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Acchioni C, Sandini S, Acchioni M, Sgarbanti M. Co-Infections and Superinfections between HIV-1 and Other Human Viruses at the Cellular Level. Pathogens 2024; 13:349. [PMID: 38787201 PMCID: PMC11124504 DOI: 10.3390/pathogens13050349] [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: 03/16/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Co-infection or superinfection of the host by two or more virus species is a common event, potentially leading to viral interference, viral synergy, or neutral interaction. The simultaneous presence of two or more viruses, even distantly related, within the same cell depends upon viral tropism, i.e., the entry of viruses via receptors present on the same cell type. Subsequently, productive infection depends on the ability of these viruses to replicate efficiently in the same cellular environment. HIV-1 initially targets CCR5-expressing tissue memory CD4+ T cells, and in the absence of early cART initiation, a co-receptor switch may occur, leading to the infection of naïve and memory CXCR4-expressing CD4+ T cells. HIV-1 infection of macrophages at the G1 stage of their cell cycle also occurs in vivo, broadening the possible occurrence of co-infections between HIV-1 and other viruses at the cellular level. Moreover, HIV-1-infected DCs can transfer the virus to CD4+ T cells via trans-infection. This review focuses on the description of reported co-infections within the same cell between HIV-1 and other human pathogenic, non-pathogenic, or low-pathogenic viruses, including HIV-2, HTLV, HSV, HHV-6/-7, GBV-C, Dengue, and Ebola viruses, also discussing the possible reciprocal interactions in terms of virus replication and virus pseudotyping.
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Affiliation(s)
| | | | | | - Marco Sgarbanti
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (C.A.); (S.S.); (M.A.)
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Du Y, Yu X, Chang ET, Lian S, Wu B, Li F, Chu B, Wei K, Zhan J, Liang X, Ye W, Ji M. Pre-diagnostic anti-EBV antibodies and primary liver cancer risk: a population-based nested case-control study in southern China. BMC Cancer 2023; 23:250. [PMID: 36922768 PMCID: PMC10015780 DOI: 10.1186/s12885-023-10709-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 03/06/2023] [Indexed: 03/17/2023] Open
Abstract
BACKGROUND We aimed to investigate associations between pre-diagnostic anti-Epstein-Barr virus (EBV) antibodies, including interactions with hepatitis B virus (HBV), and risk of primary liver cancer in southern China. METHODS In a population-based nested case-control study, we measured pre-diagnostic immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA) in 125 primary liver cancer cases and 2077 matched controls. We also explored the interaction between HBV surface antigen (HBsAg) and anti-EBV antibodies. RESULTS Participants with positive EBNA1-IgA, positive VCA-IgA or single-positive anti-EBV antibodies had two-fold odds of developing liver cancer, compared with seronegative subjects. The odds ratios (ORs) between the relative optical density of EBNA1-IgA and VCA-IgA and primary cancer, controlling for age and HBsAg, were 1.59 (95% confidence interval (CI): 1.17, 2.14) and 1.60 (95% CI: 1.07, 2.41), respectively. Subjects with both HBsAg and anti-EBV antibody seropositivity were at 50-fold increased risk compared with those negative for both biomarkers (OR: 50.67, 95% CI: 18.28, 140.46), yielding a relative excess risk due to interaction of 30.81 (95% CI: 3.42, 114.93). CONCLUSION Pre-diagnostic seropositivity for EBNA1-IgA and/or VCA-IgA was positively associated with primary liver cancer risk, especially in combination with HBsAg positivity. EBV may interact with HBV in the development of primary liver cancer, and anti-EBV antibodies might be potential biomarkers for primary liver cancer in this high-risk population.
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Affiliation(s)
- Yun Du
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Xia Yu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Ellen T Chang
- Department of Epidemiology and Biostatistics, University of California, California, USA
| | - Shifeng Lian
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Biaohua Wu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Bing Chu
- Department of Pathology, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Kuangrong Wei
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Jiyun Zhan
- Xiaolan Public Health Service Center, Zhongshan, 528400, People's Republic of China
| | - Xuejun Liang
- Xiaolan Public Health Service Center, Zhongshan, 528400, People's Republic of China
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden.
| | - Mingfang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China.
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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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Hua Y, Song J, Peng C, Wang R, Ma Z, Zhang J, Zhang Z, Li N, Hou L. Advances in the Relationship Between Regulator of Ribosome Synthesis 1 (RRS1) and Diseases. Front Cell Dev Biol 2021; 9:620925. [PMID: 33718361 PMCID: PMC7947238 DOI: 10.3389/fcell.2021.620925] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 01/20/2021] [Indexed: 12/12/2022] Open
Abstract
A regulator of ribosome synthesis 1 (RRS1) was discovered in yeast and is mainly localized in the nucleolus and endoplasmic reticulum. It regulates ribosomal protein, RNA biosynthesis, and protein secretion and is closely involved in cellular senescence, cell cycle regulation, transcription, translation, oncogenic transformation etc., Mutations in the RRS1 gene are associated with the occurrence and development of Huntington’s disease and cancer, and overexpression of RRS1 promotes tumor growth and metastasis. In this review, the structure, function, and mechanisms of RRS1 in various diseases are discussed.
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Affiliation(s)
- Yanan Hua
- Department of Neurobiology, Basic Medical College, Qingdao University, Qingdao, China
| | - Jinlian Song
- Department of Laboratory, Women and Children's Hospital of Qingdao, Qingdao, China
| | - Cuixiu Peng
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Runze Wang
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Zhongliang Ma
- Department of Breast Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jinyu Zhang
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Zheng Zhang
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Ning Li
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Lin Hou
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, China
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5
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Marrone A, Ciotti M, Rinaldi L, Adinolfi LE, Ghany M. Hepatitis B and C virus infection and risk of haematological malignancies. J Viral Hepat 2020; 27:4-12. [PMID: 31325404 DOI: 10.1111/jvh.13183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/23/2019] [Accepted: 06/20/2019] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are classified as oncogenic human viruses. Chronic HBV and HCV infections are associated with higher risk of haematological malignancy development. Direct and indirect oncogenic mechanisms have been demonstrated for both HBV and HCV in several studies. HCV and overt/occult HBV infections in patients with oncohaematological disease constitute an impediment and a threat during immunosuppressive chemotherapy treatment. We review the HBV and HCV oncogenic mechanisms and the impact and the safety of antiviral treatment in patients with haematological malignancies.
