Sarah Salehi Hammerstad
- Department of Pediatric Medicine, Oslo University Hospital, 0450 Oslo, Norway; (S.S.H.); (K.D.-J.)
- Specialist Center Pilestredet Park, Pilestredet Park 12.A, 0176 Oslo, Norway
| | - Angelo Genoni
- Medical Microbiology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy;
| | - Alessio Basolo
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy;
| | - Knut Dahl-Jorgensen
- Department of Pediatric Medicine, Oslo University Hospital, 0450 Oslo, Norway; (S.S.H.); (K.D.-J.)
- Faculty of Medicine, The University of Oslo, 0316 Oslo, Norway
| | - Antonio Toniolo
- Global Virus Network, University of Insubria, 21100 Varese, Italy;
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16
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Klann K, Tascher G, Münch C. Virus systems biology: Proteomics profiling of dynamic protein networks during infection. Adv Virus Res 2021; 109:1-29. [PMID: 33934824 DOI: 10.1016/bs.aivir.2020.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The host cell proteome undergoes a variety of dynamic changes during viral infection, elicited by the virus itself or host cell defense mechanisms. Studying these changes on a global scale by integrating functional and physical interactions within protein networks during infection is an important tool to understand pathology. Indeed, proteomics studies dissecting protein signaling cascades and interaction networks upon infection showed how global information can significantly improve understanding of disease mechanisms of diverse viral infections. Here, we summarize and give examples of different experimental designs, proteomics approaches and bioinformatics analyses that allow profiling proteome changes and host-pathogen interactions to gain a molecular systems view of viral infection.
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Affiliation(s)
- Kevin Klann
- Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany
| | - Georg Tascher
- Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany
| | - Christian Münch
- Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany; Frankfurt Cancer Institute, Frankfurt am Main, Germany; Cardio-Pulmonary Institute, Frankfurt am Main, Germany.
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17
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Emanuelli G, Nassehzadeh-Tabriz N, Morrell NW, Marciniak SJ. The integrated stress response in pulmonary disease. Eur Respir Rev 2020; 29:29/157/200184. [PMID: 33004527 PMCID: PMC7116220 DOI: 10.1183/16000617.0184-2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 07/15/2020] [Indexed: 02/07/2023] Open
Abstract
The respiratory tract and its resident immune cells face daily exposure
to stress, both from without and from within. Inhaled pathogens, including
severe acute respiratory syndrome coronavirus 2, and toxins from pollution
trigger a cellular defence system that reduces protein synthesis to minimise
viral replication or the accumulation of misfolded proteins. Simultaneously, a
gene expression programme enhances antioxidant and protein folding machineries
in the lung. Four kinases (PERK, PKR, GCN2 and HRI) sense a diverse range of
stresses to trigger this “integrated stress response”. Here we review recent
advances identifying the integrated stress response as a critical pathway in the
pathogenesis of pulmonary diseases, including pneumonias, thoracic malignancy,
pulmonary fibrosis and pulmonary hypertension. Understanding the integrated
stress response provides novel targets for the development of therapies.
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Affiliation(s)
- Giulia Emanuelli
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.,Division of Respiratory Medicine, Dept of Medicine, University of Cambridge, Cambridge, UK.,Equal first authors
| | - Nikou Nassehzadeh-Tabriz
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.,Equal first authors
| | - Nick W Morrell
- Division of Respiratory Medicine, Dept of Medicine, University of Cambridge, Cambridge, UK
| | - Stefan J Marciniak
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK .,Division of Respiratory Medicine, Dept of Medicine, University of Cambridge, Cambridge, UK
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18
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Fadl N, Salem TZ. Hepatitis C genotype 4: A report on resistance-associated substitutions in NS3, NS5A, and NS5B genes. Rev Med Virol 2020; 30:e2120. [PMID: 32478480 DOI: 10.1002/rmv.2120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/04/2020] [Accepted: 05/06/2020] [Indexed: 12/20/2022]
Abstract
AUTHOR CONTRIBUTION FN performed the literature review and wrote the manuscript; STZ coauthored, edited, and reviewed the manuscript. ABSTRACT Treatment response in Hepatitis C virus (HCV) has generated varied effects in patients. Recently, nonresponsive and relapse patients related to host and genotype variabilities have been reported in clinical trials. However, these trials included minimal sample sizes of patients with genotype 4, the most prevalent genotype in Egypt and the Middle East, compared with genotypes 1 and 2. The genetic variabilities that have been detected within the HCV genes, especially the ones associated with genotype 4, and are linked to treatment response, will be the focus of this review with emphasis on direct acting antiviral agents. In addition, the major studies and clinical trials performed globally and their inclusivity of genotype 4 are reported. This review also delineates future study areas and missing data that need further investigation when it comes to genotype 4.
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Affiliation(s)
- Nahla Fadl
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
| | - Tamer Z Salem
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt.,Department of Microbial Genetics, AGERI, ARC, Giza, Egypt
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19
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Ferreira AR, Ramos B, Nunes A, Ribeiro D. Hepatitis C Virus: Evading the Intracellular Innate Immunity. J Clin Med 2020; 9:jcm9030790. [PMID: 32183176 PMCID: PMC7141330 DOI: 10.3390/jcm9030790] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 03/02/2020] [Accepted: 03/04/2020] [Indexed: 12/25/2022] Open
Abstract
Hepatitis C virus (HCV) infections constitute a major public health problem and are the main cause of chronic hepatitis and liver disease worldwide. The existing drugs, while effective, are expensive and associated with undesirable secondary effects. There is, hence, an urgent need to develop novel therapeutics, as well as an effective vaccine to prevent HCV infection. Understanding the interplay between HCV and the host cells will certainly contribute to better comprehend disease progression and may unravel possible new cellular targets for the development of novel antiviral therapeutics. Here, we review and discuss the interplay between HCV and the host cell innate immunity. We focus on the different cellular pathways that respond to, and counteract, HCV infection and highlight the evasion strategies developed by the virus to escape this intracellular response.
