Multiple Epstein-Barr Virus Infections in Healthy Individuals

Walling, Dennis M.; Brown, Abigail L; Etienne, Wiguins; Keitel, Wendy A.; Ling, Paul D.

doi:10.1128/jvi.77.11.6546-6550.2003

Cited by 100 publications

(103 citation statements)

References 48 publications

(58 reference statements)

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“…(45). The oral cavity is also a reservoir for EpsteinBarr virus infection in healthy individuals (40,43). Other herpesviruses, such as HHV-6 and HHV-7, are also present in the oral cavity.…”

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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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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“…49,50 It seems unlikely that sterilizing immunity against EBV can be achieved via vaccination because 1 to 10 virus particles are enough for the establishment of lifelong ␥-herpesvirus infections, 51,52 and reinfection of healthy EBV carriers with new EBV strains has been documented. 53,54 Thus, more recent immunotherapeutic approaches against primary EBV infection have concentrated on inducing T-cell responses to aid in asymptomatic seroconversion, rather than preventing infection, and to target EBVassociated malignancies. Along these lines, a single CD8 ϩ T-cell peptide epitope-based vaccine for IM has been tested in a phase 1 clinical trial.…”

Section: Discussionmentioning

confidence: 99%

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Gurer

Strowig

Brilot

et al. 2008

Blood

121

129

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IntroductionEpstein-Barr virus (EBV) is a ubiquitous human ␥-herpesvirus that latently infects B cells and establishes chronic infection in more than 90% of the adult population. Although infection with EBV during adolescence can lead to infectious mononucleosis (IM), the vast majority of infected people acquires and harbors EBV as a benign lifelong infection, which is controlled by strong T-cell immunity. However, in a small subset of infected individuals, EBV latency programs with different viral antigen expression patterns are associated with malignancies such as Hodgkin and Burkitt lymphomas as well as nasopharyngeal carcinoma (NPC). 1 The nuclear antigen 1 (EBNA1) is the one EBV antigen that is expressed in all of these EBV-associated tumors as well as in EBV-positive proliferating cells in healthy carriers. 2 EBNA1 is crucial for viral persistence, because it initiates viral DNA replication and anchors the circular viral episome to the mitotic chromosomes during cell division, thereby ensuring the survival of the viral genome in proliferating cells. Thus, even in the absence of all other EBV proteins, such as in Burkitt lymphoma, EBNA1 expression must be maintained, and from an immune surveillance point of view, EBNA1 should be a critical target of protective immunity. Indeed, EBNA1 is consistently recognized by Th1-type CD4 ϩ T cells, [3][4][5][6] and can elicit CD8 ϩ T-cell responses 7-9 in healthy EBV carriers. These T cells that recognize mostly epitopes in the C-terminal domain of EBNA1 can target EBV-transformed B cells and prevent their outgrowth in vitro. 10 While EBNA1-specific T-cell responses can also be detected in peripheral blood of NPC patients, 11 they are greatly diminished in patients with EBVassociated non-Hodgkin lymphoma in the context of HIV infection, 12 EBV-associated Hodgkin disease (K. N. Heller, F.A., P. Steinherz, C. Postlook, A. Chadburn, K. Kelly, C.M., manuscript submitted) and endemic Burkitt lymphomas (Ann Moormann, Case Western Reserve University, Cleveland, OH, personal communication April 2008), thus making EBNA1, and specifically its C-terminal domain, a logical target for vaccine development against all EBV-associated malignancies.A promising cell type, to which EBNA1 could be targeted for vaccine design, is dendritic cells (DCs). These sentinels of the immune system have an exceptional T-cell stimulatory capacity, which includes their ability to efficiently process antigens, and present them on both major histocompatibility class (MHC) I and class II molecules in combination with T-cell costimulatory molecules. 13 DCs are also crucial for initiating protective innate and adaptive immune responses against bacterial and viral pathogens in vivo, 14,15 which further supports targeting DCs for therapeutic vaccination. However, many current DC-targeted immunization approaches use individualized culture, antigen loading, and activation of DCs in vitro for adoptive transfer. 16 A more recent strategy that circumvents the analysis of ex vivo DCs is to target antigens to DCs in...

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“…Similarly, some studies examined the EBV termini and reported monoclonal expansion of EBV in several kinds of lymphoma (14,29). However, in contrast to the pattern in tumor cells, multiple EBV strains were observed in peripheral blood from patients with NPC and from asymptomatic EBV carriers (11,19,39,42), as determined based on variations in LMP1 genes. These findings suggest that EBV might infect the progenitor cell before cell proliferation and then undergo monoclonal expansion in tumor cells, thereby contributing to pathogenesis.…”

mentioning

confidence: 90%

Direct Sequencing and Characterization of a Clinical Isolate of Epstein-Barr Virus from Nasopharyngeal Carcinoma Tissue by Using Next-Generation Sequencing Technology

Liu

Fang

Feng

et al. 2011

J Virol

104

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Epstein-Barr virus (EBV)-encoded molecules have been detected in the tumor tissues of several cancers, including nasopharyngeal carcinoma (NPC), suggesting that EBV plays an important role in tumorigenesis.However, the nature of EBV with respect to genome width in vivo and whether EBV undergoes clonal expansion in the tumor tissues are still poorly understood. In this study, next-generation sequencing (NGS) was used to sequence DNA extracted directly from the tumor tissue of a patient with NPC. Apart from the human sequences, a clinically isolated EBV genome 164.7 kb in size was successfully assembled and named GD2 (GenBank accession number HQ020558). Sequence and phylogenetic analyses showed that GD2 was closely related to GD1, a previously assembled variant derived from a patient with NPC. GD2 contains the most prevalent EBV variants reported in Cantonese patients with NPC, suggesting that it might be the prevalent strain in this population. Furthermore, GD2 could be grouped into a single subtype according to common classification criteria and contains only 6 heterozygous point mutations, suggesting the monoclonal expansion of GD2 in NPC. This study represents the first genome-wide analysis of a clinical isolate of EBV directly extracted from NPC tissue. Our study reveals that NGS allows the characterization of genome-wide variations of EBV in clinical tumors and provides evidence of monoclonal expansion of EBV in vivo. The pipeline could also be applied to the study of other pathogen-related malignancies. With additional NGS studies of NPC, it might be possible to uncover the potential causative EBV variant involved in NPC.Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that infects more than 90% of the worldwide human population. Following the first discovery of EBV particles in cultured lymphoma cells from patients with Burkitt's lymphoma (BL) (12, 13), EBV and its encoded molecules were also detected in cases of nasopharyngeal carcinoma (NPC) (52) and several other malignancies, such as non-Hodgkin lymphoma (NHL) (51) and T-cell and Hodgkin lymphomas (22,43,44). Both the presence of virus sequences in tumor cells and the virus's oncogenic potency (24, 46) strongly associate EBV with NPC. However, the genome-wide nature of the EBV in NPC tissue is still poorly understood.EBV harbors different genetic variations in different geographic populations (4,10,18,21,40,(48)(49)(50). Likewise, the prevalence characteristics of NPC show remarkable geographical and ethnic differences, with a high prevalence rate in southern China, especially in the Guangdong province (5). Several EBV genes, including EBNA2, LMP1, and EBNA1, have been implicated in the development of NPC (10,17,28,34). Certain EBV subtypes such as China 1 and V-val, as classified by the sequence variations of these genes, were found more frequently in patients with NPC than in controls and thus have been associated with NPC (26, 50). However, an NPCspecific EBV subtype has not yet been identified, suggesting that EBV subtypes cannot be classi...

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Multiple Epstein-Barr Virus Infections in Healthy Individuals

Cited by 100 publications

References 48 publications

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

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

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Direct Sequencing and Characterization of a Clinical Isolate of Epstein-Barr Virus from Nasopharyngeal Carcinoma Tissue by Using Next-Generation Sequencing Technology

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