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Affiliation(s)
- Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marco Ciotti
- Laboratory of Clinical Microbiology and Virology, Polyclinic Tor Vergata Foundation, Rome, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marc Ghany
- Liver Diseases Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA
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The Negative Effect of Epstein-Barr Virus on the Response of Hepatitis C Virus Patients to Interferon-ribavirin Therapy. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2019. [DOI: 10.22207/jpam.13.2.59] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Shoman S, Nabil M, Tabl A, Ghanem H, kafrawy SE. Assessment of immunological changes in Epstein-Barr virus co-infection in Egyptian chronic HCV patients. Mem Inst Oswaldo Cruz 2014; 109:722-727. [PMID: 25317700 PMCID: PMC4238763 DOI: 10.1590/0074-0276140049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 06/02/2014] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus (EBV) plays a major role in liver pathology. Similar to other members of the herpesvirus family, EBV establishes a persistent infection in more than 90% of adults. The aim of this study was to evaluate the impact of EBV and chronic hepatitis C co-infection (HCV) on biochemical and immunological responses in patients. The study was conducted in 62 patients and 33 apparently healthy controls. Patients were divided into three groups: group I, consisting of 31 patients with chronic hepatitis C infection (CHC), group II, consisting of eight patients with EBV infection and without HCV infection and group III, consisting of 23 patients with EBV and chronic HCV. The percentage of CD3⁺ cells, helper CD4⁺ cells and CD19⁺ B-cells was measured by flow cytometry. Human interferon-γ (IFN-γ) and interleukin (IL)-15 levels were measured by an ELISA. The levels of liver alanine aminotransferase and aspartate aminotransferase enzymes were higher in EBV/HCV patients compared to that in EBV and HCV mono-infected patients. EBV/HCV patients had significantly reduced percentages of CD3⁺ and CD4⁺ cells compared to EBV patients. Serum IFN-γ levels were significantly reduced in EBV/HCV patients (3.86 pg/mL) compared to CHC patients (6.76 pg/mL) and normal controls (4.69 pg/mL). A significant increase in serum IL-15 levels was observed in EBV/HCV patients (67.7 pg/mL) compared to EBV patients (29.3 pg/mL). Taken together, these observations suggest that HCV and EBV co-infection can potentiate immune response dampening in patients.
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Affiliation(s)
- Sahar Shoman
- Department of Microbiology, Faculty of Science, Ain Shams University,
Cairo, Egypt
| | - Mohamed Nabil
- Department of Microbiology, Faculty of Science, Ain Shams University,
Cairo, Egypt
| | - Ashraf Tabl
- Department of Microbial Biotechnology, National Research Centre, Giza,
Egypt
| | - Hussam Ghanem
- Department of Microbiology, Faculty of Science, Ain Shams University,
Cairo, Egypt
| | - Sherif El kafrawy
- National Liver Institute, Menufia, Egypt
- King Fahd Medical Research Canter-King Abdulaziz University, Jada,
Kingdom of Saudi Arabia
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8
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Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol 2013; 59:169-77. [PMID: 23542089 DOI: 10.1016/j.jhep.2013.03.018] [Citation(s) in RCA: 145] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 03/16/2013] [Accepted: 03/19/2013] [Indexed: 12/14/2022]
Abstract
There is ample epidemiologic evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin lymphoma (B-NHL). B-NHL subtypes most frequently associated with HCV are marginal zone lymphoma and diffuse large B-cell lymphoma. The most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). In fact, for indolent HCV-associated B-NHL, first-line AVT instead of standard immune-chemotherapy might be considered. Molecular mechanisms of HCV-NHL development are still poorly understood. Three general theories have emerged to understand the HCV-induced lymphomagenesis: (1) continuous external stimulation of lymphocyte receptors by viral antigens and consecutive proliferation; (2) HCV replication in B cells with oncogenic effect mediated by intracellular viral proteins; (3) permanent B-cell damage, e.g., mutation of tumor suppressor genes, caused by a transiently intracellular virus ("hit and run" theory). This review systematically summarizes the data on epidemiology, interventional studies, and molecular mechanisms of HCV-associated B-NHL.
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Forghieri F, Luppi M, Barozzi P, Maffei R, Potenza L, Narni F, Marasca R. Pathogenetic mechanisms of hepatitis C virus-induced B-cell lymphomagenesis. Clin Dev Immunol 2012; 2012:807351. [PMID: 22844326 PMCID: PMC3403122 DOI: 10.1155/2012/807351] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 06/01/2012] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) infection is probably the most common chronic viral infection and affects an estimated 180 million people worldwide, accounting for 3% of the global population. Although the liver is considered to be the primary target, extrahepatic manifestations are well recognized among patients with chronic HCV infection. Epidemiological studies have clearly demonstrated a correlation between chronic HCV infection and occurrence of B-cell non-Hodgkin's lymphomas (B-NHL). The clinical evidence that antiviral therapy has a significant role in the treatment at least of some HCV-associated lymphoproliferative disorders, especially indolent B-NHL, further supports the existence of an etiopathogenetic link. However, the mechanisms exploited by HCV to induce B-cell lymphoproliferation have so far not completely clarified. It is conceivable that different biological mechanisms, namely, chronic antigen stimulation, high-affinity interaction between HCV-E2 protein and its cellular receptors, direct HCV infection of B-cells, and "hit and run" transforming events, may be combined themselves and cooperate in a multifactorial model of HCV-associated lymphomagenesis.
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Affiliation(s)
- Fabio Forghieri
- Department of Oncology, Hematology, and Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy
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Borkosky SS, Whitley C, Kopp-Schneider A, zur Hausen H, deVilliers EM. Epstein-Barr virus stimulates torque teno virus replication: a possible relationship to multiple sclerosis. PLoS One 2012; 7:e32160. [PMID: 22384166 PMCID: PMC3285200 DOI: 10.1371/journal.pone.0032160] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Accepted: 01/24/2012] [Indexed: 11/20/2022] Open
Abstract
Viral infections have been implicated in the pathogenesis of multiple sclerosis. Epstein-Barr virus (EBV) has frequently been investigated as a possible candidate and torque teno virus (TTV) has also been discussed in this context. Nevertheless, mechanistic aspects remain unresolved. We report viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain in a series of EBV-positive and -negative lymphoblastoid and Burkitt's lymphoma cell lines. Our results demonstrate the replication of both transfected TTV genomes up to day 21 post transfection in all the evaluated cell lines. Quantitative amplification indicates statistically significant enhanced TTV replication in the EBV-positive cell lines, including the EBV-converted BJAB line, in comparison to the EBV-negative Burkitt's lymphoma cell line BJAB. This suggests a helper effect of EBV infections in the replication of TTV. The present study provides information on a possible interaction of EBV and TTV in the etiology and progression of multiple sclerosis.