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Affiliation(s)
| | | | | | - Daniela Ribeiro
- Correspondence: ; Tel.: +351-234-247-014; Fax: +351-234-372-587
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20
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Kumar R, Derbigny WA. TLR3 Deficiency Leads to a Dysregulation in the Global Gene-Expression Profile in Murine Oviduct Epithelial Cells Infected with Chlamydia muridarum. ACTA ACUST UNITED AC 2020; 1:1-13. [PMID: 31891165 PMCID: PMC6937138 DOI: 10.18689/ijmr-1000101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Chlamydia trachomatis replicates primarily in the epithelial cells lining the genital tract and induces the innate immune response by triggering cellular pathogen recognition receptors (PRRs). Our previous studies showed that Toll-like receptor 3 (TLR3) is expressed in murine oviduct epithelial (OE) cells, is the primary PRR triggered by C. muridarum (Cm) early during infection to induce IFN-β synthesis, and that TLR3 signaling regulates the chlamydial induced synthesis of a plethora of other innate inflammatory modulators including IL-6, CXCL10, CXCL16 and CCL5. We also showed that the expression of these cytokines induced by Chlamydia was severely diminished during TLR3 deficiency; however, the replication of Chlamydiain TLR3 deficient OE cells was more robust than in WT cells. These data suggested that TLR3 had a biological impact on the inflammatory response to Chlamydia infection; however, the global effects of TLR3 signaling in the cellular response to Chlamydia infection in murine OE cells has not yet been investigated. To determine the impact of TLR3 signaling on Chlamydia infection in OE cell at the transcriptome level, we infected wild-type (OE-WT) and TLR3-deficient (OE-TLR3KO) cells with Cm, and performed transcriptome analyses using microarray. Genome-wide expression and ingenuity pathway analysis (IPA) identified enhanced expression of host genes encoding for components found in multiple cellular processes encompassing: (1) pro-inflammatory, (2) cell adhesion, (3) chemoattraction, (4) cellular matrix and small molecule transport, (5) apoptosis, and (6) antigen-processing and presentation. These results support a role for TLR3 in modulating the host cellular responses to Cm infection that extend beyond inflammation and fibrosis, and shows that TLR3 could serve a potential therapeutic target for drug and/or vaccine development.
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Affiliation(s)
- Ramesh Kumar
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana-46202, USA
| | - Wilbert A Derbigny
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana-46202, USA
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21
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Abstract
Outbreaks of severe virus infections with the potential to cause global pandemics are increasing. In many instances these outbreaks have been newly emerging (SARS coronavirus), re-emerging (Ebola virus, Zika virus) or zoonotic (avian influenza H5N1) virus infections. In the absence of a targeted vaccine or a pathogen-specific antiviral, broad-spectrum antivirals would function to limit virus spread. Given the direct antiviral effects of type I interferons (IFNs) in inhibiting the replication of both DNA and RNA viruses at different stages of their replicative cycles, and the effects of type I IFNs on activating immune cell populations to clear virus infections, IFNs-α/β present as ideal candidate broad-spectrum antivirals.
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Affiliation(s)
- Ben X Wang
- Princess Margaret Cancer Center, Tumor Immunotherapy Program, University Health Network, Toronto, ON M5G 2M9, Canada
| | - Eleanor N Fish
- Toronto General Hospital Research Institute, University Health Network, 67 College Street, Toronto, ON M5G 2M1, Canada; Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
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22
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He B, Tran JT, Sanchez DJ. Manipulation of Type I Interferon Signaling by HIV and AIDS-Associated Viruses. J Immunol Res 2019; 2019:8685312. [PMID: 31089479 PMCID: PMC6476103 DOI: 10.1155/2019/8685312] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 02/14/2019] [Indexed: 12/20/2022] Open
Abstract
Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections.
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Affiliation(s)
- Buyuan He
- Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona 91766, California, USA
| | - James T. Tran
- Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona 91766, California, USA
| | - David Jesse Sanchez
- Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona 91766, California, USA
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23
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Patra T, Ray RB, Ray R. Strategies to Circumvent Host Innate Immune Response by Hepatitis C Virus. Cells 2019; 8:E274. [PMID: 30909456 PMCID: PMC6468774 DOI: 10.3390/cells8030274] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/13/2022] Open
Abstract
Innate immune responses generate interferons, proinflammatory cytokines, complement activation, and natural killer (NK) cell response. Ultimately, this leads to the induction of a robust virus-specific adaptive immunity. Although the host innate immune system senses and responds to eliminate virus infection, hepatitis C virus (HCV) evades immune attack and establishes persistent infection within the liver. Spontaneous clearance of HCV infection is associated with a prompt induction of innate immunity generated in an infected host. In this review, we have highlighted the current knowledge of our understanding of host⁻HCV interactions, especially for endogenous interferon production, proinflammatory response, NK cell response, and complement activation, which may impair the generation of a strong adaptive immune response for establishment of chronicity. The information may provide novel strategies in augmenting therapeutic intervention against HCV.
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Affiliation(s)
- Tapas Patra
- Departments of Internal Medicine, Saint Louis University, St. Louis, MO 63104, USA.
| | - Ratna B Ray
- Departments of Pathology, Saint Louis University, St. Louis, MO 63104, USA.
| | - Ranjit Ray
- Departments of Internal Medicine, Saint Louis University, St. Louis, MO 63104, USA.
- Molecular Microbiology & Immunology, Saint Louis University, St. Louis, MO 63104, USA.
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24
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Structural Modification in Hepatitis C Virus Envelope Protein; Potential Viral Strategy Against Interferon Therapy. Int J Pept Res Ther 2019. [DOI: 10.1007/s10989-019-09826-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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25
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Aso H, Ito J, Koyanagi Y, Sato K. Comparative Description of the Expression Profile of Interferon-Stimulated Genes in Multiple Cell Lineages Targeted by HIV-1 Infection. Front Microbiol 2019; 10:429. [PMID: 30915053 PMCID: PMC6423081 DOI: 10.3389/fmicb.2019.00429] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 02/19/2019] [Indexed: 12/31/2022] Open
Abstract
Immediately after viral infections, innate immune sensors recognize viruses and lead to the production of type I interferon (IFN-I). IFN-I upregulates various genes, referred to as IFN-stimulated genes (ISGs), and some ISGs inhibit viral replication. HIV-1, the causative agent of AIDS, mainly infects CD4+ T cells and macrophages and triggers the IFN-I-mediated signaling cascade. Certain ISGs are subsequently upregulated by IFN-I stimulus and potently suppress HIV-1 replication. HIV-1 cell biology has shed light on the molecular understanding of the IFN-I production triggered by HIV-1 infection and the antiviral roles of ISGs. However, the differences in the gene expression patterns following IFN-I stimulus among HIV-1 target cell types are poorly understood. In this study, we hypothesize that the expression profiles of ISGs are different among HIV-1 target cells and address this question by utilizing public transcriptome datasets and bioinformatic techniques. We focus on three cell types intrinsically targeted by HIV-1, including CD4+ T cells, monocytes, and macrophages, and comprehensively compare the expression patterns of ISGs among these cell types. Furthermore, we use the datasets of the differentially expressed genes by HIV-1 infection and the evolutionarily conserved ISGs in mammals and perform comparative transcriptome analyses. We defined 104 ‘common ISGs’ that were upregulated by IFN-I stimulus in CD4+ T cells, monocytes, and macrophages. The ISG expression patterns were different among these three cell types, and intriguingly, both the numbers and the magnitudes of upregulated ISGs by IFN-I stimulus were greatest in macrophages. We also found that the upregulated genes by HIV-1 infection included most ‘common ISGs.’ Moreover, we determined that the ‘common ISGs,’ particularly those with antiviral activity, were evolutionarily conserved in mammals. To our knowledge, this study is the first investigation to comprehensively describe (i) the different expression patterns of ISGs among HIV-1 target cells, (ii) the overlap in the genes modulated by IFN-I stimulus and HIV-1 infection and (iii) the evolutionary conservation in mammals of the antiviral ISGs that are expressed in HIV-1 target cells. Our results will be useful for deeply understanding the relationship of the effect of IFN-I and the modulated gene expression by HIV-1 infection.
