Transfection of a rearranged viral DNA fragment, WZhet, stably converts latent Epstein-Barr viral infection to productive infection in lymphoid cells.

Grogan, Elizabeth; Jenson, Hal B.; Countryman, Jill; Heston, Lee; Gradoville, Lynn; Miller, George

doi:10.1073/pnas.84.5.1332

Cited by 123 publications

(99 citation statements)

References 19 publications

(10 reference statements)

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“…Activation of the lytic cascade by treatment with anti-immunoglobulin results initially in the expression of two viral genes, BZLF1 and BRLF1, which exhibit similar induction kinetics (maximal mRNA levels are reached between 2 and 4 h postinduction) (14, 46). The protein products of both the BZLF1 (referred to here as Zta, but also called ZEBRA and EB1) and BRLF1 (Rta) genes have been shown to be transcriptional activators (8,10,12,25,26 speck@visar.wustl.edu.Expression of Zta and Rta leads to the activation of early genes and ultimately viral replication. Of all the viral transactivators examined, Zta is unique in that its expression alone can initiate the entire lytic cascade (10,11,40), and regulation of Zta expression appears to be central to regulating entry into the lytic cycle.…”

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DNA-binding-defective mutants of the Epstein-Barr virus lytic switch activator Zta transactivate with altered specificities.

et al. 1994

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The Epstein-Barr virus BRLF1 and BZLF1 genes are the first viral genes transcribed upon induction of the viral lytic cycle. The protein products of both genes (referred to here as Rta and Zta, respectively) activate expression of other viral genes, thereby initiating the lytic cascade. Among the viral antigens expressed upon induction of the lytic cycle, however, Zta is unique in its ability to Epstein-Barr virus (EBV) is a lymphotropic human herpesvirus that latently infects B lymphocytes, resulting in a concomitant growth transformation of the infected cell. Infection is closely associated with several human cancers, including nasopharyngeal carcinoma and African Burkitt's lymphoma, and also plays a role in several lymphoproliferative diseases in immunocompromised individuals (for a review, see reference 29). In vitro the transforming potential of EBV is evidenced by its ability to immortalize B lymphocytes to grow indefinitely in culture. Immortalization is achieved through the expression of a relatively small subset of EBV-encoded genes that serve to establish and maintain cellular transformation (for a review, see reference 45).Propagation of EBV from host to host is dependent upon the activation of an estimated 100 or more viral genes, culminating in the production of infectious virions (2, 4, 9, 27). While these genes remain quiescent during latency, a switch in the genetic program leading to the expression of viral replication associated genes can be accomplished in vitro by treatment of latently infected B lymphocytes with various reagents, including phorbol esters, butyrate, ionophore, and anti-immunoglobulin (2,28,37,46,48,51). Activation of the lytic cascade by treatment with anti-immunoglobulin results initially in the expression of two viral genes, BZLF1 and BRLF1, which exhibit similar induction kinetics (maximal mRNA levels are reached between 2 and 4 h postinduction) (14, 46). The protein products of both the BZLF1 (referred to here as Zta, but also called ZEBRA and EB1) and BRLF1 (Rta) genes have been shown to be transcriptional activators (8,10,12,25,26 speck@visar.wustl.edu.Expression of Zta and Rta leads to the activation of early genes and ultimately viral replication. Of all the viral transactivators examined, Zta is unique in that its expression alone can initiate the entire lytic cascade (10,11,40), and regulation of Zta expression appears to be central to regulating entry into the lytic cycle.We have previously identified multiple elements within the BZLF1 promoter (Zp) that play a role in regulating BZLF1 expression (15,16). Several of these elements bind cellular transcription factors that are responsive to phorbol ester stimulation (15). Zp also contains two Zta binding sites (ZIIIA and ZIIIB) that are important for autoactivation (16,33,49).Zta shares several structural similarities with other transcription factors. As described by Farrell et al. (12), Zta contains a basic region with homology to the DNA-binding domains of the AP-1 family of transcription factors (Fig. 1). In addi...