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Affiliation(s)
- Silvia S. Borkosky
- Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Corinna Whitley
- Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | | | - Harald zur Hausen
- Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Ethel-Michele deVilliers
- Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
- * E-mail:
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Kondo Y, Ueno Y, Shimosegawa T. Biological significance of HCV in various kinds of lymphoid cells. Int J Microbiol 2012; 2012:647581. [PMID: 22518147 PMCID: PMC3299277 DOI: 10.1155/2012/647581] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 12/12/2011] [Indexed: 12/21/2022] Open
Abstract
It has been reported that HCV can infect not only hepatocytes but also various kinds of lymphoid cells. Although many reports have described the biological significance of lymphotropic HCV, the issue remains controversial since the target lymphoid cells might have various kinds of functions in the immune system. One of the important roles of lymphoid cells in HCV replication is being a reservoir of HCV. Several groups described the detection of HCV-RNA in lymphoid cells after HCV eradication in plasma. Another important role of lymphotropic HCV is that it acts as a carcinogenic agent and induces immune dysfunction. In this paper, we summarize the reports regarding the biological significance of lymphotropic HCV in representative lymphoid cells.
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Affiliation(s)
- Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
| | - Yoshiyuki Ueno
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
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12
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Plasmablastic lymphoma associated to Crohn's disease and hepatitis C virus chronic infection. J Crohns Colitis 2011; 5:628-32. [PMID: 22115386 DOI: 10.1016/j.crohns.2011.07.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 07/05/2011] [Accepted: 07/05/2011] [Indexed: 02/08/2023]
Abstract
Plasmablastic lymphoma is a very rare and recently-described subtype of diffuse large B-cell lymphoma. It has a poor prognosis despite intensive chemotherapy treatment. A 57-year old woman with perianal Crohn's disease receiving azathioprine and infliximab developed this type of lymphoma after a short period of time on the treatment. She also had a hepatitis C virus chronic infection which had not been diagnosed or treated before. There is no solid scientific evidence that either immunomodulators or anti-TNF drugs have a definitive role in the appearance of malignancies, and therefore there are no clear recommendations to limit their use. In these patients, there are some other factors we have to take into account, like the inflammatory bowel disease in itself and its behaviour over time, or the comorbidities of the patient, with special attention to virus infections. In this case report, we will analyse the role of these factors in the development of lymphoproliferative disorders and the recommendations given by experts to avoid their appearance.
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van den Bosch C. A Role for RNA Viruses in the Pathogenesis of Burkitt's Lymphoma: The Need for Reappraisal. Adv Hematol 2011; 2012:494758. [PMID: 22550493 PMCID: PMC3328886 DOI: 10.1155/2012/494758] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 11/11/2011] [Indexed: 12/14/2022] Open
Abstract
Certain infectious agents are associated with lymphomas, but the strength of the association varies geographically, suggesting that local environmental factors make important contributions to lymphomagenesis. Endemic Burkitt's Lymphoma has well-defined environmental requirements making it particularly suitable for research into local environmental factors. The Epstein-Barr virus and holoendemic Malaria are recognized as important cofactors in endemic Burkitt's Lymphoma and their contributions are discussed. Additionally, infection with Chikungunya Fever, a potentially oncogenic arbovirus, was associated with the onset of endemic Burkitt's Lymphoma in one study and also with space-time case clusters of the lymphoma. Chikungunya Virus has several characteristics typical of oncogenic viruses. The Flavivirus, Hepatitis C, a Class 1 Human Carcinogen, closely related to the arboviruses, Yellow Fever, and Dengue, is also more distantly related to Chikungunya Virus. The mechanisms of oncogenesis believed to operate in Hepatitis C lymphomagenesis are discussed, as is their potential applicability to Chikungunya Virus.
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Affiliation(s)
- Corry van den Bosch
- Research Facilitation Forum, Pilgrims Hospices, Canterbury, Kent CT2 8JA, UK
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14
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Shimozuma Y, Ito T, Inokuchi M, Uchikoshi M, Miyashita M, Nozawa H, Shimazaki T, Hiroishi K, Imawari M. Reactivation of epstein-barr virus in B cells of patients with chronic hepatitis C. J Med Virol 2010; 82:2064-72. [DOI: 10.1002/jmv.21890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 2010; 117:1792-8. [PMID: 20959600 DOI: 10.1182/blood-2010-06-275818] [Citation(s) in RCA: 182] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Over the past 2 decades considerable evidence has accumulated on the association between hepatitis C virus (HCV) and hepatitis B virus (HBV) and several hematologic malignancies, most notably B-cell non-Hodgkin lymphoma (NHL). In this review we summarize this evidence, address possible mechanisms whereby hepatitis viruses may contribute to lymphomagenesis, and discuss the therapeutic fallouts from this knowledge. Most of this evidence is on HCV, and this is the main focus of the review. Moreover, we mainly address the association with NHL, the most prevalent hematologic malignancy, and the most extensively investigated with regard to an association with hepatitis viruses. Available evidence on the association with other hematologic malignancies is also addressed briefly.
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Abstract
The Epstein-Barr virus (EBV) has an important and multifaceted role in liver pathology. As a member of the herpes virus family, EBV establishes a persistent infection in more than 90% of adults. Besides acute hepatitis during primary infection, many clinical syndromes of interest for the hepatologist are associated with EBV infection. The role of EBV in the evolution of chronic hepatitis from hepatotropic viruses is considered. Chronic EBV-associated hepatitis is suspected in immunocompetent adults with compatible serology, suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T-lymphocytes. EBV is the main cause of post-transplant lymphoproliferative disorders which occur in up to 30% of cases. EBV-driven lymphoproliferative diseases are also recognized in non-immunocompromised patients and liver is involved in up to a third of the cases. Directly implicated in the pathogenesis of different tumors, EBV has a disputable role in hepatocellular carcinoma carcinogenesis. Further research is required in order to establish or reject the role of EBV in human liver cancer. This paper attempts to discuss the range of EBV-associated chronic liver diseases in immunocompetent patients, from mild, self-limiting mononuclear hepatitis to liver cancer.
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17
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Abstract
Hepatitis C (HCV) is the disease that has affected around 200 million people globally. HCV is a life threatening human pathogen, not only because of its high prevalence and worldwide burden but also because of the potentially serious complications of persistent HCV infection. Chronicity of the disease leads to cirrhosis, hepatocellular carcinoma and end-stage liver disease. HCV positive hepatocytes vary between less than 5% and up to 100%, indicating the high rate of replication of viral RNA. HCV has a very high mutational rate that enables it to escape the immune system. Viral diversity has two levels; the genotypes and Quasiaspecies. Major HCV genotypes constitute genotype 1, 2, 3, 4, 5 and 6 while more than 50 subtypes are known. All HCV genotypes have their particular patterns of geographical distribution and a slight drift in viral population has been observed in some parts of the globe.
