Persistent Productive Epstein‐Barr Virus Replication in Normal Epithelial Cells In Vivo

Walling, Dennis M.; Flaitz, Catherine M.; Nichols, C. Mark; Hudnall, S. David; Adler‐Storthz, Karen

doi:10.1086/323992

Cited by 69 publications

(75 citation statements)

References 44 publications

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“…This might indicate a response to EBV reactivation during HIV seroconversion, which would resemble the situation in primary EBV, where mostly lytic Ags are targeted (11,33). Another drive for expansion of lytic Ag-specific CD8 ϩ T cells could be EBV replication in epithelial tissue, which is frequently reported in HIV (34,35). In support of an Ag-driven expansion and differentiation of lytic Ag-specific CD8 ϩ T cells, we found an increase in the percentage of CD27-negative RAK-specific cells after HIV seroconversion.…”

Section: Discussionmentioning

confidence: 97%

Altered EBV Viral Load Setpoint after HIV Seroconversion Is in Accordance with Lack of Predictive Value of EBV Load for the Occurrence of AIDS-Related Non-Hodgkin Lymphoma

Piriou

Dort

Nanlohy

et al. 2004

The Journal of Immunology

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In contrast to the situation in the post-transplant setting, in HIV-infected individuals an elevated EBV load is not predictive of EBV-related malignancies. To study whether a high EBV load is already a normal situation early in HIV infection and is not related to a decrease in immune function over time, we investigated EBV load and EBV-specific CD8+ T cells ∼1 year before and 1 year after HIV seroconversion. EBV load significantly increased after HIV seroconversion from 205 to 1002 copies/106 PBMC (p < 0.001), whereas no further increase in EBV load was observed between 1 and 5 years after HIV seroconversion (median, 1827–2478 copies/106 PBMC; p = 0.530). Interestingly, the absolute number of EBV lytic epitope, RAKFKQLL-specific CD8+ T cells increased over HIV seroconversion (4.78 to 9.54/μl; p = 0.011). Furthermore, the fraction of CD27-negative effector, RAK-specific CD8+ T cells tended to increase (from 12.2 to 17.31% CD27−; p = 0.051), in accordance with Ag-driven differentiation. In conclusion, both virological and immunological data support the idea that a new EBV viral setpoint is reached early in HIV infection, probably by EBV reactivation, as suggested by the preferential increase in EBV lytic epitope-specific CD8+ T cells. These data may thus help to explain the lack of predictive value of EBV load for the occurrence of AIDS-related lymphoma.

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Section: Discussionmentioning

confidence: 97%

Altered EBV Viral Load Setpoint after HIV Seroconversion Is in Accordance with Lack of Predictive Value of EBV Load for the Occurrence of AIDS-Related Non-Hodgkin Lymphoma

Piriou

Dort

Nanlohy

et al. 2004

The Journal of Immunology

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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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“…EBV exclusively, lytically infects more differentiated normal epithelial cells (48)(49)(50)(51)(52)(53), and thus, the viral genome remains highly unmethylated (11). However, in the case of NPC, EBV maintains a latent infection and the viral genome becomes highly methylated (54).…”

Section: Tet2 Promotes Ebv Type III Latency Gene Expressionmentioning

confidence: 99%

Restricted TET2 Expression in Germinal Center Type B Cells Promotes Stringent Epstein-Barr Virus Latency

Wille

et al. 2017

J Virol

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Epstein-Barr virus (EBV) latently infects normal B cells and contributes to the development of certain human lymphomas. Newly infected B cells support a highly transforming form (type III) of viral latency; however, long-term EBV infection in immunocompetent hosts is limited to B cells with a more restricted form of latency (type I) in which most viral gene expression is silenced by promoter DNA methylation. How EBV converts latency type is unclear, although it is known that type I latency is associated with a germinal center (GC) B cell phenotype, and type III latency with an activated B cell (ABC) phenotype. In this study, we have examined whether expression of TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells. We found that TET2 expression is inhibited in normal GC cells and GC type lymphomas. In contrast, TET2 is expressed in normal naive B cells and ABC type lymphomas. We also demonstrate that GC type cell lines have increased 5mC levels and reduced 5hmC levels in comparison to those of ABC type lines. Finally, we show that TET2 promotes the ability of the EBV transcription factor EBNA2 to convert EBV-infected cells from type I to type III latency. These findings demonstrate that TET2 expression is repressed in GC cells independent of EBV infection and suggest that TET2 promotes type III EBV latency in B cells with an ABC or naive phenotype by enhancing EBNA2 activation of methylated EBV promoters.IMPORTANCE EBV establishes several different types of viral latency in B cells. However, cellular factors that determine whether EBV enters the highly transforming type III latency, versus the more restricted type I latency, have not been well characterized. Here we show that TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells by enhancing the ability of the viral transcription factor EBNA2 to activate methylated viral promoters that are expressed in type III (but not type I) latency. Furthermore, we demonstrate that (independent of EBV) TET2 is turned off in normal and malignant germinal center (GC) B cells but expressed in other B cell types. Thus, restricted TET2 expression in GC cells may promote type I EBV latency. KEYWORDS 5hmC, EBNA2, EBV, Epstein-Barr virus, TET2, germinal center B cell, latency E pstein-Barr virus (EBV) is human gammaherpesvirus that infects over 90% of the world population. EBV is the causative agent of infectious mononucleosis and is also associated with several malignancies of B cell and epithelial cell origin, including Burkitt lymphoma (BL), Hodgkin's disease, posttransplant lymphoproliferative disorder, diffuse large B cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and gastric carcinoma (1, 2). EBV establishes latent infection in normal B cells, in which the virus

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Persistent Productive Epstein‐Barr Virus Replication in Normal Epithelial Cells In Vivo

Cited by 69 publications

References 44 publications

Altered EBV Viral Load Setpoint after HIV Seroconversion Is in Accordance with Lack of Predictive Value of EBV Load for the Occurrence of AIDS-Related Non-Hodgkin Lymphoma

Altered EBV Viral Load Setpoint after HIV Seroconversion Is in Accordance with Lack of Predictive Value of EBV Load for the Occurrence of AIDS-Related Non-Hodgkin Lymphoma

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

Restricted TET2 Expression in Germinal Center Type B Cells Promotes Stringent Epstein-Barr Virus Latency

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