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Affiliation(s)
- Hirofumi Aso
- Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Jumpei Ito
- Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yoshio Koyanagi
- Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kei Sato
- Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Japan
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26
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Suzuki R, Matsuda M, Shimoike T, Watashi K, Aizaki H, Kato T, Suzuki T, Muramatsu M, Wakita T. Activation of protein kinase R by hepatitis C virus RNA-dependent RNA polymerase. Virology 2019; 529:226-233. [PMID: 30738360 DOI: 10.1016/j.virol.2019.01.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/28/2019] [Accepted: 01/29/2019] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) was shown to activate protein kinase R (PKR), which inhibits expression of interferon (IFN) and IFN-stimulated genes by controlling the translation of newly transcribed mRNAs. However, it is unknown exactly how HCV activates PKR. To address the molecular mechanism(s) of PKR activation mediated by HCV infection, we examined the effects of viral proteins on PKR activation. Here, we show that expression of HCV NS5B strongly induced PKR and eIF2α phosphorylation, and attenuated MHC class I expression. In contrast, expression of Japanese encephalitis virus RNA-dependent RNA polymerase did not induce phosphorylation of PKR. Co-immunoprecipitation analyses showed that HCV NS5B interacted with PKR. Furthermore, expression of NS5B with polymerase activity-deficient mutation failed to phosphorylate PKR, suggesting that RNA polymerase activity is required for PKR activation. These results suggest that HCV activates PKR by association with NS5B, resulting in translational suppression of MHC class I to establish chronic infection.
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Affiliation(s)
- Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-murayama-shi, Tokyo 208-0011, Japan.
| | - Mami Matsuda
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
| | - Takashi Shimoike
- Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-murayama-shi, Tokyo 208-0011, Japan.
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
| | - Hideki Aizaki
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
| | - Tetsuro Suzuki
- Department of Infectious Diseases, Hamamatsu University School of Medicine, Shizuoka, Japan.
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
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Suda T, Tatsumi T, Nishio A, Kegasawa T, Yoshioka T, Yamada R, Furuta K, Kodama T, Shigekawa M, Hikita H, Sakamori R, Fukuhara T, Matsuura Y, Takehara T. CEACAM1 Is Associated With the Suppression of Natural Killer Cell Function in Patients With Chronic Hepatitis C. Hepatol Commun 2018; 2:1247-1258. [PMID: 30288478 PMCID: PMC6167072 DOI: 10.1002/hep4.1240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 05/20/2018] [Indexed: 12/15/2022] Open
Abstract
Natural killer cells (NK cells) play an essential role in the immunological mechanism underlying chronic hepatitis C (CHC). Impairment of NK cell function facilitates persistent infection with hepatitis C virus (HCV) and hepatocellular carcinogenesis. However, the mechanism by which NK cell activity is suppressed in CHC is not completely understood. In this study, we focused on carcinoembryonic antigen–related cell‐adhesion molecule 1 (CEACAM1). CEACAM1 is thought to suppress NK cell function. We examined the effect of CEACAM1 on NK cell function in CHC. We investigated the function of CEACAM1 in vitro using Huh7.5.1 cells and the HCV‐Japanese fulminant hepatitis (JFH)‐1 strain. We analyzed serum CEACAM1 level, NK cell function, and CEACAM1 messenger RNA (mRNA) level in human liver samples. Levels of CEACAM1 on the cell surface, CEACAM1 mRNA levels, and soluble CEACAM1 levels in supernatants were significantly higher in Huh7.5.1 cells infected with JFH‐1 (Huh7.5.1/JFH‐1 cells) than in Huh7.5.1 cells. Significantly higher NK cell cytotoxicity was observed toward K562 cells after coculture with CEACAM1 knockout Huh7.5.1/JFH‐1 cells than after coculture with Huh7.5.1/JFH‐1 cells. CEACAM1 expression was induced by the HCV E2 glycoprotein in HCV infection. Significantly higher serum CEACAM1 levels were detected in patients with CHC compared with healthy subjects and patients who achieved sustained virological responses. The expression of CD107a on NK cells from patients with CHC was negatively correlated with serum CEACAM1 levels. Significantly higher levels of CEACAM1 mRNA were detected in HCV‐infected livers compared with uninfected livers. Conclusion: CEACAM1 expression was induced in hepatocytes following HCV infection and decreased NK cell cytotoxicity. These results demonstrate a possible role for CEACAM1 in the pathogenesis of CHC and hepatocellular carcinoma progression.
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Affiliation(s)
- Takahiro Suda
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Akira Nishio
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Tadashi Kegasawa
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Teppei Yoshioka
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Kunimaro Furuta
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Minoru Shigekawa
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Takasuke Fukuhara
- Department of Molecular Virology Research Institute for Microbial Diseases, Osaka University Suita Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology Research Institute for Microbial Diseases, Osaka University Suita Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
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29
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Rahamathulla S, Ratnagiri BSVV, Manickam M, Sultana S, Mamatha DM, Magisetty O, Nagarapu R, Ponamgi SPD. Determination of Sustained Virological Response in Hepatitis C Virus Genotypes by the Number of Mutations in the E2 and NS5A-ISDR Regions: A Meta-Analysis. RUSS J GENET+ 2018. [DOI: 10.1134/s1022795418090119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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30
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Bussey KA, Brinkmann MM. Strategies for immune evasion by human tumor viruses. Curr Opin Virol 2018; 32:30-39. [PMID: 30241043 DOI: 10.1016/j.coviro.2018.08.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 08/24/2018] [Indexed: 12/14/2022]
Abstract
Immune evasion is a hallmark of viral persistence. For the seven human tumor viruses to establish lifelong infection in their hosts, they must successfully control the host response to them. Viral inhibition of immune responses occurs at many levels. While some viruses directly target the pattern recognition receptors (PRR) of the innate immune system, they may also antagonize downstream effectors of PRR signaling cascades or activation of transcription, which would otherwise induce a type I interferon (IFN) and/or pro-inflammatory cytokine response. Secretion of IFN activates the type I interferon receptor (IFNAR) signaling pathway, which is also prone to viral inhibition. To evade the adaptive host response, viruses also target various mechanisms including antigen processing and presentation.