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Affiliation(s)
- Nazish Bostan
- Department of Biological Sciences, Quaid-i-Azam University, Islamabad-45320, Pakistan
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18
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Petrova M, Kamburov V, Nikolovska D, Kosseva O, Nikolova M, Krastev Z. Epstein-Barr virus: is there any contribution to chronic hepatitis B and C? Liver Int 2010; 30:488-9. [PMID: 19840248 DOI: 10.1111/j.1478-3231.2009.02138.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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19
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DaPalma T, Doonan BP, Trager NM, Kasman LM. A systematic approach to virus-virus interactions. Virus Res 2010; 149:1-9. [PMID: 20093154 PMCID: PMC7172858 DOI: 10.1016/j.virusres.2010.01.002] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2009] [Revised: 01/02/2010] [Accepted: 01/06/2010] [Indexed: 02/02/2023]
Abstract
A virus–virus interaction is a measurable difference in the course of infection of one virus as a result of a concurrent or prior infection by a different species or strain of virus. Many such interactions have been discovered by chance, yet they have rarely been studied systematically. Increasing evidence suggests that virus–virus interactions are common and may be critical to understanding viral pathogenesis in natural hosts. In this review we propose a system for classifying virus–virus interactions by organizing them into three main categories: (1) direct interactions of viral genes or gene products, (2) indirect interactions that result from alterations in the host environment, and (3) immunological interactions. We have so far identified 15 subtypes of interaction and assigned each to one of these categories. It is anticipated that this framework will provide for a more systematic approach to investigating virus–virus interactions, both at the cellular and organismal levels.
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Affiliation(s)
- T DaPalma
- Dept. of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, United States
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20
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Murakami K, Kimura T, Osaki M, Ishii K, Miyamura T, Suzuki T, Wakita T, Shoji I. Virological characterization of the hepatitis C virus JFH-1 strain in lymphocytic cell lines. J Gen Virol 2008; 89:1587-1592. [PMID: 18559928 DOI: 10.1099/vir.0.83618-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
While hepatocytes are the major site of hepatitis C virus (HCV) infection, a number of studies have suggested that HCV can replicate in lymphocytes. However, in vitro culture systems to investigate replication of HCV in lymphocytic cells are severely limited. Robust HCV culture systems have been established using the HCV JFH-1 strain and Huh-7 cells. To gain more insights into the tissue tropism of HCV, we investigated the infection, replication, internal ribosome entry site (IRES)-dependent translation and polyprotein processing of the HCV JFH-1 strain in nine lymphocytic cell lines. HCV JFH-1 failed to infect lymphocytes and replicate, but exhibited efficient polyprotein processing and IRES-dependent translation in lymphocytes as well as in Huh-7 cells. Our results suggest that lymphocytic cells can support HCV JFH-1 translation and polyprotein processing, but may lack some host factors essential for HCV JFH-1 infection and replication.
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Affiliation(s)
- Kyoko Murakami
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Toshiro Kimura
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Motonao Osaki
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Koji Ishii
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Tatsuo Miyamura
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Tetsuro Suzuki
- 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
| | - Ikuo Shoji
- Division of Microbiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
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21
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Abstract
To enable detailed analyses of cell interactions in tumour development, new epithelial and mesenchymal cell lines were established from human hepatocellular carcinoma by spontaneous outgrowth in culture. We obtained several hepatocarcinoma (HCC)-, B-lymphoblastoid (BLC)-, and myofibroblastoid (MF)-lines from seven cases. In-depth characterisation included cell kinetics, genotype, tumourigenicity, expression of cell-type specific markers, and proteome patterns. Many functions of the cells of origin were found to be preserved. We studied the impact of the mesenchymal lines on hepatocarcinogenesis by in vitro assays. BLC- and MF-supernatants strongly increased the DNA replication of premalignant hepatocytes. The stimulation by MF-lines was mainly attributed to HGF secretion. In HCC-cells, MF-supernatant had only minor effects on cell growth but enhanced migration. MF-lines also stimulated neoangiogenesis through vEGF release. BLC-supernatant dramatically induced death of HCC-cells, which could be largely abrogated by preincubating the supernatant with TNFβ-antiserum. Thus, the new cell lines reveal stage-specific stimulatory and inhibitory interactions between mesenchymal and epithelial tumour cells. In conclusion, the new cell lines provide unique tools to analyse essential components of the complex interplay between the microenvironment and the developing liver cancer, and to identify factors affecting proliferation, migration and death of tumour cells, neoangiogenesis, and outgrowth of additional malignancy.
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Zignego AL, Giannini C, Monti M, Gragnani L. Hepatitis C virus lymphotropism: lessons from a decade of studies. Dig Liver Dis 2007; 39 Suppl 1:S38-45. [PMID: 17936221 DOI: 10.1016/s1590-8658(07)80009-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The possibility that HCV infects lymphoid cells has been widely discussed. Evidence in favor of HCV tropism for lymphoid cells derives from a series of data including: (1) the higher sensitivity of testing HCVRNA in PBMC than in serum or plasma samples, with possible detection of HCV RNA-positive PBMC in the absence of HCV viremia; (2) short-term cultures of PBMC which yield a significant increase in the amount of viral RNA on stimulation by mitogens; (3) results of "in situ" methods (i.e. in situ hybridization, immunofluorescence); (4) efficient infection of lymphoid cell lines or PBMC from normal individuals; (5) the persistence of HCV RNA in PBMC obtained from HCV-positive subjects and injected into SCID mice; (6) the long-term persistence of HCV RNA in PBMC in spite of HCV RNA negativity of serum and liver in sustained responder patients after therapy. The principal criticisms concerning effective HCV infection of lymphoid cells arise from technical difficulty in identifying HCV RNA replicative intermediate in these elements. Conflicting data may also result from differences in PBMC infection by different genotypes, samples taken at different stages in the disease process and differences in the sensitivity of detection methods, as well as low replication levels and/or proportion of infected PBMC. Interesting available data about HCV lymphotropism, which is possibly important in influencing the natural history of infection, include: (1) possible preferential viral tropism for specific PBMC subsets; (2) different lymphotropism of different viral strains; (3) selection of distinctive viral strains; (4) identification of putative HCV cell receptors; (5) association between determination of HCV lymphatic infection and t(14; 18) translocation. The clinical correlates of HCV lymphotropism are potentially very numerous, including, first, its role in determining HCV-related lymphoproliferative disorders.
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Affiliation(s)
- A L Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Internal Medicine, University of Florence, Florence, Italy.
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23
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Hjalgrim H, Friborg J, Melbye M. The epidemiology of EBV and its association with malignant disease. HUMAN HERPESVIRUSES 2007:929-959. [DOI: 10.1017/cbo9780511545313.054] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Petrova M, Muhtarova M, Nikolova M, Magaev S, Taskov H, Nikolovska D, Krastev Z. Chronic Epstein-Barr virus-related hepatitis in immunocompetent patients. World J Gastroenterol 2006; 12:5711-6. [PMID: 17007027 PMCID: PMC4088175 DOI: 10.3748/wjg.v12.i35.5711] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate reactivated Epstein-Barr virus (EBV) infection as a cause for chronic hepatitis.
