Quantitative evaluation of the role of Epstein–Barr virus immediate-early protein BZLF1 in B-cell transformation

Katsumura, Koichi R.; Maruo, Seiji; Wu, Yi; Kanda, Teru; Takada, Kenzo

doi:10.1099/vir.0.012831-0

Cited by 29 publications

(31 citation statements)

References 58 publications

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“…This was done in the presence of cyclosporine A, an immunosuppressive drug that inhibits T cell responses, so that B cell outgrowth would not be affected by the presence of endogenous EBV-specific memory T cells in the assay. Three weeks post-infection, the absolute number of cells increased in the EBV-containing wells (Figure 1A), as previously reported for another EBV strain [25]. Flow cytometry analysis of the infected cells revealed that elevated cell numbers were due to the outgrowth of EBV transformed B cells (Figure 1B).…”

Section: Resultssupporting

confidence: 84%

Adoptive Transfer of EBV Specific CD8+ T Cell Clones Can Transiently Control EBV Infection in Humanized Mice

et al. 2014

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Epstein Barr virus (EBV) infection expands CD8+ T cells specific for lytic antigens to high frequencies during symptomatic primary infection, and maintains these at significant numbers during persistence. Despite this, the protective function of these lytic EBV antigen-specific cytotoxic CD8+ T cells remains unclear. Here we demonstrate that lytic EBV replication does not significantly contribute to virus-induced B cell proliferation in vitro and in vivo in a mouse model with reconstituted human immune system components (huNSG mice). However, we report a trend to reduction of EBV-induced lymphoproliferation outside of lymphoid organs upon diminished lytic replication. Moreover, we could demonstrate that CD8+ T cells against the lytic EBV antigen BMLF1 can eliminate lytically replicating EBV-transformed B cells from lymphoblastoid cell lines (LCLs) and in vivo, thereby transiently controlling high viremia after adoptive transfer into EBV infected huNSG mice. These findings suggest a protective function for lytic EBV antigen-specific CD8+ T cells against EBV infection and against virus-associated tumors in extra-lymphoid organs. These specificities should be explored for EBV-specific vaccine development.

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Section: Resultssupporting

confidence: 84%

Adoptive Transfer of EBV Specific CD8+ T Cell Clones Can Transiently Control EBV Infection in Humanized Mice

et al. 2014

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“…If Zta supported such a productive cycle, the host cell would be killed, aborting the EBV latent phase and potential long-term survival in the host. Instead, BZLF1 stimulates the ability of the infected resting B cells to proliferate, which has not been observed previously (41) (Fig. 4).…”

Section: Discussionsupporting

confidence: 56%

AP-1 homolog BZLF1 of Epstein–Barr virus has two essential functions dependent on the epigenetic state of the viral genome

Kalla

Schmeinck

Bergbauer

et al. 2009

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

147

232

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EBV, a member of the herpes virus family, is a paradigm for human tumor viruses and a model of viral latency amenable for study in vitro. It induces resting human B lymphocytes to proliferate indefinitely in vitro and initially establishes a strictly latent infection in these cells. BZLF1, related to the cellular activating protein 1 (AP-1) family of transcription factors, is the viral master gene essential and sufficient to mediate the switch to induce the EBV lytic phase in latently infected B cells. Enigmatically, after infection BZLF1 is expressed very early in the majority of primary B cells, but its early expression fails to induce the EBV lytic phase. We show that the early expression of BZLF1 has a critical role in driving the proliferation of quiescent naïve and memory B cells but not of activated germinal center B cells. BZLF1's initial failure to induce the EBV lytic phase relies on the viral DNA at first being unmethylated. We have found that the eventual and inevitable methylation of viral DNA is a prerequisite for productive infection in stably, latently infected B cells which then yield progeny virus lacking cytosine-phosphatidylguanosine (CpG) methylation. This progeny virus then can repeat EBV's epigenetically regulated, biphasic life cycle. Our data indicate that the viral BZLF1 protein is crucial both to establish latency and to escape from it. Our data also indicate that EBV has evolved to appropriate its host's mode of methylating DNA for its own epigenetic regulation.cytosine-phosphatidyl-guanosine methylation | latency | transcription | herpesvirus | reactivation

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“…AGS-CR2/EGFP-EBV cells were maintained in RPMI 1640 medium containing 150 g of hygromycin B and 400 g G418 per milliliter. For their preparation, an EBV-negative cell line from gastric cancer, AGS, was stably transfected with CR2 (CD21, the receptor for EBV) expression vector (22) and infected with an enhanced green fluorescent protein-expressing EBV (EGFP-EBV) strain (23) followed by G418 selection.…”

Section: Methodsmentioning

confidence: 99%

Nuclear Transport of Epstein-Barr Virus DNA Polymerase Is Dependent on the BMRF1 Polymerase Processivity Factor and Molecular Chaperone Hsp90

Kawashima

Kanda

Murata

et al. 2013

J Virol

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b Epstein-Barr virus (EBV) replication proteins are transported into the nucleus to synthesize viral genomes. We here report molecular mechanisms for nuclear transport of EBV DNA polymerase. The EBV DNA polymerase catalytic subunit BALF5 was found to accumulate in the cytoplasm when expressed alone, while the EBV DNA polymerase processivity factor BMRF1 moved into the nucleus by itself. Coexpression of both proteins, however, resulted in efficient nuclear transport of BALF5. Deletion of the nuclear localization signal of BMRF1 diminished the proteins' nuclear transport, although both proteins can still interact. These results suggest that BALF5 interacts with BMRF1 to effect transport into the nucleus. Interestingly, we found that Hsp90 inhibitors or knockdown of Hsp90␤ with short hairpin RNA prevented the BALF5 nuclear transport, even in the presence of BMRF1, both in transfection assays and in the context of lytic replication. Immunoprecipitation analyses suggested that the molecular chaperone Hsp90 interacts with BALF5. Treatment with Hsp90 inhibitors blocked viral DNA replication almost completely during lytic infection, and knockdown of Hsp90␤ reduced viral genome synthesis. Collectively, we speculate that Hsp90 interacts with BALF5 in the cytoplasm to assist complex formation with BMRF1, leading to nuclear transport. Hsp90 inhibitors may be useful for therapy for EBV-associated diseases in the future.

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Quantitative evaluation of the role of Epstein–Barr virus immediate-early protein BZLF1 in B-cell transformation

Cited by 29 publications

References 58 publications

Adoptive Transfer of EBV Specific CD8+ T Cell Clones Can Transiently Control EBV Infection in Humanized Mice

Adoptive Transfer of EBV Specific CD8+ T Cell Clones Can Transiently Control EBV Infection in Humanized Mice

AP-1 homolog BZLF1 of Epstein–Barr virus has two essential functions dependent on the epigenetic state of the viral genome

Nuclear Transport of Epstein-Barr Virus DNA Polymerase Is Dependent on the BMRF1 Polymerase Processivity Factor and Molecular Chaperone Hsp90

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