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Affiliation(s)
- Kendra A Bussey
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany; Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
| | - Melanie M Brinkmann
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany; Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
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31
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Forni D, Cagliani R, Pontremoli C, Pozzoli U, Vertemara J, De Gioia L, Clerici M, Sironi M. Evolutionary Analysis Provides Insight Into the Origin and Adaptation of HCV. Front Microbiol 2018; 9:854. [PMID: 29765366 PMCID: PMC5938362 DOI: 10.3389/fmicb.2018.00854] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 04/13/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) belongs to the Hepacivirus genus and is genetically heterogeneous, with seven major genotypes further divided into several recognized subtypes. HCV origin was previously dated in a range between ∼200 and 1000 years ago. Hepaciviruses have been identified in several domestic and wild mammals, the largest viral diversity being observed in bats and rodents. The closest relatives of HCV were found in horses/donkeys (equine hepaciviruses, EHV). However, the origin of HCV as a human pathogen is still an unsolved puzzle. Using a selection-informed evolutionary model, we show that the common ancestor of extant HCV genotypes existed at least 3000 years ago (CI: 3192–5221 years ago), with the oldest genotypes being endemic to Asia. EHV originated around 1100 CE (CI: 291–1640 CE). These time estimates exclude that EHV transmission was mainly sustained by widespread veterinary practices and suggest that HCV originated from a single zoonotic event with subsequent diversification in human populations. We also describe a number of biologically important sites in the major HCV genotypes that have been positively selected and indicate that drug resistance-associated variants are significantly enriched at positively selected sites. HCV exploits several cell-surface molecules for cell entry, but only two of these (CD81 and OCLN) determine the species-specificity of infection. Herein evolutionary analyses do not support a long-standing association between primates and hepaciviruses, and signals of positive selection at CD81 were only observed in Chiroptera. No evidence of selection was detected for OCLN in any mammalian order. These results shed light on the origin of HCV and provide a catalog of candidate genetic modulators of HCV phenotypic diversity.
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Affiliation(s)
- Diego Forni
- Bioinformatics Laboratory, Scientific Institute IRCCS E.Medea, Bosisio Parini, Italy
| | - Rachele Cagliani
- Bioinformatics Laboratory, Scientific Institute IRCCS E.Medea, Bosisio Parini, Italy
| | - Chiara Pontremoli
- Bioinformatics Laboratory, Scientific Institute IRCCS E.Medea, Bosisio Parini, Italy
| | - Uberto Pozzoli
- Bioinformatics Laboratory, Scientific Institute IRCCS E.Medea, Bosisio Parini, Italy
| | - Jacopo Vertemara
- Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy
| | - Luca De Gioia
- Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy
| | - Mario Clerici
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.,Don C. Gnocchi Foundation Onlus, IRCCS, Milan, Italy
| | - Manuela Sironi
- Bioinformatics Laboratory, Scientific Institute IRCCS E.Medea, Bosisio Parini, Italy
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32
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Carrasco SE, Hu S, Imai DM, Kumar R, Sandusky GE, Yang XF, Derbigny WA. Toll-like receptor 3 (TLR3) promotes the resolution of Chlamydia muridarum genital tract infection in congenic C57BL/6N mice. PLoS One 2018; 13:e0195165. [PMID: 29624589 PMCID: PMC5889059 DOI: 10.1371/journal.pone.0195165] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 03/16/2018] [Indexed: 12/24/2022] Open
Abstract
Chlamydia trachomatis urogenital serovars primarily replicate in epithelial cells lining the reproductive tract. Epithelial cells recognize Chlamydia through cell surface and cytosolic receptors, and/or endosomal innate receptors such as Toll-like receptors (TLRs). Activation of these receptors triggers both innate and adaptive immune mechanisms that are required for chlamydial clearance, but are also responsible for the immunopathology in the reproductive tract. We previously demonstrated that Chlamydia muridarum (Cm) induces IFN-β in oviduct epithelial cells (OE) in a TLR3-dependent manner, and that the synthesis of several cytokines and chemokines are diminished in Cm-challenged OE derived from TLR3-/- 129S1 mice. Furthermore, our in vitro studies showed that Cm replication in TLR3-/- OE is more efficient than in wild-type OE. Because TLR3 modulates the release inflammatory mediators involved in host defense during Cm infection, we hypothesized that TLR3 plays a protective role against Cm-induced genital tract pathology in congenic C57BL/6N mice. Using the Cm mouse model for human Chlamydia genital tract infections, we demonstrated that TLR3-/- mice had increased Cm shedding during early and mid-stage genital infection. In early stage infection, TLR3-/- mice showed a diminished synthesis of IFN-β, IL-1β, and IL-6, but enhanced production of IL-10, TNF-α, and IFN-γ. In mid-stage infection, TLR3-/- mice exhibited significantly enhanced lymphocytic endometritis and salpingitis than wild-type mice. These lymphocytes were predominantly scattered along the endometrial stroma and the associated smooth muscle, and the lamina propria supporting the oviducts. Surprisingly, our data show that CD4+ T-cells are significantly enhanced in the genital tract TLR3-/- mice during mid-stage Chlamydial infection. In late-stage infections, both mouse strains developed hydrosalpinx; however, the extent of hydrosalpinx was more severe in TLR3-/- mice. Together, these data suggest that TLR3 promotes the clearance of Cm during early and mid-stages of genital tract infection, and that loss of TLR3 is detrimental in the development hydrosalpinx.
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Affiliation(s)
- Sebastian E. Carrasco
- School of Veterinary Medicine and Comparative Pathology Laboratory, University of California-Davis, Davis, California, United States of America
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Sishun Hu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
| | - Denise M. Imai
- School of Veterinary Medicine and Comparative Pathology Laboratory, University of California-Davis, Davis, California, United States of America
| | - Ramesh Kumar
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - George E. Sandusky
- Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - X. Frank Yang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Wilbert A. Derbigny
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
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33
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Liao X, Wang Y, Ye H, Li S, Chen L, Duan X. Role of interferon-stimulated genes in regulation of HCV infection and type I interferon anti-HCV activity. Future Virol 2018. [DOI: 10.2217/fvl-2017-0160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
HCV chronically infects over 71 million people worldwide and is one of the leading causes of advanced liver diseases. Type I interferons (IFN-α/β) play critical role in host antiviral innate immunity. IFN-α/β exerts its anti-HCV effects through the activation of the JAK/STAT signaling pathway leading to the induction of a few hundred interferon-stimulated genes (ISGs). The interplay between ISG and HCV infection remains partially understood. In this review, we summarized the role of ISGs in HCV infection and interferon anti-HCV activity.