METHODS: Patients with occasionally established elevated serum aminotransferases were studied. HIV, HBV and HCV-infections were excluded as well as any other immunosuppressive factors, metabolic or toxic disorders. EBV viral capsid antigen (VCA) IgG and IgM, EA-R and EA-D IgG and Epstein-Barr nuclear antigen (EBNA) were measured using IFA kits. Immunophenotyping of whole blood was performed by multicolor flow cytometry. CD8+ T cell responses to EBV and PHA were determined according to the intracellular expression of IFN-γ.
RESULTS: The mean alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGTP) values exceeded twice the upper normal limit, AST/ALT ratio < 1. Serology tests showed reactivated EBV infection in all patients. Absolute number and percentages of T, B and NK cells were within the reference ranges. Fine subset analysis, in comparison to EBV+ healthy carriers, revealed a significant decrease of naive T cells (P < 0.001), accompanied by increased percentage of CD45RA- (P < 0.0001), and terminally differentiated CD28-CD27-CD8+ T cells (P < 0.01). Moderately elevated numbers of CD38 molecules on CD8+ T cells (P < 0.05) proposed a low viral burden. A significantly increased percentage of CD8+ T cells expressing IFN-γ in response to EBV and PHA stimulation was registered in patients, as compared to controls (P < 0.05). Liver biopsy specimens from 5 patients revealed nonspecific features of low-grade hepatitis.
CONCLUSION: Chronic hepatitis might be a manifestation of chronic EBV infection in the lack of detectable immune deficiency; the expansion of CD28-CD27- and increase of functional EBV-specific CD8+ T cells being the only surrogate markers of viral activity.
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Affiliation(s)
- Mihaela Petrova
- Clinic of Gastroenterology, Medical Institute Ministry of Interior, Skobelev 79, Sofia 1606, Bulgaria.
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25
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Nasimuzzaman M, Kuroda M, Dohno S, Yamamoto T, Iwatsuki K, Matsuzaki S, Mohammad R, Kumita W, Mizuguchi H, Hayakawa T, Nakamura H, Taguchi T, Wakiguchi H, Imai S. Eradication of Epstein-Barr virus episome and associated inhibition of infected tumor cell growth by adenovirus vector-mediated transduction of dominant-negative EBNA1. Mol Ther 2005; 11:578-90. [PMID: 15771960 DOI: 10.1016/j.ymthe.2004.12.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2003] [Accepted: 12/18/2004] [Indexed: 11/28/2022] Open
Abstract
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1), a latent viral protein consistently expressed in infected proliferating cells, is essentially required in trans to maintain EBV episomes in cells. We constructed a mutant (mt) EBNA1 and examined whether it exerted dominant-negative effects on maintenance of the viral episome thereby leading to abrogation of EBV-infected tumor cell growth. Using lymphocyte and epithelial cell lines converted with neomycin-resistant recombinant EBV (rEBV) as models, adenovirus vector-mediated transduction of mtEBNA1, but not LacZ, brought about rapid and striking reductions in rEBV-derived wild-type EBNA1 levels and viral genomic loads in converted lines of three major viral latencies. This outcome was further validated at the single-cell level by cellular loss of G418 resistance and viral signals in situ. The mtEBNA1 transduction significantly impaired growth of naturally EBV-harboring Burkitt lymphoma cells in vitro and in vivo, largely in association with the eradication of viral episomes. Expression of mtEBNA1 per se caused no detectable cytotoxicity in EBV-uninfected cells. These results indicate that mtEBNA1 can act as a dominant-negative effector that efficiently impedes the EBV-dependent malignant phenotypes in cells regardless of viral latency or tissue origin. The mutant will afford an additional therapeutic strategy specifically targeting EBV-associated malignancies.
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Affiliation(s)
- Md Nasimuzzaman
- Department of Molecular Microbiology and Infections, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan
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26
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Si MW, Thorson JA, Lauwers GY, DalCin P, Furman J. Hepatocellular lymphoepithelioma-like carcinoma associated with epstein barr virus: a hitherto unrecognized entity. ACTA ACUST UNITED AC 2005; 13:183-9. [PMID: 15322431 DOI: 10.1097/01.pas.0000124336.90615.8d] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Lymphoepithelioma-like carcinoma (LELC) is an undifferentiated carcinoma with a dense lymphoid stroma. It has been reported in diverse organs and shows variable association with Epstein-Barr virus (EBV). Only a few EBV positive cases have been observed in the hepatobiliary system, all of which were considered to be cholangiocarcinomas. We report a unique case of hepatocellular LELC arising in a cirrhotic liver with EBV demonstrated in the tumor cells. METHODS AND RESULTS A 39-year-old Hispanic female underwent an orthotopic liver transplant for end stage liver disease secondary to chronic hepatitis C. A high-grade hepatocellular carcinoma with a dense lymphocytic infiltrate was found in the explant as well as in a portal lymph node. Three months posttransplant, the patient developed numerous hepatic nodules with enlarged periaortic and portacaval lymph nodes. Biopsy of the hepatic nodules showed a recurrent hepatocellular carcinoma devoid of a dense lymphocytic infiltrate. Both the primary and recurrent tumors were positive for EBV by molecular studies. The patient eventually expired from liver failure over a 6-week period. CONCLUSION This case represents the first report of EBV-positive hepatocellular LELC. It is particularly interesting given the precipitous clinical outcome, which was possibly related to immunosuppresive therapy.
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MESH Headings
- Adult
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/virology
- Chromosomes, Human, Pair 11/genetics
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/pathology
- Female
- Gene Dosage
- Herpesvirus 4, Human/isolation & purification
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Liver Cirrhosis/virology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Liver Transplantation
- Lymphatic Metastasis/pathology
- Polymerase Chain Reaction
- Tumor Virus Infections/complications
- Tumor Virus Infections/pathology
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Affiliation(s)
- Michael W Si
- Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA
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27
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Abstract
Malaria and Epstein-Barr virus (EBV), recognised cofactors for endemic Burkitt's lymphoma, are ubiquitous within the lymphoma belt of Africa, and, unless other cofactors are involved, the tumour should be much more common than it is. Malaria and EBV alone cannot account for the occasional shifting foci and space-time case clusters of endemic Burkitt's lymphoma. Arboviruses and plant tumour promoters are other possible local cofactors that could explain such characteristics. The geographical and age distributions of endemic Burkitt's lymphoma parallel those of potentially oncogenic, mosquito-borne arboviruses. Arboviruses seem to be associated with case clusters of endemic Burkitt's lymphoma, and symptoms compatible with arbovirus infection have been seen immediately before the onset of the tumour. RNA and DNA viruses, including EBV, are promoted by extracts of a commonly used plant, Euphorbia tirucalli, the distribution of which coincides with the boundaries of the lymphoma belt. Extracts of E tirucalli are tumour promoters and can induce the characteristic 8;14 translocation of endemic Burkitt's lymphoma in EBV-infected cell-lines. They also activate latent EBV in infected cells, enhance EBV-mediated cell transformation, and modulate EBV-specific immunity.
