Rationally repurposed nitroxoline inhibits preclinical models of Epstein–Barr virus-associated lymphoproliferation

AbstractRepurposing of currently used drugs for new indications benefits from known experience with those agents. Rational repurposing can be achieved when newly uncovered molecular activities are leveraged against diseases that utilize those mechanisms. Nitroxoline is an antibiotic with metal-chelating activity used to treat urinary tract infections. This small molecule also inhibits the function of bromodomain and extraterminal (BET) proteins that regulate oncogene expression in cancer. Lymphoproliferation driven by the Epstein–Barr virus (EBV) depends on these same proteins. We therefore tested the efficacy of nitroxoline against cell culture and small animal models of EBV-associated lymphoproliferation. Nitroxoline indeed reduces cell and tumor growth. Nitroxoline also acts faster than the prototype BET inhibitor JQ1. We suggest that this rational repurposing may hold translational promise.

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Chronic active Epstein-Barr virus: a multidisciplinary approach

BMJ Case Reports ◽

10.1136/bcr-2020-236287 ◽

2020 ◽

Vol 13 (12) ◽

pp. e236287

Author(s):

Jessica Wauchope ◽

Colm Brendan Dorris ◽

Caroline Patricia Smith ◽

Brendan Hanna

Keyword(s):

Epstein Barr Virus ◽

Elevated Serum ◽

Cervical Lymphadenopathy ◽

Epstein Barr Virus Infection ◽

Cell Transplant ◽

Upper Respiratory Tract ◽

Oral Ulceration ◽

Barr Virus ◽

Epstein Barr ◽

Tract Infections

A 17-year-old Caucasian male presented to ENT with angular stomatitis, oral ulceration and cervical lymphadenopathy. Over the subsequent 18 months he developed recurrent upper respiratory tract infections, pyrexia of unknown origin, oral ulceration and maxillary sinus osteomyelitis. Extensive investigation ensued from various specialties. Positive investigations included a mild but persistently elevated serum Epstein-Barr virus PCR; however, no unifying diagnosis was elicited. It is noteworthy that a significant factor contributing to a delay in his diagnosis was poor compliance with invasive investigations. Ultimately, deteriorating liver function prompted liver biopsy which confirmed a diagnosis of chronic active Epstein-Barr virus infection (CAEBV). This enabled referral for curative treatment in the form of a stem cell transplant. CAEBV is extremely rare in Western countries. Due to fatal complications early diagnosis is critical for successful treatment. Our case highlights the need for regular clinical re-evaluation and a comprehensive multispecialty approach in such cases.

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JQ1 reduces Epstein-Barr virus-associated lymphoproliferative disease in mice without sustained oncogene repression

10.1101/152306 ◽

2017 ◽

Author(s):

Amanda He ◽

JJ L. Miranda

Keyword(s):

Cell Lines ◽

Epstein Barr Virus ◽

Tumor Development ◽

Xenograft Model ◽

Lymphoproliferative Disease ◽

Post Transplantation ◽

Bet Inhibitor ◽

Barr Virus ◽

Mouse Xenograft Model ◽

Epstein Barr

Small molecule inhibitors of bromodomain and extra-terminal (BET) proteins are seeing increased investigation in clinical trials for treatment of hematological malignancies. These compounds also repress oncogene expression driven by the human Epstein-Barr virus (EBV) in cell culture. We therefore tested the efficacy of the prototypical BET inhibitor JQ1 against a mouse xenograft model of post-transplantation lymphoproliferative disorder. JQ1 potently inhibits growth of lymphoblastoid cell lines (LCLs) in culture at low nM concentrations. Growth of other cell lines with similar EBV type III latency transcription programs is comparably inhibited. JQ1 also slows tumor development of an LCL xenograft in immunocompromised mice, but oncogene repression is not observed in endpoint biopsies. We find reduction of EBV-associated lymphoproliferative disease in an animal model encouraging of further studies.

