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Defective Epstein–Barr virus in chronic active infection and haematological malignancy
- Source :
- Nature Microbiology. 4:404-413
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Epstein-Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14-7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.
- Subjects :
- Male
Microbiology (medical)
Epstein-Barr Virus Infections
Herpesvirus 4, Human
Immunology
Lymphoproliferative disorders
DNA-Directed DNA Polymerase
Biology
medicine.disease_cause
Applied Microbiology and Biotechnology
Microbiology
Immediate early protein
Immediate-Early Proteins
Mice
Viral Proteins
03 medical and health sciences
Chronic active EBV infection
hemic and lymphatic diseases
Genetics
medicine
Animals
Humans
Epstein–Barr virus infection
Neoplastic Processes
030304 developmental biology
0303 health sciences
030306 microbiology
Cell Biology
Middle Aged
medicine.disease
Epstein–Barr virus
Virology
Lymphoproliferative Disorders
BZLF1
Lymphoma
DNA-Binding Proteins
MicroRNAs
Lytic cycle
Hematologic Neoplasms
Mutation
Trans-Activators
Heterografts
Female
Gene Deletion
Subjects
Details
- ISSN :
- 20585276
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- Nature Microbiology
- Accession number :
- edsair.doi.dedup.....66e806d03af451bf0b5df746e6a21e8f