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28
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Li W, Wu BA, Zeng YM, Chen GC, Li XX, Chen JT, Guo YW, Li MH, Zeng Y. Epstein-Barr virus in hepatocellular carcinogenesis. World J Gastroenterol 2004; 10:3409-13. [PMID: 15526357 PMCID: PMC4576219 DOI: 10.3748/wjg.v10.i23.3409] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: In recent years, studies have suggested that Epstein-Barr virus (EBV) is associated with HCC. The present study was to determine the prevalence of EBV in HCC patients, and whether EBV acted synergistically with hepatitis viruses in HCC carcinogenesis.
METHODS: Liver tissue 115 HCC patients and 26 non-carcinoma patients were studied. Polymerase chain reaction (PCR) was performed to detect EBV BamHI W DNA, EBV LMP1 DNA, HBV X DNA, and HBV S DNA. Reverse transcription PCR (RT-PCR) was performed to detect HCV RNA and HDV RNA. Immunohistochemistry was performed to detect LMP1, HBsAg, HBcAg and HCV. The positive ratios were compared between HCC group and control group by χ2 test.
RESULTS: Totally, 78 HCC samples whose β -globulin DNA was positively detected by amplified PCR were selected. PCR was performed in all cases for EBV DNA and HBV DNA. RT-PCR was performed in 18 cases for HCV RNA and HDV RNA. EBV BamHI W and EBV LMP1 were positive in 18 and 6 cases, respectively. HBV X gene and HBV S gene were positive in 42 and 27 cases respectively. HCV was positive in one of the 18 cases, and none was positive for HDV. The positive rates were 28.2% (22 of 78) for EBV DNA (BamHI W and/or LMP1) and 56.4% (44 of 78) for HBV DNA (X gene and/or S gene) respectively. In addition, 12 cases were positive for both EBV DNA and HBV DNA. Among the 26 cases in the control group, 2 cases were positive for EBV BamHI W, 4 positive for HBV X gene and 3 positive for HBV S gene. The positive rates were 8.0% (2 of 26) and 23.1% (6 of 26), respectively, for EBV DNA and HBV DNA. The result of DNA sequencing of BamHI W was 100% homologous with the corresponding sequence of B95-8. There was significant difference in EBV infection rate between HCC patients and controls (χ2 = 4.622, P < 0.05). The difference in HBV infection rate was also significant (χ2 = 8.681, P < 0.05). However, there was no obvious correlation between HBV and EBV in HCC patients (χ2 = 0.835, P > 0.05). LMP1, HBV (HBsAg, HBcAg) and HCV were detected positively in 25, 45 and 6 of 78 cases of HCC tissues respectively. In the 26 control cases, the corresponding positive cases were 2, 4 and 0. The difference in EBV infection rate between HCC patients and control cases was statistically significant (χ2 = 6.02, P < 0.05). The difference in HBV infection rate was also statistically significant (χ2 = 10.03, P < 0.05). In the 25 cases with positive LMP1 expression, 6 were in the nuclei of tumor cells, 9 in the cytoplasm of tumor cells and 10 in mesenchymal lymphocyte cytoplasm.
CONCLUSION: The existence of EBV infection in HCC tissues suggests that EBV may be involved in the hepatocellular carcinogenesis in China. HBV infection may be a major cause of HCC. There is no correlation between EBV and HBV in the development of HCC. The prevalence of HCV infection is low in our area, and HDV appears not to play a direct role in hepatocellular carcinogenesis.
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Affiliation(s)
- Wei Li
- Department of General Surgery, the First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China.
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29
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Lu CC, Wu CW, Chang SC, Chen TY, Hu CR, Yeh MY, Chen JY, Chen MR. Epstein-Barr virus nuclear antigen 1 is a DNA-binding protein with strong RNA-binding activity. J Gen Virol 2004; 85:2755-2765. [PMID: 15448336 DOI: 10.1099/vir.0.80239-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) plays key roles in both the regulation of gene expression and the replication of the EBV genome in latently infected cells. To characterize the RNA-binding activity of EBNA-1, it was demonstrated that EBNA-1 binds efficiently to RNA homopolymers that are composed of poly(G) and weakly to those composed of poly(U). All three RGG boxes of EBNA-1 contributed additively to poly(G)-binding activity and could mediate RNA binding when attached to a heterologous protein in an RNA gel mobility-shift assay. In vitro-transcribed EBV and non-EBV RNA probes revealed that EBNA-1 bound to most RNAs examined and the affinity increased as the content of G and U increased, as demonstrated in competition assays. Among these probes, the 5' non-coding region (NCR) (nt 131-278) of hepatitis C virus RNA appeared to be the strongest competitor for EBNA-1 binding to the EBV-encoded small nuclear RNA 1 (EBER1) probe, whereas a mutant 5' NCR RNA with partially disrupted secondary structure was a weak competitor. Furthermore, the interaction of endogenous EBNA-1 and EBER1 in EBV-infected cells was demonstrated by a ribonucleoprotein immunoprecipitation assay. These results revealed that EBNA-1 is a DNA-binding protein with strong binding activity to a relatively broad spectrum of RNA and suggested an additional biological impact of EBNA-1 through its ability to bind to RNA.
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Affiliation(s)
- Chih-Chung Lu
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
| | - Chia-Wei Wu
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
| | - Shin C Chang
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
| | - Tzu-Yi Chen
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
| | - Chwan-Ren Hu
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
| | - Ming-Yi Yeh
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
| | - Jen-Yang Chen
- National Health Research Institutes, Taipei, Taiwan
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
| | - Mei-Ru Chen
- Graduate Institute of Microbiology, College of Medicine, No. 1, Jen-Ai Road, 1st Section, National Taiwan University, Taipei, Taiwan
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30
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Zur Hausen A, van Beek J, Bloemena E, Ten Kate FJ, Meijer CJLM, van den Brule AJC. No role for Epstein-Barr virus in Dutch hepatocellular carcinoma: a study at the DNA, RNA and protein levels. J Gen Virol 2003; 84:1863-1869. [PMID: 12810881 DOI: 10.1099/vir.0.19217-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) has been suggested to play a role in hepatocellular carcinoma (HCC). However, reports on detailed EBV transcript analyses in HCCs are limited. It was shown recently that expression of the transforming BARF1 (BamHI A rightward open reading frame 1) gene of EBV is restricted to latently EBV-infected epithelial malignancies, i.e. nasopharyngeal carcinoma and gastric carcinoma. The aim of this study was to test the presence of EBV in Dutch HCCs. A semiquantitative DNA PCR-enzyme immunoassay (PCR-EIA) for the BamHI W fragment of EBV was used to assess the presence of EBV in frozen and paraffin-embedded tissues of 16 HCCs. In addition, several RNA detection techniques, i.e. nucleic acid sequence-based amplification (NASBA), RT-PCR, RNA in situ hybridization (RISH) and immunohistochemistry (IHC), were applied. Five of 16 HCCs and two of four hepatitis C virus hepatitis samples were weakly positive for EBV DNA by PCR-EIA. Using sensitive RNA transcription techniques, no transcripts were found for BARF1, EBNA-1 and BARTs (BamHI A rightward transcripts) in any of the liver tissues tested. In addition, RISH for EBER1/2 and BARTs and IHC for EBNA-1, LMP-1 and ZEBRA, performed on the paraffin-embedded tissue of the PCR-EIA-positive cases and on adjacent non-neoplastic liver tissues, were negative. The absence of epithelial-specific BARF1 transcripts and other EBV transcripts and proteins in the EBV DNA PCR-positive cases argues strongly against a role for EBV in HCC.