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Affiliation(s)
- Xinzhong Liao
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, 610052 Chengdu, PR China
| | - Yancui Wang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, 610052 Chengdu, PR China
| | - Haiyan Ye
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, 610052 Chengdu, PR China
| | - Shilin Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, 610052 Chengdu, PR China
| | - Limin Chen
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, 610052 Chengdu, PR China
| | - Xiaoqiong Duan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, 610052 Chengdu, PR China
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34
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Watanabe T, Imamura T, Hiasa Y. Roles of protein kinase R in cancer: Potential as a therapeutic target. Cancer Sci 2018; 109:919-925. [PMID: 29478262 PMCID: PMC5891186 DOI: 10.1111/cas.13551] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 02/15/2018] [Accepted: 02/17/2018] [Indexed: 01/13/2023] Open
Abstract
Double‐stranded (ds) RNA‐dependent protein kinase (PKR) is a ubiquitously expressed serine/threonine protein kinase. It was initially identified as an innate immune antiviral protein induced by interferon (IFN) and activated by dsRNA. PKR is recognized as a key executor of antiviral host defense. Moreover, it contributes to inflammation and immune regulation through several signaling pathways. In addition to IFN and dsRNA, PKR is activated by multiple stimuli and regulates various signaling pathways including the mitogen‐activated protein kinase (MAPK) and nuclear factor kappa‐light‐chain‐enhancer of activated B cells pathways. PKR was initially thought to be a tumor suppressor as a result of its ability to suppress cell growth and interact with major tumor suppressor genes. However, in several types of malignant disease, such as colon and breast cancers, its role remains controversial. In hepatocellular carcinoma, hepatitis C virus (HCV) is the main cause of liver cancer, and PKR inhibits HCV replication, indicating its role as a tumor suppressor. However, PKR is overexpressed in cirrhotic patients, and acts as a tumor promoter through enhancement of cancer cell growth by mediating MAPK or signal transducer and activator of transcription pathways. Moreover, PKR is reportedly required for the activation of inflammasomes and influences metabolic disorders. In the present review, we introduce the multifaceted roles of PKR such as antiviral function, tumor cell growth, regulation of inflammatory immune responses, and maintaining metabolic homeostasis; and discuss future perspectives on PKR biology including its potential as a therapeutic target for liver cancer.
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Affiliation(s)
- Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takeshi Imamura
- Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.,Translational Research Center, Ehime University Hospital, Toon, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
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35
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Lei J, Hilgenfeld R. RNA-virus proteases counteracting host innate immunity. FEBS Lett 2017; 591:3190-3210. [PMID: 28850669 PMCID: PMC7163997 DOI: 10.1002/1873-3468.12827] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 08/21/2017] [Accepted: 08/22/2017] [Indexed: 01/20/2023]
Abstract
Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.
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Affiliation(s)
- Jian Lei
- Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Germany
| | - Rolf Hilgenfeld
- Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Germany.,German Center for Infection Research (DZIF), Hamburg - Lübeck - Borstel - Riems Site, University of Lübeck, Germany
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36
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Ortega-Prieto AM, Dorner M. Immune Evasion Strategies during Chronic Hepatitis B and C Virus Infection. Vaccines (Basel) 2017; 5:E24. [PMID: 28862649 PMCID: PMC5620555 DOI: 10.3390/vaccines5030024] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 08/25/2017] [Accepted: 08/30/2017] [Indexed: 12/15/2022] Open
Abstract
Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are a major global healthcare problem with more than 240 million and 70 million infected, respectively. Both viruses persist within the liver and result in progressive liver disease, resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma. Strikingly, this pathogenesis is largely driven by immune responses, unable to clear an established infection, rather than by the viral pathogens themselves. Even though disease progression is very similar in both infections, HBV and HCV have evolved distinct mechanisms, by which they ensure persistence within the host. Whereas HCV utilizes a cloak-and-dagger approach, disguising itself as a lipid-like particle and immediately crippling essential pattern-recognition pathways, HBV has long been considered a "stealth" virus, due to the complete absence of innate immune responses during infection. Recent developments and access to improved model systems, however, revealed that even though it is among the smallest human-tropic viruses, HBV may, in addition to evading host responses, employ subtle immune evasion mechanisms directed at ensuring viral persistence in the absence of host responses. In this review, we compare the different strategies of both viruses to ensure viral persistence by actively interfering with viral recognition and innate immune responses.
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Affiliation(s)
| | - Marcus Dorner
- Section of Virology, Department of Medicine, Imperial College London, London W2 1PG, UK.
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37
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Hepatitis C Virus NS5A Targets Nucleosome Assembly Protein NAP1L1 To Control the Innate Cellular Response. J Virol 2017; 91:JVI.00880-17. [PMID: 28659470 DOI: 10.1128/jvi.00880-17] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 06/19/2017] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) is a single-stranded positive-sense RNA hepatotropic virus. Despite cellular defenses, HCV is able to replicate in hepatocytes and to establish a chronic infection that could lead to severe complications and hepatocellular carcinoma. An important player in subverting the host response to HCV infection is the viral nonstructural protein NS5A, which, in addition to its role in replication and assembly, targets several pathways involved in the cellular response to viral infection. Several unbiased screens identified nucleosome assembly protein 1-like 1 (NAP1L1) as an interaction partner of HCV NS5A. Here we confirmed this interaction and mapped it to the C terminus of NS5A of both genotype 1 and 2. NS5A sequesters NAP1L1 in the cytoplasm, blocking its nuclear translocation. However, only NS5A from genotype 2 HCV, and not that from genotype 1, targets NAP1L1 for proteosome-mediated degradation. NAP1L1 is a nuclear chaperone involved in chromatin remodeling, and we demonstrated the NAP1L1-dependent regulation of specific pathways involved in cellular responses to viral infection and cell survival. Among those, we showed that lack of NAP1L1 leads to a decrease of RELA protein levels and a strong defect of IRF3 TBK1/IKKε-mediated phosphorylation, leading to inefficient RIG-I and Toll-like receptor 3 (TLR3) responses. Hence, HCV is able to modulate the host cell environment by targeting NAP1L1 through NS5A.IMPORTANCE Viruses have evolved to replicate and to overcome antiviral countermeasures of the infected cell. Hepatitis C virus is capable of establishing a lifelong chronic infection in the liver, which could develop into cirrhosis and cancer. Chronic viruses are particularly able to interfere with the cellular antiviral pathways by several different mechanisms. In this study, we identified a novel cellular target of the viral nonstructural protein NS5A and demonstrated its role in antiviral signaling. This factor, called nucleosome assembly protein 1-like 1 (NAP1L1), is a nuclear chaperone involved in the remodeling of chromatin during transcription. When it is depleted, specific signaling pathways leading to antiviral effectors are affected. Therefore, we provide evidence for both a novel strategy of virus evasion from cellular immunity and a novel role for a cellular protein, which has not been described to date.
