Epstein-Barr virus is a human herpesvirus that infects most people in the world early in life and then persists life-long. Primary EBV infection that is delayed until adolescence or adulthood frequently causes infectious mononucleosis (glandular fever). Most carriers of EBV show no symptoms or pathology but in some circumstances EBV is associated with human cancers, the virus normally being present in all of the tumour cells of an EBV associated case. These cancers include lymphomas in immunosuppressed people (either as a result of medication after transplant surgery or AIDS), Hodgkin's disease, Burkitt's lymphoma in central Africa, nasopharyngeal carcinoma in South-East Asia and some gastric carcinomas. EBV infects human B lymphocytes and certain epithelial cells; infection of lymphocytes is readily accomplished in the laboratory and EBV drives the cells into a state of permanent proliferation.
We are studying the mechanisms by which EBV causes human cells to grow, the role of the virus in human cancers and the regulation of the switch between latent persistence and virus replication. The virus proteins EBNA-1, EBNA-2, EBNA-3A, EBNA-3C, EBNA-LP and LMP-1 are required for EBV to cause permanent growth of human B lymphocytes and expression of the virus protein BZLF1 is the key switch from latency to the replicative cycle.
Sequence variation of EBV strains - possible relationship to disease
The unusual geographic distribution of some diseases associated with EBV, together with evidence of partial deletion or mutation of the viral genome in some lymphoma cases, raises the possibilty of natural variation of the virus genome affecting disease incidence. We recently analysed the sequences of 250 isolates of EBV from various parts of the world. The main natural variation that occurs in EBV strains is in EBNA2 and EBV strains are classified as type 1 or type 2 based on their EBNA2 sequence. Type 1 strains are much better at producing proliferating human B cell lines upon infection than type 2 strains. We developed a new assay for EBNA2 in cell proliferation that distinguishes type 1 and type 2 EBNA2 and a mechanism for this natural functional difference in EBV types.
Although EBV mainly infects B lymphocytes, using cloned EBV strains we have now shown that some T lymphocytes from cord blood or young children (but not adults) can also be infected. Since infectious mononucleosis and multiple sclerosis are linked to primary infection of teenagers or adults, we are interested in the possibility that the T cell infection in infants (which is the natural form of infection) somehow avoids that disease risk.
Cell genes regulated by EBV - role of RUNX genes
EBNA-2 is an EBV transcription factor required for cell proliferation observed in response to EBV infection and we identified cell genes regulated by EBNA-2. One of these, RUNX3 (AML-2), is a member of the Runt domain family of transcription factors. Quiescent B cells express RUNX-1 but 48 hours after virus infection, levels of RUNX-1 decreased dramatically while the amount of RUNX-3 protein increased. Reduction of RUNX3 expression in LCLs by RNAi slowed cell proliferation. We showed that the mutually exclusive expression of RUNX1 and RUNX3 is a consequence of cross regulation of the RUNX1 promoter by RUNX3. We are now investigating the role that RUNX proteins may play in the proliferation of B cells induced by EBV and the mechanism by which RUNX1 prevents B cell proliferation.
EBV virology keynote lecture, 17th International EBV conference, Zurich, 2016