ArticlePLoS pathogens2015
Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers, 1 of them a synthesis that pooled it.
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Who cites it
82 citing papers in PubMed, 1 synthesis or guideline pooled it, 98 citations in OpenAlex.
- Laryngeal squamous cell carcinoma: a functional "two-hit" model of papillomavirus-Epstein-Barr virus synergistic carcinogenesis.Frontiers in cellular and infection microbiology · 2026Pooled it
- Natural Variations in BRLF1 Promoter Contribute to the Elevated Reactivation Level of Epstein-Barr Virus in Endemic Areas of Nasopharyngeal Carcinoma.EBioMedicine · 2018Trial
- Circulating cell-free Epstein-Barr virus DNA measurement for nasopharyngeal carcinoma: advancing towards ctDNA-guided, risk-adaptive individualized treatment.Science China. Life sciences · 2026Review
- Review
- KSHV-infected endothelial cells expand and up-regulate angiogenic pathways and CXCR4 in patient-derived Kaposi sarcoma models.Science translational medicine · 2026Article
- The interaction between virus-bound KLF4 and host-bound PARP1 directs the localization of wild-type adeno-associated virus type 2 (wtAAV2) to cellular sites of DNA damage.Journal of virology · 2026Article
- EBV nuclear antigen 1 hijacks DDX5/BZLF1 axis to facilitate viral lytic replication.Virologica Sinica · 2026Article
- [Establishment of an Epstein-Barr virus infection model using human nasal organoids].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- What could cause the reactivation of Epstein-Barr virus in individuals with long COVID.Emerging microbes & infections · 2025Article
- Lysine-specific histone demethylase complex restricts Epstein-Barr virus lytic reactivation.Nature microbiology · 2025Article
- Analysis of the Role of KLF4 in the Regulation of Porcine Epidemic Diarrhea Virus Infection.Animals : an open access journal from MDPI · 2025Article
- Chromatin Control of EBV Infection and Latency.Current topics in microbiology and immunology · 2025Article
- Characterizing resistant cellular states in nasopharyngeal carcinoma during EBV lytic induction.Oncogene · 2025Article
- IRF6 controls Epstein-Barr virus (EBV) lytic reactivation and differentiation in EBV-infected epithelial cells.PLoS pathogens · 2025Article
- Inhibition of the Integrated stress response by Epstein-Barr virus oncoprotein LMP1 attenuates epithelial cell differentiation and lytic viral reactivation.PLoS pathogens · 2025Article
- Epstein-Barr virus replication within differentiated epithelia requires pRb sequestration of activator E2F transcription factors.Journal of virology · 2024Article
- Inhibition of human cytomegalovirus entry into mucosal epithelial cells.Antiviral research · 2024Article
- Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models.bioRxiv : the preprint server for biology · 2024Article
- Identifying the key regulators orchestrating Epstein-Barr virus reactivation.Frontiers in microbiology · 2024Review
- A distinct isoform of lymphoid enhancer binding factor 1 (LEF1) epigenetically restricts EBV reactivation to maintain viral latency.PLoS pathogens · 2023Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
Epstein-Barr virus (EBV) is a human herpesvirus associated with B-cell and epithelial cell malignancies. EBV lytically infects normal differentiated oral epithelial cells, where it causes a tongue lesion known as oral hairy leukoplakia (OHL) in immunosuppressed patients. However, the cellular mechanism(s) that enable EBV to establish exclusively lytic infection in normal differentiated oral epithelial cells are not currently understood. Here we show that a cellular transcription factor known to promote epithelial cell differentiation, KLF4, induces differentiation-dependent lytic EBV infection by binding to and activating the two EBV immediate-early gene (BZLF1 and BRLF1) promoters. We demonstrate that latently EBV-infected, telomerase-immortalized normal oral keratinocyte (NOKs) cells undergo lytic viral reactivation confined to the more differentiated cell layers in organotypic raft culture. Furthermore, we show that endogenous KLF4 expression is required for efficient lytic viral reactivation in response to phorbol ester and sodium butyrate treatment in several different EBV-infected epithelial cell lines, and that the combination of KLF4 and another differentiation-dependent cellular transcription factor, BLIMP1, is highly synergistic for inducing lytic EBV infection. We confirm that both KLF4 and BLIMP1 are expressed in differentiated, but not undifferentiated, epithelial cells in normal tongue tissue, and show that KLF4 and BLIMP1 are both expressed in a patient-derived OHL lesion. In contrast, KLF4 protein is not detectably expressed in B cells, where EBV normally enters latent infection, although KLF4 over-expression is sufficient to induce lytic EBV reactivation in Burkitt lymphoma cells. Thus, KLF4, together with BLIMP1, plays a critical role in mediating lytic EBV reactivation in epithelial cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.