Hairy Leukoplakia: an Unusual Combination of Transforming and Permissive Epstein-Barr Virus Infections

Webster‐Cyriaque, Jennifer; Middeldorp, Jaap M.; Raab‐Traub, Nancy

doi:10.1128/jvi.74.16.7610-7618.2000

Cited by 84 publications

(73 citation statements)

References 39 publications

(33 reference statements)

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“…However, other cell types have been found to provide a more permissive environment. In the case of hairy leukoplakia, a lesion associated with the differentiated layers of the tongue epithelium, there is aggressive EBV lytic replication with extensive virion production along with concurrent expression of EBV latency genes (22,50,51). In vitro infection of both nonepithelial cells, for example, primary monocytes and explanted tissue from leiomyosarcoma (26,40,45), as well as epithelial cells derived from gastric carcinoma and nasopharyngeal carcinoma (29,55,56), has also resulted in cultures in which both latency gene expression and lytic BZLF1 gene expression have been detected.…”

Section: Discussionmentioning

confidence: 99%

Lytic Viral Replication as a Contributor to theDetection of Epstein-Barr Virus in BreastCancer

Huang¹,

Chen

Hutt-Fletcher

et al. 2003

J Virol

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Epstein-Barr virus (EBV)has an accepted association with the epithelial malignancy nasopharyngeal carcinoma and has also been reported in other more controversial carcinoma settings. Evaluation of EBV association with epithelial carcinomas such as breast cancer would benefit from a better understanding of the outcome of EBV infection of these cells. Cell-free preparations of a green fluorescent protein-expressing virus, BX1, were used to infect breast cancer cell lines, which were then examined for EBV gene expression and viral genome copy number. Reverse transcription-PCR analyses revealed that the cells supported a mixture of latency II and lytic EBV gene expression. Lytic Zta and BMRF1 protein expression was detected by immunohistochemistry, and DNA PCR analyses estimated an EBV copy number of 300 to 600 genomes per infected cell. Evidence for lytic EBV expression was also found in breast tissue, where reverse transcription-PCR analyses detected lytic Zta transcripts in 7 of 10 breast carcinoma tissues and 4 of 10 normal tissues from the same patients. Scattered cells immunoreactive for Zta protein were also detectable in breast carcinoma. Quantitative real-time PCR analysis of EBV-positive breast carcinoma tissues suggested that less than 0.1% of the cells contained viral genomes. We suggest that sporadic lytic EBV infection may contribute to PCR-based detection of EBV in traditionally nonvirally associated epithelial malignancies.

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Section: Discussionmentioning

confidence: 99%

Lytic Viral Replication as a Contributor to theDetection of Epstein-Barr Virus in BreastCancer

Huang¹,

Chen

Hutt-Fletcher

et al. 2003

J Virol

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“…Duplicate cDNA samples generated with (RT ϩ lanes; 161-bp product from spliced template) and without added reverse transcriptase (RT Ϫ lanes; 255-bp product from unspliced template) served as controls to detect genomic DNA. (45). The oral cavity is also a reservoir for EpsteinBarr virus infection in healthy individuals (40,43).…”

Section: Discussionmentioning

confidence: 99%

Wild-Type Kaposi's Sarcoma-Associated Herpesvirus Isolated from the Oropharynx of Immune-Competent Individuals Has Tropism for Cultured Oral Epithelial Cells

Duus

Lentchitsky

Wagenaar

et al. 2004

J Virol

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Based on the observation that wild-type Kaposi's sarcoma-associated herpesvirus (KSHV) DNA can be detected in the oral cavity of healthy, immunocompetent individuals, we hypothesized that epithelial cells could be infected in vitro by wild-type (WT) KSHV isolated from immunocompetent individuals. Primary oral epithelial (P-EPI) cells and telomerase-immortalized oral epithelial cells were generated from human gingival tissue and were then infected in vitro with WT KSHV isolated from throat wash samples. Markers of lytic and latent KSHV infection were detected in cultures by 24 h postinfection by immunofluorescence confocal microscopic assays. The infectivity of the WT and BCBL virus was blocked by neutralizing antibodies against KSHV gB. The presence of KSHV DNA in these cells was confirmed by real-time PCR amplification of different regions of the viral genome. The significant in vitro viral replication that had occurred was inhibited by ganciclovir and by neutralizing antibodies against gB. When infected cultures were examined by scanning electron microscopy, thousands of KSHV particles were clearly visible across the surfaces of P-EPI cells. The detection of enveloped particles indicated that the infectious cycle had proceeded through assembly and egress. We thus demonstrated that oral WT KSHV isolated from immunocompetent individuals was able to infect and replicate in vitro in a relevant primary cell type. Furthermore, our results provide compelling evidence for KSHV transmission within infected oral epithelial cells derived from healthy, immunocompetent populations.Kaposi's sarcoma-associated herpesvirus (KSHV; also called human herpesvirus 8 ) is the etiologic agent of Kaposi's sarcoma (KS) (12) and peripheral effusion lymphoma (PEL) (10). The human herpesviruses are generally ubiquitous among human populations, are generally shed in the oral cavity, and are primarily transmitted via the salivary route. However, current serological tests for KSHV have determined that the seroprevalence within the general U.S. population is low, suggesting that, unlike the other human herpesviruses (with the exception of herpes simplex virus type 2 [HSV-2]), KSHV is not ubiquitous among healthy human populations.The primary mode of KSHV transmission remains unresolved, as extensive evidence exists for both sexual (8,25,30,31) and oral (5, 29, 34) transmission routes in immunosuppressed individuals. However, recent epidemiology studies suggested that oral transmission of KSHV does occur among healthy populations (14,15). Complicating the transmission issue, the identities of the cell types harboring KSHV in vivo in the oral cavity and producing the virus detected in saliva are not known. Endothelial cells are the primary infected cells in KS lesions (7). Recently, KSHV antigens were detected in oral epithelial cells of an early KS lesion (44). In addition, the ability of the virus to infect primary human keratinocytes has also been demonstrated (3, 9). Based on the above evidence, we hypothesized that the wild-type (WT) isol...

