ArticlePLoS pathogens2017
Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus's natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter.
Article in PLoS pathogens, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 73 citations in OpenAlex.
- Multiple Sclerosis and Viruses: « Liaisons Dangereuses ».Reviews in medical virology · 2026Review
- Hypoxia increases the activity of oncolytic adenoviruses through HIF-2α-stimulated E1A expression.Signal transduction and targeted therapy · 2026Article
- The HIF-1α-Th17/Treg axis in pediatric infectious mononucleosis: a clinical investigation of metabolic-immune dysregulation.BMC infectious diseases · 2026Article
- Transcriptional factor ATF3 impairs KSHV lytic replication by suppressing the expression of viral bZIP protein K8.PLoS pathogens · 2026Article
- Stage-specific regulation of KSHV infection by HIF-1α.Journal of virology · 2026Article
- Antagonistic co-evolution throughout the herpesvirus life cycle.Virus evolution · 2026Review
- The IDO1/AhR-HIF-1α metabolic axis: ARNT competition as a central antagonistic switch in autoimmune pathogenesis.Frontiers in immunology · 2026Review
- Increased Frequency of the Chemokine Receptor CCR2 on Circulating CD19+CD5+ Lymphocytes in Therapy-Naïve CLL Patients With the Detectable EBV DNA and High-Avidity Antibodies Against the EBV Capsid Antigen.The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale · 2026Article
- Longitudinal proteomic profiling of cerebrospinal fluid in untreated multiple sclerosis defines evolving disease biology.Nature communications · 2025Article
- Hypoxia increases susceptibility of human intestinal epithelial cells to rotavirus infection through repression of interferon induction.Gut microbes · 2025Article
- The critical role of ferroptosis in virus-associated hematologic malignancies and its potential value in antiviral-antitumor therapy.Virulence · 2025Review
- 2-Deoxyglucose as a therapeutic strategy for EBV-associated gastric carcinoma: Glycolytic and lytic reactivation inhibition under hypoxic conditions.Journal of virus eradication · 2025Article
- Epstein-Barr virus infection and vitamin D deficiency are both "causal" for multiple sclerosis (MS) - could the common denominator be their effects on hepcidin levels?Metabolic brain disease · 2025Review
- Model Systems of Gammaherpesvirus Infection, Immunity, and Disease.Journal of medical virology · 2025Review
- Multiple sclerosis and infection: history, EBV, and the search for mechanism.Microbiology and molecular biology reviews : MMBR · 2025Review
- Is There such a Thing as Post-Viral Depression?: Implications for Precision Medicine.Biomolecules & therapeutics · 2024Review
- The Emerging Role of Ferroptosis in EBV-Associated Cancer: Implications for Cancer Therapy.Biology · 2024Review
- Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) Enhances ATP Production in B Cell Tumors through mTOR and HIF-1α.International journal of molecular sciences · 2024Article
- Oxygen-dependent histone lysine demethylase 4 restricts hepatitis B virus replication.The Journal of biological chemistry · 2024Article
- The N6-methyladenosine demethylase ALKBH5 regulates the hypoxic HBV transcriptome.PLoS pathogens · 2024Article
6 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies.
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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.