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Affiliation(s)
- Axel Zur Hausen
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Josine van Beek
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Elisabeth Bloemena
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Fiebo J Ten Kate
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Chris J L M Meijer
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
| | - Adriaan J C van den Brule
- Department of Pathology, Section Molecular Pathology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
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31
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Akhter S, Liu H, Prabhu R, DeLucca C, Bastian F, Garry RF, Schwartz M, Thung SN, Dash S. Epstein-Barr virus and human hepatocellular carcinoma. Cancer Lett 2003; 192:49-57. [PMID: 12637152 DOI: 10.1016/s0304-3835(02)00695-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent studies suggest that Epstein-Barr virus (EBV) may act as a helper virus for the development of hepatocellular carcinoma by promoting replication of the hepatitis C virus (HCV) in the infected liver. Detection of EBV DNA in a high percentage of HCV-positive human hepatocellular carcinomas (HCC) from Japanese patients has supported this concept. In order to determine whether EBV infection is associated with HCC, we examined paraffin-embedded tissues from 31 cases of non-cirrhotic livers with hepatocellular carcinoma for the presence of EBV, HCV and hepatitis B virus (HBV) infection. RNA prepared from tumor samples were used as a template for reverse transcription followed by double-nested PCR with primers for the 5' untranslated region (NT) of HCV. DNA extracts of tumor samples were tested by single polymerase chain reaction for the detection of EBV and HBV (X- and/or S-gene) DNA sequences. To control for nucleic acid integrity, all tumor samples were amplified for human beta-globin DNA by polymerase chain reaction and subjected to Southern blot hybridization. None of the cases was found to be positive for EBV. Ten HCC cases (32%) tested positive for HCV and 12 HCC cases (38%) tested positive for HBV. Six of the surveyed patients had nucleic acids of both HCV and HBV in their tumor tissue. All HCC tumor samples were positive for beta-globin. Our study shows that HCV and HBV infections, but not EBV infection, are associated with hepatocarcinogenesis in non-cirrhotic livers. Other unknown risk factors seem to be in effect in the development of hepatocellular carcinoma in non-cirrhotic livers.
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Affiliation(s)
- Shamim Akhter
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
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Hu Y, Shahidi A, Park S, Guilfoyle D, Hirshfield I. Detection of Extrahepatic Hepatitis C Virus Replication by a Novel, Highly Sensitive, Single-Tube Nested Polymerase Chain Reaction. Am J Clin Pathol 2003. [DOI: 10.1309/33tajlb748klmxvg] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Challine D, Buisson M, Cadilhac M, Germanidis G, Joab I, Eliaszewicz M, Caumes E, Flahault A, Fillet AM, Pawlotsky JM, Seigneurin JM. Hepatitis C virus-Epstein-Barr virus interaction in patients with AIDS. J Med Virol 2002; 67:510-5. [PMID: 12115996 DOI: 10.1002/jmv.10130] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Immortalization of B cells by Epstein-Barr virus (EBV) and their subsequent proliferation leads to B-cell non-Hodgkin's lymphoma in immunocompromised patients. The role of hepatitis C virus (HCV) in B-cell non-Hodgkin's lymphoma has recently been raised, and an interaction between HCV and EBV is supported by recent in vitro experiments. The aim of this study was to investigate in vivo interactions between HCV and EBV in patients with AIDS, i.e., patients exposed to the risk of EBV-related B-cell non-Hodgkin's lymphoma. A total of 135 patients were prospectively studied. Serological and molecular markers of HCV, EBV, and human immunodeficiency virus (HIV) infection were sought. All the patients harbored latent EBV infection, and 20% had detectable HCV RNA in serum. No significant relationship was found between HIV, HCV, and EBV viral load in peripheral blood mononuclear cells or plasma. There was no difference between anti-HCV-positive and -negative patients or between HCV RNA-positive and -negative patients with regard to the prevalence of EBV markers, especially EBV replication markers. The presence of EBV replication markers was not related to HCV RNA seropositivity or to HCV viral load. Five patients subsequently developed B-cell non-Hodgkin's lymphoma, none of whom had markers of EBV or HCV replication. These results argue against an in vivo interaction between HCV and EBV in patients with AIDS, and against a role of HCV infection in the occurrence of B-cell non-Hodgkin's lymphoma in these patients.
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Affiliation(s)
- Dominique Challine
- Department of Virology (EA 3489), Hôpital Henri Mondor, Université Paris XII, Créteil, France
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Kang MS, Hung SC, Kieff E. Epstein-Barr virus nuclear antigen 1 activates transcription from episomal but not integrated DNA and does not alter lymphocyte growth. Proc Natl Acad Sci U S A 2001; 98:15233-8. [PMID: 11734622 PMCID: PMC65012 DOI: 10.1073/pnas.211556598] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2001] [Indexed: 11/18/2022] Open
Abstract
By binding to a cis-acting element (oriP) in the Epstein-Barr virus (EBV) genome, EBV nuclear antigen 1 (EBNA1) enables persistence and enhances transcription from EBV episomes. To investigate whether EBNA1 also directly affects cell gene transcription, we conditionally expressed a Flag-tagged dominant negative EBNA1 (FDNE) in an EBV immortalized lymphoblastoid cell line, in which the EBV genome is integrated into cell DNA. FDNE induction inhibited expression from an EBNA1-dependent oriP reporter plasmid by more than 90% in these cells but did not affect expression from integrated EBV or oriP reporter DNA. FDNE induction also did not alter expression of more than 1,800 cellular mRNAs. Lymphoblastoid cell line growth under a variety of conditions was unaffected by FDNE induction. Although Gal4-VP16 and EBNA1 strongly activated and coactivated a Gal4-VP16- and oriP-dependent promoter that was on an episome, only Gal4-VP16 activated the promoter when it was integrated into chromosomal DNA. These data indicate that EBNA1 is specifically deficient in activation of an integrated oriP enhancer and does not affect cell growth or gene expression through an interaction with cognate chromosomal DNA.