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Establishment of Latent Epstein-Barr Virus Infection and Stable Episomal Maintenance in Murine B-Cell Lines

Journal of Virology ◽

10.1128/jvi.75.6.3016-3020.2001 ◽

2001 ◽

Vol 75 (6) ◽

pp. 3016-3020 ◽

Cited By ~ 17

Author(s):

Keith M. Haan ◽

Ashok Aiyar ◽

Richard Longnecker

Keyword(s):

B Cell ◽

Viral Entry ◽

Epstein Barr Virus ◽

Small Animal ◽

Nuclear Antigen ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection ◽

Episomal Maintenance

ABSTRACT Epstein-Barr virus (EBV) is a strict human pathogen for which no small animal models exist. Plasmids that contain the EBV plasmid origin of replication, oriP, and express EBV nuclear antigen 1 (EBNA1) are stably maintained extrachromosomally in human cells, whereas these plasmids replicate poorly in rodent cells. However, the ability of oriP and EBNA1 to maintain the entire EBV episome in proliferating rodent cells has not been determined. Expression of the two human B-cell receptors for EBV on the surfaces of murine B cells allows efficient viral entry that leads to the establishment of latent EBV infection and long-term persistence of the viral genome. Latent gene expression in these cells resembles the latency II profile in that EBNA1 and LMP1 can be detected whereas EBNA2 and the EBNA3s are not expressed.

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A Quantitative Ultrastructural Study of Peripheral Blood Lymphocytes Containing Parallel Tubular Arrays in Epstein-Barr Virus and Cytomegalo-Virus Mononucleosis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100098769 ◽

1981 ◽

Vol 39 ◽

pp. 454-455

Author(s):

C. M. Payne ◽

P. M. Tennican

Keyword(s):

Peripheral Blood ◽

Lymphocyte Count ◽

Epstein Barr Virus ◽

Absolute Lymphocyte Count ◽

Peripheral Blood Lymphocytes ◽

Clinical State ◽

Barr Virus ◽

The Absolute ◽

Epstein Barr ◽

Tubular Arrays

In the normal peripheral circulation there exists a sub-population of lymphocytes which is ultrastructurally distinct. This lymphocyte is identified under the electron microscope by the presence of cytoplasmic microtubular-like inclusions called parallel tubular arrays (PTA) (Figure 1), and contains Fc-receptors for cytophilic antibody. In this study, lymphocytes containing PTA (PTA-lymphocytes) were quantitated from serial peripheral blood specimens obtained from two patients with Epstein -Barr Virus mononucleosis and two patients with cytomegalovirus mononucleosis. This data was then correlated with the clinical state of the patient.It was determined that both the percentage and absolute number of PTA- lymphocytes was highest during the acute phase of the illness. In follow-up specimens, three of the four patients' absolute lymphocyte count fell to within normal limits before the absolute PTA-lymphocyte count.In one patient who was followed for almost a year, the absolute PTA- lymphocyte count was consistently elevated (Figure 2). The estimation of absolute PTA-lymphocyte counts was determined to be valid after a morphometric analysis of the cellular areas occupied by PTA during the acute and convalescent phases of the disease revealed no statistical differences.

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Studies of Epstein-Barr Virus Antigens Using Immunoperoxidase and Immunofluorescence Techniques

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010011533x ◽

1975 ◽

Vol 33 ◽

pp. 342-343

Author(s):

R. Stephens ◽

K. Traul ◽

D. Woolf ◽

P. Gaudreau

Keyword(s):

Electron Microscopy ◽

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Barr Virus ◽

If Technique ◽

Infected Cells ◽

Virus Antigens ◽

Epstein Barr ◽

Virus Capsid Antigen ◽

Antigen Reactivity

A number of antigens have been found associated with persistent EBV infections of lymphoblastoid cells. Identification and localization of these antigens were principally by immunofluorescence (IF) techniques using sera from patients with nasopharyngeal carcinoma (NPC), Burkitt lymphoma (BL), and infectious mononucleosis (IM). Our study was mainly with three of the EBV related antigens, a) virus capsid antigen (VCA), b) membrane antigen (MA), and c) early antigens (EA) using immunoperoxidase (IP) techniques with electron microscopy (EM) to elucidate the sites of reactivity with EBV and EBV infected cells.Prior to labeling with horseradish peroxidase (HRP), sera from NPC, IM, and BL cases were characterized for various reactivities by the indirect IF technique. Modifications of the direct IP procedure described by Shabo and the indirect IP procedure of Leduc were made to enhance penetration of the cells and preservation of antigen reactivity.

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