The Epstein–Barr Virus Lytic Life Cycle

Swaminathan, Sankar; Kenney, Shannon C.

doi:10.1007/978-0-387-68945-6_13

Cited by 10 publications

(10 citation statements)

References 223 publications

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“…In common with all herpesviruses, both KSHV and EBV sequentially express immediate-early (IE), early (E) and late (L) genes during the lytic phase of replication. Immediate-early genes in the γ-herpesviruses encode transcriptional activators that initiate the lytic cycle and are necessary for virus reactivation from latency [ 3 ]. Many early gene products are required for lytic viral DNA replication, which is carried out by virus-encoded homologs of the cellular DNA replication machinery [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Continuous DNA replication is required for late gene transcription and maintenance of replication compartments in gammaherpesviruses

Swaminathan

2018

PLoS Pathog

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Late gene transcription in herpesviruses is dependent on viral DNA replication in cis but the mechanistic basis for this linkage remains unknown. DNA replication results in demethylated DNA, topological changes, removal of proteins and recruitment of proteins to promoters. One or more of these effects of DNA replication may facilitate late gene transcription. Using 5-azacytidine to promote demethylation of DNA, we demonstrate that late gene transcription cannot be rescued by DNA demethylation. Late gene transcription precedes significant increases in DNA copy number, indicating that increased template numbers also do not contribute to the linkage between replication and late gene transcription. By using serial, timed blockade of DNA replication and measurement of late gene mRNA accumulation, we demonstrate that late gene transcription requires ongoing DNA replication. Consistent with these findings, blocking DNA replication led to dissolution of DNA replication complexes which also contain RNA polymerase II and BGLF4, an EBV protein required for transcription of several late genes. These data indicate that ongoing DNA replication maintains integrity of a replication-transcription complex which is required for recruitment and retention of factors necessary for late gene transcription.

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Section: Introductionmentioning

confidence: 99%

Continuous DNA replication is required for late gene transcription and maintenance of replication compartments in gammaherpesviruses

Swaminathan

2018

PLoS Pathog

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“…The EBV member of this family, which includes herpes simplex virus ICP27, cytomegalovirus (CMV) UL69, and Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57, is known as SM (2). SM acts posttranscriptionally to enhance accumulation of many lytic EBV transcripts.…”

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confidence: 99%

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Verma

Thompson

Swaminathan

2016

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

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Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses. . EBV infects the majority of humans worldwide and establishes a persistent, lifelong latent infection in memory B cells. Occasional reactivation from latency occurs, and EBV enters a lytic phase of replication, during which a tightly regulated series of lytic genes is expressed, culminating in lysis of the host cell and release of infectious viral progeny. All herpesviruses share these abilities to establish asymptomatic latent infection and reactivate intermittently.All herpesviruses also express a regulatory protein early in lytic replication that is essential for efficient gene expression and infectious virion production. The EBV member of this family, which includes herpes simplex virus ICP27, cytomegalovirus (CMV) UL69, and Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57, is known as SM (2). SM acts posttranscriptionally to enhance accumulation of many lytic EBV transcripts. SM activity is highly gene-specific and preferentially enhances expression of several late lytic transcripts, including those encoding the major viral capsid antigen (VCA) and gp350, which is required for infection of B lymphocytes (3-5). SM and its homologs in other herpesviruses may also enhance transcription and translation of specific viral genes (6).Currently, all available antiherpesvirus drugs target viral DNA polymerases and are usually highly effective, but toxicity and development of resistance limits their use (7). To discover potential novel therapeutic compounds, we applied a cell-based screening assay to identify compounds that would specifically target SM function (8). Using this assay, spironolactone (SPR), a drug in clinical use for over 50 y, was identified as inhibiting SM function and EBV virion production. SPR is an aldosterone antagonis...

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“…Infected cells then enter lymph node germinal centers, where EBV gene expression is down-modulated, presumably to limit immune-detection. EBV subsequently establishes persistent infection of the memory B-cell compartment, from which it periodically reactivates [4,5,6]. …”

Section: Introductionmentioning

confidence: 99%

NF-κB and IRF7 Pathway Activation by Epstein-Barr Virus Latent Membrane Protein 1

Ersing

Bernhardt

Gewurz

2013

Viruses

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The principal Epstein-Barr virus (EBV) oncoprotein, Latent Membrane Protein 1 (LMP1), is expressed in most EBV-associated human malignancies. LMP1 mimics CD40 receptor signaling to provide infected cells with constitutive NF-κB, MAP kinase, IRF7, and PI3 kinase pathway stimulation. EBV-transformed B-cells are particularly dependent on constitutive NF-κB activity, and rapidly undergo apoptosis upon NF-κB blockade. Here, we review LMP1 function, with special attention to current understanding of the molecular mechanisms of LMP1-mediated NF-κB and IRF7 pathway activation. Recent advances include the elucidation of transmembrane motifs important for LMP1 trafficking and ligand-independent signaling, analysis of genome-wide LMP1 gene targets, and the identification of novel cell proteins that mediate LMP1 NF-κB and IRF7 pathway activation.

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The Epstein–Barr Virus Lytic Life Cycle

Cited by 10 publications

References 223 publications

Continuous DNA replication is required for late gene transcription and maintenance of replication compartments in gammaherpesviruses

Continuous DNA replication is required for late gene transcription and maintenance of replication compartments in gammaherpesviruses

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

NF-κB and IRF7 Pathway Activation by Epstein-Barr Virus Latent Membrane Protein 1

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