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Affiliation(s)
- M S Kang
- Program in Virology and Departments of Medicine and Microbiology and Molecular Genetics, Harvard University, Boston, MA 02115, USA
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Yeh CT, Lai HY, Chen TC, Chu CM, Liaw YF. Identification of a hepatic factor capable of supporting hepatitis C virus replication in a nonpermissive cell line. J Virol 2001; 75:11017-24. [PMID: 11602742 PMCID: PMC114682 DOI: 10.1128/jvi.75.22.11017-11024.2001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Although hepatitis C virus E2 protein can bind to human cells by interacting with a putative viral receptor, CD81, the interaction alone is not sufficient to establish permissiveness for hepatitis C virus infection. Using an Epstein-Barr virus-based extrachromosomal replication system, we have screened through a human liver cDNA library and successfully identified a cDNA capable of supporting hepatitis C virus replication in an otherwise nonpermissive cell line. This cDNA encodes a protein exhibiting homology to a group of proteins derived from various evolutionarily distant species, including Oryza sativa submergence-induced protein 2A. The mRNAs encoding this factor are heterogeneous at the 5' ends and are ubiquitously expressed in multiple tissues, albeit in a very small amount. The longest mRNA contains an in-frame and upstream initiation codon and codes for a larger protein. This 5'-extended form of mRNA was detected in hepatocellular carcinoma, but not in normal liver tissue. Immunofluorescence analysis demonstrated that the hepatic factor was distributed evenly in cells, but occasionally formed aggregations in the peri- or intranuclear areas. In summary, we have identified a hepatic factor capable of supporting hepatitis C virus replication in an otherwise nonpermissive cell line. This factor belongs to a previously uncharacterized protein family. The physiological function of this protein awaits further study.
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Affiliation(s)
- C T Yeh
- Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei, Taiwan.
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Chu PG, Chen YY, Chen W, Weiss LM. No direct role for Epstein-Barr virus in American hepatocellular carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2001; 159:1287-92. [PMID: 11583956 PMCID: PMC1850508 DOI: 10.1016/s0002-9440(10)62515-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Epstein-Barr virus (EBV) was recently linked to hepatocellular carcinogenesis in Japanese patients. It is not clear whether EBV infection is also associated with hepatocellular carcinoma (HCC) occurring in American patients. We studied 41 cases of HCC from the Los Angeles area for evidence of EBV infection by in situ hybridization, immunohistochemistry, and polymerase chain reaction methods. Of 41 cases, 16 were seropositive for hepatitis B virus surface antigen (39%), 9 of 29 tested were seropositive for hepatitis C virus antibody (31%); in total, 22 cases were seropositive for hepatitis B virus and/or hepatitis C virus (53%). Of 41 cases, 1 was positive for EBV-encoded small nonpolyadenylated RNA (EBER)-1 (2%) by in situ hybridization. By immunohistochemistry, two cases were positive for EBV nuclear antigen (EBNA)-1 (5%), one was positive for the transactivating immediate early BZLF1 (ZEBRA) (2%), and none was positive for latent membrane protein-1. None of the 41 cases was positive for latent membrane protein-1 and EBV nuclear antigen (EBNA)-4 DNAs by polymerase chain reaction assay. All four positive cases showed rare EBER-1-, ZEBRA-, or EBNA-1- positive cells (<0.1%); in none of these cases was there expression of any other EBV viral genes. In the one case each that was positive for EBER-1 and ZEBRA, both of which occurred in patients of non-Asian ethnicity, the staining was limited to infiltrating small lymphocytes, and tumor cells were negative. In the two cases that were positive for EBNA-1, both of which occurred in patients of Asian ethnicity, the staining was limited to tumor cells, and infiltrating small lymphocytes were negative. Our study indicates that rare cases of American HCC may contain EBV-infected cells, but it is unlikely that EBV plays a major role in the carcinogenesis of HCC.
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Affiliation(s)
- P G Chu
- Department of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA.
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Abstract
Hepatitis C virus pathogenesis and cycle are difficult to study because of the lack of culture system able to replicate efficiently the virus. Furthermore such a system will permit screen new antiviral drugs. Studies were realized to select cell culture system able to allow hepatitis C virus replication. Primary cell cultures and cell lines were used to performed HCV culture. Most of these works used lymphocyte and hepatocyte primary cultures or cell lines because of HCV tropism in these cells in vivo. Animals and arthropods cell lines were used as well for their capacity to bind and replicate HCV. The aim of this review is to present the different cell systems used to replicate HCV in culture and the results obtained.
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Affiliation(s)
- R Germi
- Laboratoire de virologie moléculaire et structurale, faculté de médecine/pharmacie de Grenoble, France.
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Imai S, Nishikawa J, Kuroda M, Takada K. Epstein-Barr virus infection of human epithelial cells. Curr Top Microbiol Immunol 2001; 258:161-84. [PMID: 11443861 DOI: 10.1007/978-3-642-56515-1_11] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- S Imai
- Department of Microbiology, Kochi Medical School, Kohasu, Okoh-cho, Nankoku, Kochi 783-8505, Japan
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Tsujii R, Miyoshi K, Tsuno A, Matsui Y, Toh-e A, Miyakawa T, Mizuta K. Ebp2p, yeast homologue of a human protein that interacts with Epstein-Barr virus nuclear antigen 1, is required for pre-rRNA processing and ribosomal subunit assembly. Genes Cells 2000; 5:543-53. [PMID: 10947841 DOI: 10.1046/j.1365-2443.2000.00346.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND A defect in the secretory pathway causes the transcriptional repression of both rRNA and ribosomal protein genes in Saccharomyces cerevisiae, suggesting a coupling of ribosome synthesis and plasma membrane synthesis. Rrs1p, an essential nuclear protein, is required for the secretory response. RESULTS EBP2, encoding the yeast homologue of a human protein that interacts with Epstein-Barr virus Nuclear Antigen 1, was cloned in a two-hybrid screen using RRS1 as a bait. The rrs1-1 mutation, which produces Rrs1p without the C-terminal half and causes a defect in the secretory response, almost abolished the interaction with Ebp2p. Ebp2p is essential for growth and is mainly localized in the nucleolus. The effects of Ebp2p depletion on ribosome biogenesis is quite similar to that of Rrs1p depletion; in the Ebp2p-depleted cells, the rate of pre-rRNA processing is slower, and significantly less mature 25S rRNA is produced compared to those in wild-type cells. The polysome pattern indicates that Ebp2p-depletion causes a decrease of 80S monosomes and polysomes, an accumulation of 40S subunits, and the appearance of half-mer polysomes. CONCLUSIONS Ebp2p is required for the maturation of 25S rRNA and 60S subunit assembly. Ebp2p may be one of the target proteins of Rrs1p for executing the signal to regulate ribosome biogenesis.
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Affiliation(s)
- R Tsujii
- Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Kagamiyama 1-4-1, Higashi-Hiroshima 739-8527, Japan
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Affiliation(s)
- R Bartenschlager
- Institute for Virology, Johannes-Gutenberg University Mainz, Obere Zahlbacher Strabetae 67, 55131 Mainz, Germany.
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