Research Group Viral Latency

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Epstein-Barr Virus (EBV) and Kaposi's Sarcoma-associated Herpesvirus (KSHV) associated B cell malignancies

A characteristic feature of all herpesviruses is their capacity to switch between the lytic and latent life cycle. Environmental external stimuli, which are translated into intracellular signaling cascades can cause lytic cycle activation and de novo production of infectious progeny virus. Alternatively, persistence of the viruses in the host can be established and maintained by latent gene expression programs.

A specific hallmark of both human γ-herpesviruses, EBV (Epstein-Barr Virus) and KSHV (Kaposi's Sarcoma-associated Herpesvirus), is a latent gene expression program in B cells, which initiates and maintains the proliferation of these cells. Both γ-herpesviruses are associated with the pathogenesis of B cell malignancies caused by latently infected proliferating cells which arise in immunocompromized individuals like late stage AIDS patients or immunosuppressed transplant patients. EBV is associated with the development of Burkitt's and Hodgkin's lymphoma. The Primary Effusion Lymphoma and Multicentric Castleman Disease of HIV patients are caused by KSHV.

CSL/CBF1 dependent control of gene expression in EBV and KSHV infected B cells

We are focussing on the analysis of molecular mechanisms by which viral factors mimic or antagonize canonical Notch signaling in viral pathogenesis. EBV infected B cells proliferate via the concerted action of EBV nuclear antigens (EBNAs) and latent membrane proteins. CSL proteins (C promoter binding factor, Suppressor of hairless, Lag1 also designated RBP-Jκ) are cellular DNA binding proteins and the major effectors of Notch signaling.
Notch receptors are proteolytically cleaved upon activation. An intracellular Notch fragment uses CSL/CBF1 as a DNA adaptor to activate cellular genes.
The viral nuclear antigens EBNA2, EBNA3A, -3B, and -3C are either activators or repressors of transcription but each of them uses the CSL/CBF1 protein as an adaptor to bind to DNA. While EBV uses the CSL/CBF1 protein to establish and maintain latency, CSL/CBF1 signaling is involved in lytic reactivation of KSHV infected cells. K-Rta, the replication and transcription activator of KSHV, can also use CSL/CBF1 as a DNA anchor. In addition latent and lytic viral proteins (LANA1 and vIRF4) antagonize or enhance RTA activities and thereby influence the balance of latent and lytic life cycle.

Figure: Herpesviral proteins are recruited by CSL/CBF1 to DNA and re-interpret Notch signaling.
Figure: Herpesviral proteins are recruited by CSL/CBF1 to DNA and re-interpret Notch signaling. In a simplified model, a dynamic equilibrium of EBNA2 or EBNA3 protein complexes anchored by CSL to the genome determines gene expression patterns by either recruiting co-activator or co-repressor complexes in EBV infected B cells. In KSHV infected cells the viral proteins RTA, vIRF4 and LANA should target the same sets of genes. Surprisingly, not all cellular target genes are shared by herpesviral proteins which bind to CSL. Most likely, distinct biological activities of the viral proteins in combination with specific genetic or epigenetic features of the individual targets determine the final target gene spectra and need to be identified in future projects; AGV