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- Title
EBNA2-deleted Epstein-Barr virus (EBV) isolate, P3HR1, causes Hodgkin-like lymphomas and diffuse large B cell lymphomas with type II and Wp-restricted latency types in humanized mice.
- Authors
Li, Chunrong; Romero-Masters, James C.; Huebner, Shane; Ohashi, Makoto; Hayes, Mitchell; Bristol, Jillian A.; Nelson, Scott E.; Eichelberg, Mark R.; Van Sciver, Nicholas; Ranheim, Erik A.; Scott, Rona S.; Johannsen, Eric C.; Kenney, Shannon C.
- 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+ CHLs have type II latency and are largely driven by the EBV LMP1/LMP2A proteins, while EBV+ 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. Author summary: The EBV protein, EBNA2, is required for the ability of EBV to transform B cells in vitro, but EBV-infected cells that express EBNA2 (and its downstream viral gene targets) are highly immunogenic and thus EBV+ tumors in immunocompetent patients almost never express EBNA2. Currently, there are no model systems for studying how EBV causes B-cell lymphomas in the absence of EBNA2 expression in the context of the intact viral genome. Here we show that a naturally occurring EBNA2-deleted EBV strain (P3HR1) isolated from a human BL causes two different types of lymphomas in a cord blood-humanized mouse model. Some P3HR1-infected lymphoma cells phenotypically resemble the RS cell of CHL and express high levels of the viral LMP1 protein, a protein thought to drive EBV+ human CHLs. The other P3HR1-induced lymphomas resemble DLBCLs and have a viral protein expression pattern consistent with Wp-restricted latency (EBNA-LP positive, LMP1 negative) similar to that occurring in human 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 CHLs and DLBCLs.
- Subjects
DIFFUSE large B-cell lymphomas; IMMUNOGLOBULIN class switching; EPSTEIN-Barr virus; HODGKIN'S disease; VIRAL proteins; LYMPHOPROLIFERATIVE disorders; B cells
- Publication
PLoS Pathogens, 2020, Vol 16, Issue 6, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008590