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DNA-binding-defective mutants of the Epstein-Barr virus lytic switch activator Zta transactivate with altered specificities.

et al. 1994

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“…Epstein-Barr virus (EBV) is a member of the herpes virus family, which is widespread and has been associated with a variety of disease processes, including glandular fever, Burkitt's lymphoma, nasopharyngeal carcinoma, lymphoma and post-transplant lymphoproliferative disease [6][7][8][9]. Burkitt's lymphoma and nasopharyngeal carcinoma are both associated with latent EBV infection [10,11].…”

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High levels of Epstein–Barr virus in COPD

McManus¹,

Marley²,

Baxter³

et al. 2008

Eur Respir J

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Latent viral infection has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). Epstein-Barr virus (EBV) is known to be important in pulmonary fibrosis. The current authors hypothesised that EBV is associated with the pathogenesis of COPD.Sputum samples were collected from patients both during exacerbations of COPD and when stable. A control group of smokers who did not have airways obstruction also had their sputum examined. The presence of EBV DNA was established and quantified using a real-time nucleic acid amplification assay.A total of 136 patients with COPD were recruited during an acute exacerbation and a total of 68 when stable. EBV was detected in 65 (48%) exacerbation cases and 31 (46%) stable patients. In the comparison group of 16 nonobstructed smokers, EBV was demonstrated in only one (6%) case. Risk of COPD in patients with EBV and who are smokers confers an odds ratio of 12.6.Epstein-Barr virus DNA is more frequently identified in the respiratory tract of chronic obstructive pulmonary disease patients in comparison with unaffected smokers. It is present both during exacerbation and when stable, suggesting that infection is persistent. Smokers who do not develop chronic obstructive pulmonary disease rarely have Epstein-Barr virus in their sputum. This finding may be of importance in the pathogenesis of chronic obstructive pulmonary disease.

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“…which acts as EBV's immediate early transcriptional activator. (17,70,137,190,191). Derepression of the BZLF1 gene probably underlies the action of most chemical and physical inducers of lytic replication and the mechanism is commonly referred to as the latent/lytic switch.…”

Section: Immortalizationmentioning

confidence: 99%

Epstein-barr virus immortalization and latency

Rowe¹

1999

Front Biosci

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Epstein-Barr virus infects human B lymphocytes.The interaction between the virus and these cells has been the subject of investigation for over three decades. Recent in vitro and in vivo studies, reviewed here, are revealing the mechanisms by which EBV induces and controls proliferation through the expression of six viral nuclear proteins and two plasma membrane proteins. This genetic program is referred to as immortalization and it is suggested that the purpose of immortalization is to use the innate proliferative potential of B cells to inflate the numbers of infected cells prior to virus production and cell lysis. Latency, on the other hand, has only been detected in situ in latently infected humans. It is characterized by the presence of very low numbers of viral episomes that appear to express the RNA for only one protein (Latent Membrane Protein 2) in B cells that bear the markers of a non-activated resting memory subset. Two models are proposed for the mechanism that establishes this state. The differences between immortalization and latency are highlighted in this review and it is suggested that many of the functions currently attributed to latency are actually features of immortalization. An appreciation of this distinction may assist the discussion of the nature of the interaction between the virus and the host in EBV-associated lymphoproliferative diseases and tumors.

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Transfection of a rearranged viral DNA fragment, WZhet, stably converts latent Epstein-Barr viral infection to productive infection in lymphoid cells.

Cited by 123 publications

References 19 publications

DNA-binding-defective mutants of the Epstein-Barr virus lytic switch activator Zta transactivate with altered specificities.

DNA-binding-defective mutants of the Epstein-Barr virus lytic switch activator Zta transactivate with altered specificities.

High levels of Epstein–Barr virus in COPD

Epstein-barr virus immortalization and latency

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