Universitaetsklinikum Schleswig-Holstein Campus Kiel
Our laboratory is interested in the understanding of regulatory processes and pathogenesis of human cytomegalovirus (HCMV; human herpesvirus 5, HHV 5). HCMV belongs to the herpesvirus family and establishes lifelong persistence in infected individuals. It causes severe infections under immunosuppression, in transplant recipients or AIDS patients. In addition, HCMV is one of the most common causes of congenital infection, which may be accompanied by severe complications. 1. Protein interactions of human cytomegalovirus tegument proteins Currently, we investigate protein interactions of tegument proteins and their role in immediate-early regulation and virus assembly. Tegument proteins are critical constituents of the virus particle that play a role in particle assembly, virus entry and exit, establishment of infection and immunomodulation. We have established a map of protein interactions between tegument proteins, which provides a scaffold for further definition of virus structure assembly and function. In the moment, a main focus is the interaction between ppUL82 (pp71) and ppUL35. Both proteins localize to PML oncogenic domains and cooperatively transactivate the immediate-early enhancer of HCMV. In addition, deletion of the UL35 gene affects virus assembly by modulating nucleocytoplasmic localization of other tegument proteins. Thus, ppUL35 is part of a cell-biological switch critical for immediate-early regulation and virus assembly. 2. Target-cell tropism of human cytomegalovirus An important aspect of HCMV biology and pathogenesis is its dissemination into the bloodstream via infection of endothelial cells or monocytes. Attenuated virus strains, originally developed for use as vaccine, have reduced pathogenicity as demonstrated by lack of systemic infection. In cell culture, the attenuated strains have lost the tropism for endothelial and myeloid cells. Several proteins have been implicated in endothelial tropism of HCMV (UL128, UL130, UL131) or murine cytomegalovirus (M45). We have identified a novel structural protein that is critical for endothelial tropism and are currently analyzing its function and interactions. 3. Antiviral targets and inhibitor screening Antiviral therapy along with careful monitoring has strongly reduced morbidity and mortality of HCMV infection after transplantation. Currently used drugs (e.g. ganciclovir) are effective but are associated with high toxicity and the emergence of resistant virus strains. Therefore, additional antiviral drugs are needed and novel viral targets are desirable, since all therapeutically used drugs target two genes (UL97 and UL54, the viral DNA polymerase). We are developing novel recombinant viruses which allow more efficient screening and testing of antiviral compounds. One application makes use of these variant strains for the identification of compounds targeting viral protein interactions.
Institut fuer Infektionsmedizin
Brunswiker Str. 4
Forschung & Lehre