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“…LMP1 expression with EBV replication in epithelial cells (44,45) and with latency III infection in lymphoblasts, should activate IRF7, NF-B, JNK, and p38, and synergistically induce IFN expression (46)(47)(48). IFN can prevent EBV from converting other lymphocytes to proliferating lymphoblasts (49,50).…”

Section: Discussionmentioning

confidence: 99%

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

Song

Izumi

Shinners

et al. 2008

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

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Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1), a constitutively aggregated and activated pseudoreceptor, activates IFN regulatory factor 7 (IRF7) through RIP1. We now report that the LMP1 cytoplasmic carboxyl terminal amino acids 379 -386 bound IRF7 and activated IRF7. IRF7 activation required TRAF6 and RIP1, but not TRAF2 or TRAF3. LMP1 Y384YD386, which are required for TRADD and RIP1 binding and for NF-B activation, were not required for IRF7 binding, but were required for IRF7 activation, implicating signaling through TRADD and RIP1 in IRF7 activation. Association with active LMP1 signaling complexes was also critical for IRF7 activation because (i) a dominant-negative IRF7 bound to LMP1, blocked IRF7 association and activation, but did not inhibit LMP1 induced NF-B or TBK1 or Sendai virus-mediated IFN stimulated response element activation; and (ii) two different LMP1 transmembrane domain mutants, which fail to aggregate, each bound IRF7 and prevented LMP1 from binding and activating IRF7 in the same cell, but did not prevent NF-B activation. Thus, efficient IRF7 activation required association with LMP1 CTAR2 in proximity to LMP1 CTAR2 mediated kinase activation sites. LMP1 has a 24-aa cytoplasmic N-terminus, six hydrophobic transmembrane domains (amino acids 25 to 186) and a 200-aa cytoplasmic C-terminus (amino acids 187 to 386). The transmembrane domains induce LMP1 aggregation in plasma membrane lipid rafts and barges and constitutively activate two C-terminal cytoplasm signaling domains referred to as C-terminal activation regions (CTAR) or transformation effector sites (TES) 1 and 2, which were initially defined as amino acids 187-231 and 352-386, respectively (Fig. 1A) (2-9). CTAR1 amino acids 201 to 210 engage tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) 1, 3, 2, and 5 and CTAR2 amino acids 376-386 engage TNFRassociated death domain proteins TRADD and RIP1 (4-12). Both signaling domains activate NF-B, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, thereby altering cell gene expression, cell survival, and immune responses (13-17).LMP1 also induces and activates IFN regulatory factor 7 (IRF7) (18-20), a critical transcription factor for type 1 IFN (IFN)-mediated innate and adaptive immune responses (21-24). IRF7 is comprised of DNA binding, constitutive activation, virus activated, inhibitory, and signal response domains and is activated by serine 477 and 479 phosphorylation (25). Although IRF7 is expressed at low levels in nonstimulated cells, IRF7 is critical for type I IFN expression, particularly in plasmacytoid dendritic cells (24,26,27). Toll-like receptor activation, LMP1 expression, viral infection, and other signals that activate IRF3 and induce IFN ␤ (IFN␤), can up-regulate IRF7 expression (18, 21-24, 28, 29). IRF7 can bind and localize to MyD88 until ligand-activated Toll-like receptors 7, 8, or 9 engage MyD88 and activate IRF7, which enters the nucleus and up-regulates IFN stimulated response elements (ISREs) to activate I...

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Hairy Leukoplakia: an Unusual Combination of Transforming and Permissive Epstein-Barr Virus Infections

Cited by 84 publications

References 39 publications

Lytic Viral Replication as a Contributor to theDetection of Epstein-Barr Virus in BreastCancer

Lytic Viral Replication as a Contributor to theDetection of Epstein-Barr Virus in BreastCancer

Wild-Type Kaposi's Sarcoma-Associated Herpesvirus Isolated from the Oropharynx of Immune-Competent Individuals Has Tropism for Cultured Oral Epithelial Cells

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

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