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38
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Extracellular Interactions between Hepatitis C Virus and Secreted Apolipoprotein E. J Virol 2017; 91:JVI.02227-16. [PMID: 28539442 DOI: 10.1128/jvi.02227-16] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 05/04/2017] [Indexed: 12/12/2022] Open
Abstract
Interactions between hepatitis C virus (HCV) and lipoproteins in humans play an important role in the efficient establishment of chronic infection. Apolipoprotein E (ApoE) on the HCV envelope mediates virus attachment to host cells as well as immune evasion. This interaction is thought to occur in hepatocytes, as ApoE plays dual functions in HCV assembly and maturation as well as cell attachment. In the present study, we found that secreted ApoE (sApoE) can also bind to viral particles via its C-terminal domain after HCV is released from the cell. Furthermore, the binding affinity of interactions between the sApoE N terminus and cell surface receptors affected HCV infectivity in a dose-dependent manner. The extracellular binding of sApoE to HCV is dependent on HCV envelope proteins, and recombinant HCV envelope proteins are also able to bind to sApoE. These results suggest that extracellular interactions between HCV and sApoE may potentially complicate vaccine development and studies of viral pathogenesis.IMPORTANCE End-stage liver disease caused by chronic HCV infection remains a clinical challenge, and there is an urgent need for a prophylactic method of controlling HCV infection. Because host immunity against HCV is poorly understood, additional investigations of host-virus interactions in the context of HCV are important. HCV is primarily transmitted through blood, which is rich in lipoproteins. Therefore, it is of interest to further determine how HCV interacts with lipoproteins in human blood. In this study, we found that secreted ApoE (sApoE), an exchangeable component found in lipoproteins, participates in extracellular interactions with HCV virions. More significantly, different variants of sApoE differentially affect HCV infection efficiency in a dose-dependent manner. These findings provide greater insight into HCV infection and host immunity and could help propel the development of new strategies for preventing HCV infection.
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39
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Chang YH, Lau KS, Kuo RL, Horng JT. dsRNA Binding Domain of PKR Is Proteolytically Released by Enterovirus A71 to Facilitate Viral Replication. Front Cell Infect Microbiol 2017; 7:284. [PMID: 28702377 PMCID: PMC5487429 DOI: 10.3389/fcimb.2017.00284] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 06/12/2017] [Indexed: 01/18/2023] Open
Abstract
Enterovirus 71 (EV-A71) causes hand, foot and mouth disease in young children and infants, but can also cause severe neurological complications or even death. The double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), an interferon-induced antiviral protein, phosphorylates the regulatory α-subunit of the eukaryotic translation initiation factor 2 in response to viral infection, thereby blocking the translation of cellular and viral mRNA and promoting apoptosis. The cleavage of PKR after infection with poliovirus, a prototype enterovirus, has been reported by others, but the underlying mechanism of this cleavage and its role in viral replication remain unclear. In the present study, we show that viral 3C protease cleaves PKR at a site, Q188, which differs from the site cleaved during apoptosis, D251. In contrast to the conventional phosphorylation of PKR by dsRNA, EV-A71 3C physically interacts with PKR to mediate the phosphorylation of PKR; this effect is dependent on 3C protease activity. Overexpression of a catalytically inactive PKR mutant (K296H) accelerates viral protein accumulation and increases virus titer, whereas a K64E substitution in the dsRNA binding site abolishes this advantage. We also demonstrate that PKR cleavage mediated by EV-A71 3C protease produces a short N-terminal PKR fragment that can enhance EV-A71 replication, in terms of viral RNA, viral protein, and viral titers. We conclude that PKR is co-opted by EV-A71 via viral protease 3C-mediated proteolytic activation to facilitate viral replication.
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Affiliation(s)
- Yu-Hsiu Chang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan.,National Defense Medical Center, Institute of Preventive MedicineTaipei, Taiwan
| | - Kean Seng Lau
- Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan
| | - Rei-Lin Kuo
- Research Center for Emerging Viral Infections, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan.,Molecular Infectious Disease Research Center, Chang Gung Memorial HospitalTaoyuan, Taiwan
| | - Jim-Tong Horng
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan.,Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan.,Research Center for Emerging Viral Infections, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan.,Molecular Infectious Disease Research Center, Chang Gung Memorial HospitalTaoyuan, Taiwan.,Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and TechnologyTaoyuan, Taiwan
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40
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Holmes JA, Yu ML, Chung RT. Hepatitis B reactivation during or after direct acting antiviral therapy - implication for susceptible individuals. Expert Opin Drug Saf 2017; 16:651-672. [PMID: 28471314 PMCID: PMC5589072 DOI: 10.1080/14740338.2017.1325869] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The FDA issued a warning following 24 cases of HBV reactivation during DAA therapy for HCV, including individuals with inactive, occult and past HBV infection. Clinical presentations ranged from asymptomatic fluctuations in HBV DNA to fulminant hepatic failure, liver transplantation and death. The mechanism is unknown. Areas covered: HCV/HBV coinfection is common, particularly in regions endemic for HBV. HCV and HBV utilize host factors to support replication; both viruses evade/impair host immunity. Clinical presentations of HBV reactivation during DAAs are summarized. Other causes of HBV reactivation are revisited and recent data regarding HBV reactivation are presented. Expert opinion: HBV reactivation during DAAs for HCV occurs, with life-threatening consequences in some individuals. The risk of HBV reactivation is observed in all HBV stages. The rapid removal of HCV likely alters and liberates host-viral ± viral-viral interactions that lead to increased HBV replication. As immune reconstitution occurs with HCV removal, host recognition of HBV DNA likely ensues followed by vigorous host immune responses leading to liver injury (HBV flare). These cases highlight the importance of HBV testing prior to initiating DAA therapy, the need for close monitoring of HBV during therapy and timely administration of anti-HBV therapy to prevent serious sequelae.
