Viral Ortholog Complements Mir-155 Deficiency-Associated Abnormalities and Together with Additional Viral Mirnas Causes B Cell Hyperplasia and B Cell Lymphoma

Abstract 4866

MicroRNA-155 (miR-155) is overexpressed in many types of cancers including B cell lymphomas. It has also an essential function in GC development. These functions are conserved among species and miR-155 knockout (ko) mice are deficient in GC development in Peyer's patches (PP) and lymph nodes. The human tumor virus Kaposi sarcoma associated herpesvirus (KSHV) encodes an ortholog to miR-155, named miR-K12-11. MiR-155 and miR-K12-11 share 100% seed sequence homology (Nature. 2007 Dec 13;450(7172):1096-9, J Virol. 2007 Dec;81(23):12836-45). Another human herpesvirus, Epstein-Barr Virus, induces mir-155 upon infection and immortalization of naïve B cells in culture. To test the hypothesis that miR-K12-11 can complement the normal function of miR-155 in vivo, we generated transgenic mice, which express miR-K12-11, as well as the other 21 KSHV miRNAs. Using this mouse model, we show that KSHV latency locus which contains a viral ortholog of miR-155, KSHV miR-K12-11 complements B cell abnormalities associated with the lack of miR-155. Germinal center (GC) formation is rescued in spleen and PP and lowered immunoglobulin level is also augmented to normal in KSHV latency locus transgenic mice with miR-155 ko background. Furthermore, mature B cells were chronically activated, leading to hyperglobulinemia triggered by increased plasma cell frequency. Marginal zone (MZ) B cells developed hyperplasia and the mice had an augmented response to T-dependent antigen as well as the TLR4 ligand LPS in vivo. This suggests that by mimicking miR-155 (and other functions) this human tumor virus drives the expansion of infected B cells, which if left unchecked can accumulate secondary mutations leading to post-GC lymphoma and multicentric Castleman's disease.