Interestingly, not all 10 genes are expressed simultaneously during latency in all cases. BamHI rightward-transcript RNAs are present in all latency types but are not essential for transformation, and their role remains to be fully elucidated ( 70). EBV-encoded RNAs (EBERs) are nontranslated viral RNAs of unknown function that might be involved in preventing the programmed cell death of infected cells ( 35). LMP1 is critically involved in the effective immortalization and proliferation of B cells that are latently infected by EBV, whereas LMP2 (a and b) proteins serve to block reactivation from latency and increase B-cell survival ( 33, 37, 41). The EBNA leader protein (EBNA-LP) stimulates EBNA2 transcriptional activation ( 27). The EBNA3 family of proteins (3A, 3B, and 3C) encode transcription factors that upregulate viral and cellular genes and play a role in the transformation of human primary B cells ( 7, 70). EBNA2 has multiple functions, including the regulation of expression of latent membrane proteins 1 and 2 (LMP1 and -2), which in turn contribute to the growth and transformation of B cells ( 7). EBV nuclear antigen 1 (EBNA1) is required for replication and for maintenance of the viral genome ( 70). The 10 genes that are generally expressed during latency encode six nuclear proteins, two types of nontranslated RNA, and two membrane proteins. The highly restricted expression of the vast majority of its genes enables EBV to avoid immune detection by cytotoxic T lymphocytes (CTLs) ( 7). In contrast, >100 genes are expressed during lytic replication ( 7). After infection, EBV is maintained in a latent form in which only a few genes are expressed. Once a person is exposed to the virus, EBV persists in vivo within infected B cells for the entire life span of the individual. Although in immunocompetent hosts infection is generally subclinical ( 14), infection in immunodeficient patients can produce significant morbidity and/or mortality ( 40). EBV represents an important health concern since 90% of the world's population is infected ( 14, 55, 70). These data demonstrate that NOD/SCID mice that are reconstituted with human CD34 + cells are susceptible to infection by EBV and accurately recapitulate important aspects of EBV pathogenesis.Įpstein-Barr virus (EBV) is a human gammaherpesvirus that predominantly infects B cells and epithelial cells ( 17, 18, 45, 56). Finally, we also demonstrate that infection with an enhanced green fluorescent protein (EGFP)-tagged virus can be monitored by the detection of infected EGFP + cells and EGFP + tumors. EBV + lymphoblastoid cell lines expressing human CD45, CD19, CD21, CD23, CD5, and CD30 were readily established from the bone marrow and spleens of infected animals. In addition, tumor cells expressed EBNA1, LMP1, and LMP2a mRNAs, which is consistent with a type II latency program. Their characterization is consistent with that of large cell immunoblastic lymphoma. These tumors stained positive for human CD79a, CD20, CD30, and EBV-encoded RNAs and were light chain restricted. Infected mice presented large visible tumors in multiple organs, most prominently in the spleen. All infected mice lost weight and showed decreased activity levels. High levels of viral DNA were detected in the peripheral blood of all infected mice. We therefore infected reconstituted mice with EBV. NOD/SCID mice engrafted with human CD34 + cells and reconstituted mainly with human B lymphocytes may serve as a useful xenograft model to study EBV infection and pathogenesis. Currently there is no in vivo model that can adequately recapitulate EBV infection and its association with B-cell lymphomas. Impaired T-cell immunity allows the outgrowth of transformed cells with the subsequent production of predominantly B-cell lymphomas. Epstein-Barr virus (EBV)-induced lymphoproliferative disease is an important complication in the context of immune deficiency.
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