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Affiliation(s)
- Jacinta A. Holmes
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, USA
- Department of Gastroenterology, St Vincent’s Hospital, University of Melbourne, Fitzroy, Australia
| | - Ming-Lung Yu
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, USA
- Division of Hepatobiliary, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Raymond T. Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, USA
- Department of Medicine, Harvard Medical School, Boston, USA
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41
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Replication and Oncolytic Activity of an Avian Orthoreovirus in Human Hepatocellular Carcinoma Cells. Viruses 2017; 9:v9040090. [PMID: 28441762 PMCID: PMC5408696 DOI: 10.3390/v9040090] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 04/19/2017] [Accepted: 04/19/2017] [Indexed: 12/13/2022] Open
Abstract
Oncolytic viruses are cancer therapeutics with promising outcomes in pre-clinical and clinical settings. Animal viruses have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. We isolated an avian orthoreovirus (ARV-PB1), and tested it against a panel of hepatocellular carcinoma cells. We found that ARV-PB1 replicated well and induced strong cytopathic effects. It was determined that one mechanism of cell death was through syncytia formation, resulting in apoptosis and induction of interferon stimulated genes (ISGs). As hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma worldwide, we investigated the effect of ARV-PB1 against cells already infected with this virus. Both HCV replicon-containing and infected cells supported ARV-PB1 replication and underwent cytolysis. Finally, we generated in silico models to compare the structures of human reovirus- and ARV-PB1-derived S1 proteins, which are the primary targets of neutralizing antibodies. Tertiary alignments confirmed that ARV-PB1 differs from its human homolog, suggesting that immunity to human reoviruses would not be a barrier to its use. Therefore, ARV-PB1 can potentially expand the repertoire of oncolytic viruses for treatment of human hepatocellular carcinoma and other malignancies.
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Human Herpesvirus 6A Exhibits Restrictive Propagation with Limited Activation of the Protein Kinase R-eIF2α Stress Pathway. J Virol 2017; 91:JVI.02120-16. [PMID: 28202752 PMCID: PMC5391470 DOI: 10.1128/jvi.02120-16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 02/06/2017] [Indexed: 11/28/2022] Open
Abstract
The eIF2α protein plays a critical role in the regulation of translation. The production of double-stranded RNA (dsRNA) during viral replication can activate protein kinase R (PKR), which phosphorylates eIF2α, leading to inhibition of the initial step of translation. Many viruses have evolved gene products targeting the PKR-eIF2a pathway, indicating its importance in antiviral defense. In the present study, we focused on alternations of PKR-eIF2a pathway during human herpesvirus 6A (HHV-6A) infection while monitoring viral gene expression and infectious viral yields. We have found increased phosphorylated PKR as well as phosphorylated eIF2α coincident with accumulation of the late gp82-105 viral protein. The level of total PKR was relatively constant, but it decreased by 144 h postinfection. The phosphorylation of eIF2a led to a moderate increase in activating transcription factor 4 (ATF4) accumulation, indicating moderate inhibition of protein translation during HHV-6A infection. The overexpression of PKR led to decreased viral propagation coincident with increased accumulation of phosphorylated PKR and phosphorylated eIF2a. Moreover, addition of a dominant negative PKR mutant resulted in a moderate increase in viral replication. HHV-6A exhibits relatively low efficiency of propagation of progeny virus secreted into the culture medium. This study suggests that the replicative strategy of HHV-6A involves a mild infection over a lengthy life cycle in culture, while preventing severe activation of the PKR-eIF2α pathway. IMPORTANCE Human herpesvirus 6A (HHV-6A) and HHV-6B are common, widely prevalent viruses, causing from mild to severe disease. Our study focused on the PKR-eIF2α stress pathway, which limits viral replication. The HHV-6 genome carries multiple genes transcribed from the two strands, predicting accumulation of dsRNAs which can activate PKR and inhibition of protein synthesis. We report that HHV-6A induced the accumulation of phosphorylated PKR and phosphorylated eIF2α and a moderate increase of activating transcription factor 4 (ATF4), which is known to transcribe stress genes. Overexpression of PKR led to increased eIF2α phosphorylation and decreased viral replication, whereas overexpression of a dominant negative PKR mutant resulted in a moderate increase in viral replication. These results suggest that the HHV-6A replication strategy involves restricted activation of the PKR-eIF2α pathway, partial translation inhibition, and lower yields of infectious virus. In essence, HHV-6A limits its own replication due to the inability to bypass the eIF2α phosphorylation.
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Zhang Y, Chen LM, He M. Hepatitis C Virus in mainland China with an emphasis on genotype and subtype distribution. Virol J 2017; 14:41. [PMID: 28231805 PMCID: PMC5324300 DOI: 10.1186/s12985-017-0710-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 02/15/2017] [Indexed: 02/08/2023] Open
Abstract
Due to the low fidelity of the RNA-dependent RNA polymerase, Hepatitis C virus (HCV) mutates quite frequently. There are seven genetically divergent genotypes (GTs) distributed in the world, each of which contains several closely related subtypes. The peer-reviewed literatures reporting the prevalence rate of HCV GTs in Chinese hospitalized patients were identified by systematic searching of three electronic databases, and the prevalence rates were pooled through 137 qualified studies. The significant difference between HCV GT and HCV viral load and severity of hepatitis were analyzed under Chi-squared or Fisher's exact test. Data from epidemiological studies on hospitalized patients demonstrated that HCV GTs 1-6 have been found in China, of which 1b (62.78%(95% CI: 59.54-66.02%)) and 2a (17.39% (95% CI: 15.67-19.11%)) are the two predominant subtypes. HCV GTs and subtypes exhibits significant regional divergence. In North, Northwest, Northeast, East (except Jiangxi province) and Central China (except Hunan province), HCV-1b, 2a remain the two predominant subtypes; South China shows the most abundant genetic diversity that 14 subtypes were found, and HCV-3 in the Southwest China remains higher prevalent subtype than the other regions. In addition, co-infection in Liaoning province of Northeast China is the most diverse with 10 co-infection types, and Tibet has the highest rate of co-infection. The associations between HCV GTs and patients group, severity of illness and antiviral treatment efficacy were also discussed in this review.
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Affiliation(s)
- Yu Zhang
- Institute of Blood Transfusion, Peking Union Medical College, Chinese Academy of Medical Sciences, Chengdu, 610052 China
- Sichuan Blood Safety and Blood Substitute, International Science and Technology Cooperation Base, Chengdu, 610052 China
| | - Li-Min Chen
- Institute of Blood Transfusion, Peking Union Medical College, Chinese Academy of Medical Sciences, Chengdu, 610052 China
- Sichuan Blood Safety and Blood Substitute, International Science and Technology Cooperation Base, Chengdu, 610052 China
- Toronto General Research Institute, University of Toronto, Toronto, ON Canada
| | - Miao He
- Institute of Blood Transfusion, Peking Union Medical College, Chinese Academy of Medical Sciences, Chengdu, 610052 China
- Sichuan Blood Safety and Blood Substitute, International Science and Technology Cooperation Base, Chengdu, 610052 China
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Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein. Proc Natl Acad Sci U S A 2017; 114:2018-2023. [PMID: 28159892 DOI: 10.1073/pnas.1614623114] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to down-regulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.
