EBV MicroRNAs in Primary Lymphomas and Targeting of <i>CXCL-11</i> by ebv-mir-BHRF1-3

Xia, Tianli; O'Hara, Andrea; Araújo, Iguaracyra; Barreto, José; Carvalho, Eny; Sapucaia, Jose Bahia; Ramos, Juan Carlos; Luz, Estela; Pedroso, Célia; Manrique, Michele; Toomey, Ngoc L.; Brites, Carlos; Dittmer, Dirk P.; Harrington, William J.

doi:10.1158/0008-5472.can-07-5126

Cited by 288 publications

(257 citation statements)

References 39 publications

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“…As large subsets of viral miRNAs are expressed in all phases of EBV's life cycle (48), it appears plausible that viral miRNAs inhibit these target molecules globally. For example, miRNAs miR-BART1, miR-BART2, and miR-BART22, which target IL-12 (35), are all highly expressed not only in latency III but also in EBV-infected germinal center B cells (latency II) and memory B cells (latency 0/I) from healthy donors as well as different types of EBV-associated cancer cells (34,48,49). Therefore, miRNA-mediated reduction of IL-12 could lead to decreased T-cell activation and recognition at different stages of infection and malignant disease.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

126

122

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Infection with Epstein-Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44 microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4 + T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated whether EBV miRNAs also counteract surveillance by CD8 + T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8 + T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8 + T cells. Moreover, miRNAmediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8 + T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4 + but also by antiviral CD8 + T cells.adaptive immunity | immune evasion | herpesvirus | CD8 T cells | microRNA E pstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects the majority of the human population worldwide. Although EBV infection persists for life, most carriers remain asymptomatic due to a stringent control by virus-specific immunity. An important component of this immunity is EBV-specific CD8 + T cells, which often expand to high numbers in healthy carriers or after primary infection. Conversely, the absence of EBV-specific CD8 + T cells predicts the emergence of EBVassociated disease in patients after stem cell transplantation or when afflicted with AIDS (1-3). Dangerous EBV-mediated complications can be reversed or prevented by transfer of EBVspecific T cells (4, 5), which further confirms the important role of continuous T-cell control of EBV infection. Among EBVspecific T cells, CD8 + T cells predominate; about 0.05-1% of all CD8 + T cells in healthy donors are typically specific for EBV latent antigens and about twice as many for lytic antigens (6, 7).EBV predominantly infects B cells and establishes a latent infection before production of progeny virus becomes possible (8). Four distinct programs of EBV latent infection have been defined according to their expression profiles of latent viral genes (9-11). One of these programs, known as latency III or the "growth program," is characterized by the expression of a restricted set of approximately eight viral proteins, which activate B cells and drive their proliferation, thus increasing the viral reservoir. Latency III is found in EBV-associated malignancies in immunosuppressed patients (9) and likely reemerges continuously in healthy carriers (9, 12), indicati...

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Section: Discussionmentioning

confidence: 99%

“…Many EBV miRNAs have no known function. A function of viral miRNAs in innate immunity was suggested earlier by findings showing that some regulate the inflammasome component NLRP3 (32), the natural killer group 2D (NKG2D) ligand MICB (33), and the chemokine CXCL11 (34).…”

Section: Significancementioning

confidence: 96%

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

126

122

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“…EBV is a common, potentially oncogenic, γ-herpesvirus, the first virus known to encode miRNAs (EBV-miRNAs) (11), and exploits host cellular pathways for its own benefit (12). EBV-miRNAs are separated into three clusters of the viral genome: BHRF1 and cluster 1 and cluster 2 BARTs (13,14), which are abundantly expressed in EBV-associated tumors (13,15) and EBV-transformed lymphoblastoid B cells (LCL) (13). Although the expression pattern of EBV-miRNAs in vivo is unexplored, and their targets are largely unknown, comprehensive studies in vitro indicate that their expression pattern is linked to viral latency stage (13,14,16).…”

