Abstract
EBV transforms B cells in vitro and causes human B-cell lymphomas including classical Hodgkin lymphoma (CHL), Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). The EBV latency protein, EBNA2, transcriptionally activates the promoters of all latent viral protein-coding genes expressed in type III EBV latency and is essential for EBV’s ability to transform B cells in vitro. However, EBNA2 is not expressed in EBV-infected CHLs and BLs in humans. EBV-positive CHLs have type II latency and are largely driven by the EBV LMP1/LMP2A proteins, while EBV-positive BLs, which usually have type I latency are largely driven by c-Myc translocations, and only express the EBNA1 protein and viral non-coding RNAs. Approximately 15% of human BLs contain naturally occurring EBNA2-deleted viruses that support a form of viral latency known as Wp-restricted (expressing the EBNA-LP, EBNA3A/3B/3C, EBNA1 and BHRF1 proteins), but whether Wp-restricted latency and/or EBNA2-deleted EBV can induce lymphomas in humanized mice, or in the absence of c-Myc translocations, is unknown. Here we show that a naturally occurring EBNA2-deleted EBV strain (P3HR1) isolated from a human BL induces EBV-positive B-cell lymphomas in a subset of infected cord blood-humanized (CBH) mice. Furthermore, we find that P3HR1-infected lymphoma cells support two different viral latency types and phenotypes that are mutually exclusive: 1) Large (often multinucleated), CD30-positive, CD45-negative cells reminiscent of the Reed-Sternberg (RS) cells in CHL that express high levels of LMP1 but not EBNA-LP (consistent with type II viral latency); and 2) smaller monomorphic CD30-negative DLBCL-like cells that express EBNA-LP and EBNA3A but not LMP1 (consistent with Wp-restricted latency). These results reveal that EBNA2 is not absolutely required for EBV to form tumors in CBH mice and suggest that P3HR1 virus can be used to model EBV positive lymphomas with both Wp-restricted and type II latency in vivo.
Highlights
Epstein-Barr virus (EBV) is a human herpesvirus that contributes to a variety of different lymphomas in humans and transforms normal B cells in vitro into immortalized lymphoblastoid cell lines (LCLs)
The other P3HR1-induced lymphomas resemble diffuse large B-cell lymphomas (DLBCLs) and have a viral protein expression pattern consistent with Wprestricted latency (EBNA-LP positive, LMP1 negative) similar to that occurring in human Burkitt lymphomas (BLs) infected with EBNA2-deleted EBV
These studies are the first to show that an EBNA2-deleted EBV can cause lymphomas in humanized mice with restricted forms of viral latency that resemble human classical Hodgkin lymphomas (CHLs) and DLBCLs
Summary
Epstein-Barr virus (EBV) is a human herpesvirus that contributes to a variety of different lymphomas in humans and transforms normal B cells in vitro into immortalized lymphoblastoid cell lines (LCLs). There are several different gene expression patterns observed in latent EBV infection (commonly referred to as type I, type II and type III) that differ in regard to the number of viral proteins expressed, whether the virus can transform B cells in vitro, and the ability of T cells to recognize and kill EBV-infected B cells in vivo. B cells containing the most transforming, and immunogenic, form of EBV latency (type III) express all 9 EBV encoded latency proteins. EBV-induced lymphomas occurring in more immunocompetent individuals, including BL, CHL and DLBCLs, usually have more stringent (and less immunogenic) forms of EBV latency, in which EBNA2 expression is turned off and fewer viral proteins are expressed [2,4]. Since stringent types of viral latency which have no EBNA2 expression are non-transforming in vitro, it has been difficult to model how EBV infection promotes lymphomas in the absence of EBNA2 expression
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