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Ashraf A, Chakravarti A, Roy P, Kar P, Siddiqui O. Frequency of nucleotide sequence variations in the internal ribosome entry site region of hepatitis C virus RNA isolated from responding and non-responding patients with hepatitis C virus genotype 3 infection. Virusdisease 2016; 27:251-259. [PMID: 28466036 PMCID: PMC5394696 DOI: 10.1007/s13337-016-0335-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 07/27/2016] [Indexed: 01/18/2023] Open
Abstract
Located within 5' untranslated region of HCV RNA is internal ribosome entry site (IRES) which directs cap-independent translation of viral polyprotein. Mutations in IRES sequence have been shown to cause changes in efficiency of protein translation in vitro in few instances. No study has been done to investigate association between frequency of nucleotide sequence variations in IRES region of HCV-3 RNA and response to pegylated interferon-α plus ribavirin therapy. Hence, this study was planned to analyze relationship between frequency of nucleotide sequence variations of HCV-3 IRES region and response to therapy. Twenty-seven HCV-3 patients were studied, of whom 19 responded to therapy and 8 did not. Alanine aminotransferase and aspartate aminotransferase levels were significantly lower in responders compared to non-responders. HCV RNA detection and genotyping was performed by nested-PCR and RFLP respectively. Viral load quantification in pre and post therapy samples was done by real time PCR. The viral load was significantly lower in the patients after treatment as compared to before treatment. HCV IRES region from pre-treatment sera of 27 HCV-3 infected patients was amplified by nested PCR and sequenced. Secondary structure of IRES region of HCV-3 was predicted using the M fold Web Server. Mutational analysis revealed hot spot of mutations in HCV-3 IRES region from 40-80 and 210-280 nucleotides. Though more mutations were found in non-responders as compared to responders, this difference was statistically insignificant. Therefore, in addition to IRES region of HCV-3, some other host and viral factors may contribute to therapy outcome.
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Affiliation(s)
- Anzar Ashraf
- Virology Laboratory, Department of Microbiology, Maulana Azad Medical College, New Delhi, Delhi 110002 India
| | - Anita Chakravarti
- Virology Laboratory, Department of Microbiology, Maulana Azad Medical College, New Delhi, Delhi 110002 India
- 79, South Park Apartment, Kalkaji, New Delhi, Delhi 110019 India
| | - Priyamvada Roy
- Virology Laboratory, Department of Microbiology, Maulana Azad Medical College, New Delhi, Delhi 110002 India
| | - Premashish Kar
- Department of Medicine, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, Delhi 110002 India
| | - Oves Siddiqui
- Virology Laboratory, Department of Microbiology, Maulana Azad Medical College, New Delhi, Delhi 110002 India
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Innate immunity against hepatitis C virus. Curr Opin Immunol 2016; 42:98-104. [PMID: 27366996 DOI: 10.1016/j.coi.2016.06.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 06/09/2016] [Accepted: 06/15/2016] [Indexed: 12/24/2022]
Abstract
Hepatitis C virus (HCV) infection tends persistent and causes chronic liver diseases, including inflammation, cirrhosis and hepatocellular carcinoma. Innate immune responses triggered by HCV infection, particularly the production of interferons and pro-inflammatory cytokines, shape the early host antiviral defense, and orchestrate subsequent HCV-specific adaptive immunity. Host has evolved multifaceted means to sense HCV infection to induce innate immune responses, whereas HCV has also developed elaborate strategies to evade immune attack. Recent studies in the field have provided many new insights into the interplay of HCV and innate immunity. In this review, we summarized these recent advances, focusing on pathogen recognition by innate sensors, newly discovered anti-HCV innate effectors and new viral strategies to evade innate immunity.
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Champeimont R, Laine E, Hu SW, Penin F, Carbone A. Coevolution analysis of Hepatitis C virus genome to identify the structural and functional dependency network of viral proteins. Sci Rep 2016; 6:26401. [PMID: 27198619 PMCID: PMC4873791 DOI: 10.1038/srep26401] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 05/03/2016] [Indexed: 12/20/2022] Open
Abstract
A novel computational approach of coevolution analysis allowed us to reconstruct the protein-protein interaction network of the Hepatitis C Virus (HCV) at the residue resolution. For the first time, coevolution analysis of an entire viral genome was realized, based on a limited set of protein sequences with high sequence identity within genotypes. The identified coevolving residues constitute highly relevant predictions of protein-protein interactions for further experimental identification of HCV protein complexes. The method can be used to analyse other viral genomes and to predict the associated protein interaction networks.
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Affiliation(s)
- Raphaël Champeimont
- Sorbonne Universités, UPMC-Univ P6, CNRS, Laboratoire de Biologie Computationnelle et Quantitative - UMR 7238, 15 rue de l’Ecole de Médecine, 75006 Paris, France
| | - Elodie Laine
- Sorbonne Universités, UPMC-Univ P6, CNRS, Laboratoire de Biologie Computationnelle et Quantitative - UMR 7238, 15 rue de l’Ecole de Médecine, 75006 Paris, France
| | - Shuang-Wei Hu
- Sorbonne Universités, UPMC-Univ P6, CNRS, Laboratoire de Biologie Computationnelle et Quantitative - UMR 7238, 15 rue de l’Ecole de Médecine, 75006 Paris, France
| | - Francois Penin
- CNRS, UMR5086, Bases Moléculaires et Structurales des Systèmes Infectieux, Institut de Biologie et Chimie des Protéines, 7 Passage du Vercors, Cedex 07, F-69367 Lyon, France
- LABEX Ecofect, Université de Lyon, Lyon, France
| | - Alessandra Carbone
- Sorbonne Universités, UPMC-Univ P6, CNRS, Laboratoire de Biologie Computationnelle et Quantitative - UMR 7238, 15 rue de l’Ecole de Médecine, 75006 Paris, France
- Institut Universitaire de France, 75005, Paris, France
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Honda T. Links between Human LINE-1 Retrotransposons and Hepatitis Virus-Related Hepatocellular Carcinoma. Front Chem 2016; 4:21. [PMID: 27242996 PMCID: PMC4863659 DOI: 10.3389/fchem.2016.00021] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/22/2016] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposon, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.
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Affiliation(s)
- Tomoyuki Honda
- Department of Viral Oncology, Institute for Virus Research, Kyoto UniversityKyoto, Japan; Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of MedicineSuita, Japan
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Fabre T, Shoukry NH. Immunology of the Liver. ENCYCLOPEDIA OF IMMUNOBIOLOGY 2016:13-22. [DOI: 10.1016/b978-0-12-374279-7.19005-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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50
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Serum level of interleukin-8 and interleukin-10 as predictors for response to interferon–ribavirin combined therapy. EGYPTIAN LIVER JOURNAL 2016. [DOI: 10.1097/01.elx.0000481902.94221.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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