Epstein‐Barr Viral Latency and Cell Immortalization as Targets for Antisense Oligomersa

Pagano, Joseph S.; Jiménez, Gustavo Guerrero; Sung, Nancy S.; Raab, Nancy; Lin, Jung‐Chung

doi:10.1111/j.1749-6632.1992.tb21063.x

Cited by 22 publications

(14 citation statements)

References 16 publications

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“…For these reasons, we sought to determine whether antiviral approaches targeting the EBNA-1 protein could inhibit EBV-induced cell proliferation. Previous studies showed that antisense oligonucleotides directed to EBNA-1 partially inhibited EBNA-1 expression and also suppressed B cell proliferation (28,29). However, sufficient quantities of antisense oligonucleotides cannot be efficiently delivered to B cells and their relatively short half-life inside cells has hindered utilization of this antiviral approach.…”

Section: Discussionmentioning

confidence: 99%

Growth arrest of Epstein–Barr virus immortalized B lymphocytes by adenovirus-delivered ribozymes

Huang

Stupack

Mathias

et al. 1997

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

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Epstein-Barr virus (EBV) infection is associated with several human diseases that involve unrestricted proliferation of B lymphocytes. EBV nuclear antigen 1 (EBNA-1) is expressed in all EBV-infected cells and plays an essential role in persistence of the EBV genome. EBNA-1 has also been reported to have oncogenic potential. As an approach for treating EBV infections, we examined the capacity of EBNA-1 ribozymes delivered by recombinant adenoviruses to suppress EBNA-1 expression and to block virus-induced B cell proliferation. In contrast to primary B cells, EBVtransformed B lymphoblastoid cell lines expressed ␣v integrins, the adenovirus internalization receptors, and were also susceptible to adenovirus-mediated gene delivery. Adenovirus delivery of a specific ribozyme (RZ1) to lymphoblastoid cell lines, suppressed EBNA-1 mRNA and protein expression, significantly reduced the number of EBV genomes, and nearly abolished cell proliferation in low serum. Adenovirus delivery of RZ1 also prevented EBV infection of an established EBVnegative B cell line. These studies demonstrate the potential use of adenovirus-encoded ribozymes to treat EBV-induced lymphoproliferative disorders.

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Section: Discussionmentioning

confidence: 99%

Growth arrest of Epstein–Barr virus immortalized B lymphocytes by adenovirus-delivered ribozymes

Huang

Stupack

Mathias

et al. 1997

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

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“…1B, lanes 5 and 6; Fig. 3D, lanes 1 and 2; also data not shown) (34,51). In contrast, the IRF-1 level is basically unchanged in type I and III cells.…”

Section: Expression Of Irf-2 Is Associated With Ebv Type III Latencymentioning

confidence: 91%

Interferon Regulatory Factor 2 Represses the Epstein-Barr Virus Bam HI Q Latency Promoter in Type III Latency

Zhang

Pagano

1999

Molecular and Cellular Biology

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Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) is the essential protein for maintenance of the EBV episome and establishment of latency. The BamHI Q promoter (Qp) is used for the transcription of EBNA-1 mRNA in type I and type II latency, which are EBV infection states exemplified by Burkitt's lymphoma and nasopharyngeal carcinoma. However, Qp is inactive in type III latency, and other promoters (the BamHI C promoter and/or the BamHI W promoter) are used for EBNA-1. The involvement of interferon regulatory factors (IRFs) in the regulation of Qp is suggested by the presence of an essential interferon-stimulated response element (ISRE) in the promoter. In this work, expression of IRF-2 is shown to be inversely associated with Qp status, i.e., IRF-2 levels are high in type III latency (when Qp is inactive) and low in type I latency (when Qp is active). Also, IRF-2 is identified by electrophoretic mobility shift assay as the major protein binding to the Qp ISRE in type III latency. In transient transfection assays, IRF-2 represses the activity of Qp-reporter constructs. Overexpression of IRF-2 in a type I latency cell line did not activate the endogenous Qp but marginally reduced the EBNA-1 mRNA level. Switching from type III latency (Qp inactive) to type II latency (Qp active), as produced by cell fusion, is directly associated with greatly reduced expression of IRF-2. These data strongly suggest that IRF-2 is a negative regulator of Qp and may contribute to the silencing of Qp in type III latency.The biologic hallmark of Epstein-Barr virus (EBV) and its usual interaction with B lymphocytes is latency. Three types of latency, each having a distinct pattern of gene expression, have been described. Type I latency is exemplified by Burkitt's lymphoma (BL) tumors in vivo and earlier passages of cultured cell lines derived from BL biopsy specimens. Only EBV nuclear antigen 1 (EBNA-1) is expressed in this form of latency. Several reports suggest that a type I-like form of latency exists in healthy carriers of EBV (4,29,38,53). Interestingly, cells in type I latency can escape host immune surveillance because EBNA-1 can interfere with its peptide presentation on major histocompatibility complex class I molecules (25), which might explain the lifelong reservoir of virus in immunocompetent, seropositive persons. Type II latency is found in fusions between lymphoblastoid cell lines (LCLs) and epithelial cell lines, in nasopharyngeal carcinoma and in Hodgkin's disease. EBNA-1, latent membrane protein 1 (LMP-1), LMP-2A, and LMP-2B are expressed in type II latency. Type III latency is represented by LCLs established after EBV infection of adult primary B cells in vitro and by group III BL lines. Nine viral proteins are expressed, including six nuclear proteins (EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, and EBNA-LP) and three integral membrane proteins (LMP-1, LMP-2A, and LMP-2B) (reviewed in references 22 and 40).EBNA-1 is the sole protein needed for the replication of the EBV episome and maintenance of the latent infecti...

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“…Latency types were confirmed by detection of EBNA1, EBNA2, and LMP1 proteins by Western blot analysis with specific antibodies (data not shown). IRF-7A was also expressed at a higher level in SFC-4 and CB95 cells, which are type III (33), than in Akata type I cells (reference 45 and data not shown). Therefore, without exception, in all the cell lines tested, the expression of IRF-7 is greater in type III than in type I latency.…”

Section: Cloning Of Irf-mentioning

confidence: 99%

IRF-7, a New Interferon Regulatory Factor Associated with Epstein-Barr Virus Latency

Zhang

Pagano

1997

Molecular and Cellular Biology

239

283

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Epstein‐Barr Viral Latency and Cell Immortalization as Targets for Antisense Oligomersa

Cited by 22 publications

References 16 publications

Growth arrest of Epstein–Barr virus immortalized B lymphocytes by adenovirus-delivered ribozymes

Growth arrest of Epstein–Barr virus immortalized B lymphocytes by adenovirus-delivered ribozymes

Interferon Regulatory Factor 2 Represses the Epstein-Barr Virus Bam HI Q Latency Promoter in Type III Latency

IRF-7, a New Interferon Regulatory Factor Associated with Epstein-Barr Virus Latency

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