mentioning

confidence: 99%

Functional delivery of viral miRNAs via exosomes

Pegtel

Cosmopoulos

Thorley‐Lawson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

1,422

1,187

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Noncoding regulatory microRNAs (miRNAs) of cellular and viral origin control gene expression by repressing the translation of mRNAs into protein. Interestingly, miRNAs are secreted actively through small vesicles called "exosomes" that protect them from degradation by RNases, suggesting that these miRNAs may function outside the cell in which they were produced. Here we demonstrate that miRNAs secreted by EBV-infected cells are transferred to and act in uninfected recipient cells. Using a quantitative RT-PCR approach, we demonstrate that mature EBV-encoded miRNAs are secreted by EBV-infected B cells through exosomes. These EBV-miRNAs are functional because internalization of exosomes by MoDC results in a dose-dependent, miRNAmediated repression of confirmed EBV target genes, including CXCL11/ ITAC, an immunoregulatory gene down-regulated in primary EBVassociated lymphomas. We demonstrate that throughout coculture of EBV-infected B cells EBV-miRNAs accumulate in noninfected neighboring MoDC and show that this accumulation is mediated by transfer of exosomes. Thus, the exogenous EBV-miRNAs transferred through exosomes are delivered to subcellular sites of gene repression in recipient cells. Finally, we show in peripheral blood mononuclear cells from patients with increased EBV load that, although EBV DNA is restricted to the circulating B-cell population, EBV BART miRNAs are present in both B-cell and non-B-cell fractions, suggestive of miRNA transfer. Taken together our findings are consistent with miRNA-mediated gene silencing as a potential mechanism of intercellular communication between cells of the immune system that may be exploited by the persistent human γ-herpesvirus EBV.

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“…These miRNAs not only target the virus' own genes, but also target the host genes [28]. Xia et al [29] reported that miR-BHRF1-3 targets the host gene, CXCL11, the repression of which will protect EBV-infected B cells from attack by cytotoxic T cells. Choy et al [30] also demonstrated that miR-BART5 targets the host gene, PUMA (p53-upregulated modulator of apoptosis), the down-regulation of which will inhibit apoptosis of the virus infected host cells.…”

Section: Mirna and Ebvmentioning

confidence: 99%

miRNA and nasopharyngeal carcinoma

2011

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MicroRNAs (miRNAs) constitute a family of small non-coding RNA molecules 22-25 nucleotides in length. miRNAs control the expression of target genes at the post-transcriptional level by inhibiting translation or by degrading target mRNA through binding to complementary sequences in the 3′-untranslated regions. Recent studies have demonstrated that miRNAs are intimately involved in processes leading to nasopharyngeal carcinoma, such as the Epstein-Barr virus-encoded latent membrane protein 1 activated signal transduction pathways, gene-regulatory networks, mitosis, tumor angiogenesis, invasion and migration. Exploring the relationship between miRNAs and the development of nasopharyngeal carcinoma, will further the understanding of this cancer and provide new avenues for diagnosis and treatment. . Nasopharyngeal carcinoma (NPC) is a head and neck epithelial malignancy that occurs frequently in Southern China [2]. It is characterized by high invasiveness and metastasis, and involves Epstein-Barr virus (EBV) infection and numerous genetic factors [3]. In this review, we focus on recent studies [4] that have described miRNA involvement in the carcinogenesis of NPC.1 miRNA biogenesis, regulatory mechanisms and biological functions 1.1 miRNA biogenesis and regulatory mechanisms miRNAs are small non-coding RNA molecules of about *Corresponding author (email: Lqz2010@hotmail.com; xiaoqing1213@sina.com) 22-25 nucleotides in length. miRNA genes are first transcribed by RNA polymerase II, to produce molecules hundreds of nucleotides in length, called pri-miRNAs. Then, Drosha, an RNA polymerase III, processes pri-miRNAs into stem-loop structures, 60-70 nucleotides in length, called pre-miRNAs. The transportation protein, Exportin-5, identifies and combines with the 3′-end of pre-miRNAs and, in a Ran-GTP-dependent manner, pre-miRNAs are exported from the nucleus into cytoplasm. With the involvement of another RNase III Dicer, the pre-miRNAs are further cleaved into double stranded RNAs (dsRNAs). A helicase then degrades one strand of the dsRNA, leaving the other strand a mature active miRNA to enter the nucleus and form the miRNA-associated RNA-induced silencing complex (miRISC) [5][6][7]. Within this complex, miRNAs can play essential roles in biological functions.miRNAs control the expression of target genes at the post-transcriptional level by inhibiting protein translation or by degrading cognate target mRNAs through binding to their 3′-untranslated regions (UTRs) with varying degrees of sequence complementarity. miRNAs are also involved in

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EBV MicroRNAs in Primary Lymphomas and Targeting of CXCL-11 by ebv-mir-BHRF1-3

Cited by 288 publications

References 39 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Functional delivery of viral miRNAs via exosomes

miRNA and nasopharyngeal carcinoma

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EBV MicroRNAs in Primary Lymphomas and Targeting of CXCL-11 by ebv-mir-BHRF1-3

Cited by 288 publications

References 39 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Functional delivery of viral miRNAs via exosomes

miRNA and nasopharyngeal carcinoma

Contact Info

Product

Resources

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Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells