Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency.

Gratama, Jan W.; Oosterveer, M. A. P.; Zwaan, F. E.; Lepoutre, J.; Klein, George; Ernberg, Ingemar

doi:10.1073/pnas.85.22.8693

Cited by 209 publications

(110 citation statements)

References 31 publications

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“…Latency is established in small B-lymphocytes, with lytic infection rarely detected in oral epithelium. 17,18 In the present study, EBV as expected was detected in all eight cases within numerous tissues, most prominently hematolymphoid tissues (lymph node, spleen, tonsil, thymus, bone marrow, blood), pharyngeal tissues (tongue, parotid gland), and digestive tissues (esophagus, stomach, small intestine, large intestine, liver, pancreas).…”

Section: Discussionsupporting

confidence: 77%

Anatomical mapping of human herpesvirus reservoirs of infection

Chen

Hudnall

2006

Modern Pathology

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Section: Discussionsupporting

confidence: 77%

Anatomical mapping of human herpesvirus reservoirs of infection

Chen

Hudnall

2006

Modern Pathology

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“…Accordingly, the work calls into question earlier models of EBV persistence, which envisaged latent infection being maintained within the basal epithelial compartment (Rickinson et al, 1985;Allday & Crawford, 1988), and refocuses attention on the B lymphoid system as a reservoir of latent EBV. Similarly, results from two other recent studies of the EBV carrier state stress the importance of B cells as a site of virus persistence (Gratama et al, 1988 ;Yao et al, 1989 a, b). If HL does indeed represent a focus of self-sustained virus replication, how might this be achieved in the absence of latent infection in the underlying basal layer?…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Infection in Oral Hairy Leukoplakia: Virus Replication in the Absence of a Detectable Latent Phase

Niedobitek

Young

Lau

et al. 1991

Journal of General Virology

164

102

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Epstein-Barr virus (EBV) infects both B lymphocytes and oropharyngeal epithelium, and it has been argued that the true reservoir of virus persistence in vivo is the self-renewing basal epithelial compartment. The identification of oral hairy leukoplakia (HL) of AIDS patients as a clinically apparent focus of EBV replication in lingual epithelium therefore provides a means of studying the EBV-epithelial cell interaction in situ. Replicative EBV DNA and productive cycle antigens are restricted to the upper, more differentiated epithelial layers in HL, and here we have applied highly sensitive in situ hybridization and immunohistological methods to examine the lower basal/suprabasal layers for evidence of latent EBV infection. We could not detect EBV DNA in these layers using an in situ DNA hybridization protocol which, on reference B cell lines, detected 1 viral genome/cell. Likewise, using sensitive in situ RNA hybridization for both the small non-polyadenylated EBER RNAs (abundant transcripts seen in all known forms of EBV latency) and the latent membrane protein (LMP) mRNA (the most abundant viral mRNA in B lymphoblastoid cell lines), the basal/suprabasal cells in HL were consistently negative; immunohistological staining with specific monoclonal antibodies also gave no evidence of latently infected LMP-positive cells. When the biopsy extracts were analysed by immunoblotting with selected human antisera, in addition to abundant productive cycle antigens, a band of constant size (66K) was observed which also reacted with immunopurified antibodies monospecific for one of the latency-associated nuclear antigens, EBNA l; the cellular origin of this EBNA 1 could not be ascertained, but it is possible that in HL the protein is expressed during the productive cycle. The absence of demonstrable EBV latency in the basal/ suprabasal cells of HL suggests that this is purely a virus replicative lesion which is sustained by continual re-infection of the maturing epithelium, not by the maturation of latently infected cells from the basal compartment. IntroductionEpstein-Barr virus (EBV) is a human herpesvirus infecting more than 90~ of the population world-wide and persisting for life in the infected host. The best characterized target cell for EBV infection both in vivo and in vitro is the B lymphocyte; thus, when peripheral blood lymphocytes from virus carriers are placed in culture, EBV-immortalized B lymphoblastoid cell lines (LCLs) can be established by spontaneous outgrowth (Pope, 1967;Nilsson et al., 1971). Similarly, immortalization of B lymphocytes from previously uninfected individuals can be achieved by experimental EBV infection in vitro. Although a small subset of cells in LCLs may sustain EBV replication, the vast majority of cells remains non-productively (i.e. latently) infected. These latently infected B cells constitutively express a subset of viral genes encoding six EBV-encoded nuclear antigens (EBNA 1, 2, 3a, 3b, 3c and LP) and two membrane proteins, latent membrane protein (LMP) and terminal protein or ...

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“…Recently we have found that the haematopoetic compartment is probably responsible for long-term viral persistence (Gratama et al, 1988). The normal precursor of the BL cell is a likely candidate for this role.…”

Section: Discussionmentioning

confidence: 99%

The Role of Methylation in the Phenotype-dependent Modulation of Epstein-Barr Nuclear Antigen 2 and Latent Membrane Protein Genes in Cells Latently Infected with Epstein-Barr Virus

Ernberg

Falk

Minárovits

et al. 1989

Journal of General Virology

114

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SUMMARYSeven virus-encoded proteins are regularly expressed in Epstein-Barr virus (EBV)-transformed lymphoblastoid (LCL) cell lines: the EBV nuclear antigens EBNA 1 to 6 and the latent membrane protein (LMP). In nasopharyngeal carcinoma (NPC), only EBNA 1 is regularly expressed; LMP is detected in about 50~ of the tumours. In Burkitt's lymphoma (BL) tumours, only EBNA 1 is expressed. Also, in BL-derived cell lines that maintain the phenotypic markers characteristic of the in vivo tumour (group I), only EBNA 1 is expressed. EBV was rescued by induction or cocultivation from one BL cell line with a restricted group I pattern, and from one NPC tumour, into normal B cells. In the resulting LCLs EBNA 1 to 6 and LMP were expressed. We assessed the level of methylation in the genes encoding EBNA 2 and LMP by restriction fragment analysis using the methylation-sensitive enzymes SmaI and HpalI. These genes were extensively methylated in the group I BL line Rael and the nude mouse-passaged C15 NPC tumour, but were demethylated in the derived LCLs. In the LMP expressing the NPC tumour, but were demethylated in the derived LCLs. In the LMP-expressing coding exons were methylated. The EBNA 1 coding exon was methylated in the Rael line and in NPC, in spite of expression. In contrast, CpG pairs in ori P were originally hypomethylated and remained so after their transfer to LCLs. The cell phenotypedependent pattern of EBV gene methylation correlated with the phenotype-dependent pattern of EBNA and LMP expression. The specific patterns of methylation localized to controlling regions (ori P and 5' flanking sequences) also suggest a specific role for methylation in the regulation of EBNA and LMP expression.

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Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency.

Cited by 209 publications

References 31 publications

Anatomical mapping of human herpesvirus reservoirs of infection

Anatomical mapping of human herpesvirus reservoirs of infection

Epstein-Barr Virus Infection in Oral Hairy Leukoplakia: Virus Replication in the Absence of a Detectable Latent Phase

The Role of Methylation in the Phenotype-dependent Modulation of Epstein-Barr Nuclear Antigen 2 and Latent Membrane Protein Genes in Cells Latently Infected with Epstein-Barr Virus

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