Complex transcription of the Epstein-Barr virus BamHI fragment H rightward open reading frame 1 (BHRF1) in latently and lytically infected B lymphocytes.

Austin, Penelope; Flemington, Erik K.; Yandava, Chandri; Strominger, Jack L.; Speck, Samuel H.

doi:10.1073/pnas.85.11.3678

Cited by 61 publications

(51 citation statements)

References 38 publications

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“…BHRF1-specific transcripts can be initiated either from the Cp/Wp promoter in EBVtransformed cells or from a promoter located immediately 5Ј of miR-BHRF1-1 in cells undergoing lytic replication (2). We examined latent BHRF1-specific transcription using a qPCRbased assay in which the 5Ј primer binds to Wp; it therefore identifies latent BHRF1 mRNA transcripts and not the EBNA introns from which the miRNAs are produced (19).…”

Section: Resultsmentioning

confidence: 99%

The Members of an Epstein-Barr Virus MicroRNA Cluster Cooperate To Transform B Lymphocytes

Feederle

Haar

Bernhardt

et al. 2011

J Virol

111

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Epstein-Barr virus (EBV) transforms B lymphocytes through the expression of the latent viral proteins EBNA and latent membrane protein (LMP).Recently, it has become apparent that microRNAs (miRNAs) also contribute to EBV's oncogenic properties; recombinant EBVs that lack the BHRF1 miRNA cluster display a reduced ability to transform B lymphocytes in vitro. Furthermore, infected cells evince a marked upregulation of the EBNA genes. Using recombinant viruses that lack only one member of the cluster, we now show that all three BHRF1 miRNAs contribute to B-cell transformation. Recombinants that lacked miR-BHRF1-2 or miR-BHRF1-3 displayed enhanced EBNA expression initiated at the Cp and Wp promoters. Interestingly, we find that the deletion of miR-BHRF1-2 reduced the expression level of miR-BHRF1-3 and possibly that of miR-BHRF1-1, demonstrating that the expression of one miRNA can potentiate the expression of other miRNAs located in the same cluster. Therefore, the phenotypic traits of the miR-BHRF1-2 null mutant could result partly from reduced miR-BHRF1-1 and miR-BHRF1-3 expression levels. Nevertheless, using an miR-BHRF1-1 and miR-BHRF1-3 double mutant, we could directly assess and confirm the contribution of miR-BHRF1-2 to B-cell transformation. Furthermore, we found that the potentiating effect of miR-BHRF1-2 on miR-BHRF1-3 synthesis can be reproduced with simple expression plasmids, provided that both miRNAs are processed from the same transcript. Therefore, this enhancing effect does not result from an idiosyncrasy of the EBV genome but rather reflects a general property of these miRNAs. This study highlights the advantages of arranging the BHRF1 miRNAs in clusters: it allows the synchronous and synergistic expression of genetic elements that cooperate to transform their target cells.

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Section: Resultsmentioning

confidence: 99%

The Members of an Epstein-Barr Virus MicroRNA Cluster Cooperate To Transform B Lymphocytes

Feederle

Haar

Bernhardt

et al. 2011

J Virol

111

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“…Expression of BHRF1 during latency has been suggested in the past, because differentially spliced BHRF1-containing mRNAs were detected by Northern blot analysis in latently infected LCLs (35) and in EBVassociated B cell lymphomas (36). However, Kieff et al (37) reported that neither BHRF1 mRNA nor BHRF1 protein could be detected in latently infected cells.…”

Section: Discussionmentioning

confidence: 99%

Long-Term MHC Class II Presentation of the EBV Lytic Protein BHRF1 by EBV Latently Infected B Cells following Capture of BHRF1 Antigen

Landais

Saulquin

Bonneville

et al. 2005

The Journal of Immunology

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Although T lymphocytes are considered essential for the control of EBV infection, it remains uncertain how this control occurs. We previously reported unexpected killing of EBV-transformed B-lymphoblastoid cells (LCLs) that did not express BHRF1 by CD4+ T cells specific for BHRF1, an EBV lytic cycle protein. Using LCLs transformed with an EBV mutant, in which the BHRF1 gene was deleted, we showed that killing of latently infected cells through the recognition of a protein produced during the lytic cycle is due to transfer of BHRF1 from lytically infected to latently infected cells, which occurs in culture. Accordingly, LCLs efficiently presented exogenous BHRF1 protein. Furthermore, we present evidence for persistence of captured BHRF1 Ag for several days. Due to this long-term persistence, repeated loading of suboptimal amounts of BHRF1 led to accumulation of BHRF1 Ags in LCLs and, ultimately, to their optimal recognition by BHRF1-specific CD4+ T cells. These results unveil an MHC class II-dependent pathway that could be important for the control of EBV latent infection through recognition of lytic cycle Ags.

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“…BALF1 from all sequenced viruses appears to initiate at a conserved methionine within BALF0, suggesting that EBV BALF1 protein also initiates at this "internal methionine." Though BHRF1 and BALF1 are reported to be expressed during the early lytic virus replication cycle, several laboratories have identified spliced BHRF1 transcripts apparently derived from a latent cycle promoter (2,6,59). Like BHRF1, BALF1 is positioned downstream of another latency promoter, and others have suggested that BALF1 is also expressed during latency (52).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus BALF1 Is a BCL-2-Like Antagonist of the Herpesvirus Antiapoptotic BCL-2 Proteins

Bellows¹,

Howell

Pearson

et al. 2002

J Virol

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Cellular BCL-2 family proteins can inhibit or induce programmed cell death in part by counteracting the activity of other BCL-2 family members. All sequenced gammaherpesviruses encode a BCL-2 homologue that potently inhibits apoptosis and apparently escapes some of the regulatory mechanisms that govern the functions of their cellular counterparts. Examples of these protective proteins include BHRF1 of Epstein-Barr virus (EBV) and KSBcl-2 of Kaposi's sarcoma-associated herpesvirus, also known as human herpesvirus 8. The gamma-1 subgroup of these viruses, such as EBV, encodes a second BCL-2 homologue. We have now found that this second BCL-2 homologue encoded by EBV, BALF1, inhibits the antiapoptotic activity of EBV BHRF1 and of KSBcl-2 in several transfected cell lines. However, BALF1 failed to inhibit the cellular BCL-2 family member, BCL-x L . Thus, BALF1 acts as a negative regulator of the survival function of BHRF1, similar to the counterbalance observed between cellular BCL-2 family members. Unlike the cellular BCL-2 family antagonists, BALF1 lacked proapoptotic activity and could not be converted into a proapoptotic factor in a manner similar to cellular BCL-2 proteins by caspase cleavage or truncation of the N terminus. Coimmunoprecipitation experiments and immunofluorescence assays suggest that a minimal amount, if any, of the BHRF1 and BALF1 proteins colocalizes inside cells, suggesting that mechanisms other than direct interaction explain the suppressive function of BALF1.

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Complex transcription of the Epstein-Barr virus BamHI fragment H rightward open reading frame 1 (BHRF1) in latently and lytically infected B lymphocytes.

Cited by 61 publications

References 38 publications

The Members of an Epstein-Barr Virus MicroRNA Cluster Cooperate To Transform B Lymphocytes

The Members of an Epstein-Barr Virus MicroRNA Cluster Cooperate To Transform B Lymphocytes

Long-Term MHC Class II Presentation of the EBV Lytic Protein BHRF1 by EBV Latently Infected B Cells following Capture of BHRF1 Antigen

Epstein-Barr Virus BALF1 Is a BCL-2-Like Antagonist of the Herpesvirus Antiapoptotic BCL-2 Proteins

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