The development of medication like antibiotics has fostered the assumption that modern medicine will, in due time, provide the means to solve the problem of infectious diseases. However, infection is still one leading cause of morbidity and mortality throughout the world. The reasons for this apparent failure in the control are multifarious. Resistance to antimicrobial chemotherapy, like in tuberculosis or in staphylococcal infection has revived pathogens that appeared to be close to control. Novel pathogens like HIV were introduced that, by immune depression, pave the way for opportunistic secondary infections. Crossing the species barrier like in avian influenza or SARS, in combination with increased human mobility may lead to widely unlimited spread with consequences that may well be beyond our conception. On the other hand, medical progress like transplantation of stem cells for cancer therapy creates clinical settings, where patients may be highly susceptible to opportunistic infections, e.g. with fungi or herpesviruses.
In latent or persistent viral infections, the interplay between antiviral defence of the host and mechanisms of the virus to evade these control strategies is important for the understanding of pathogenesis and for the development of antiviral therapeutics and vaccines. Long term co-evolution of complex herpesviruses, like the cytomegaloviruses with their particular host has led to the development of multiple levels of interference of these pathogens with the immune system. Consequently, studying the molecular events of antigen processing and presentation in combination with what is called immune evasion not only provides insight into the biology of HCMV, thereby laying the basis for development and refinement of vaccine strategies; it also helps so understand general mechanisms of the subversion of the immune system by persistent viruses.
Human cytomegalovirus (HCMV), a ß-herpesvirus, is characterized by its strict host specificity. The virus had become widely appreciated as a cause of congenital infection already at the beginning of the 20th century, but has recently also received medical attention for its role in pathogenesis in immunocompromised individuals like transplant recipients or AIDS-patients. HCMV has a linear double stranded DNA genome of high complexity and a coding capacity of over 150 different genes. With that it is one of the most complex of all known human viruses. Little is known about the molecular mechanisms that govern HCMV pathogenesis in vivo. The viral genome has recently become accessible to site-directed mutagenesis thus allowing studies on the function of particular viral genes.
The main interest of the HCMV group at the Institute of Virology in Mainz is the analysis of the virus-host interactions with particular focus on host defence mechanisms and the development of prophylactic strategies for the prevention of HCMV infection and disease. Further areas of interest are studies on viral particle assembly and protein transport in infected cells
The research programme is subdivided in a Basic Science-level, a level of Translational Science and a Translation-level. Major focus in the group are basic science investigations to widen our understanding of the interaction of viruses that cause persistent or latent infection with their host, using HCMV as an example (see Figure 1). One central issue of this programme is the analysis of the regulation of antigen presentation during HCMV infection. Directly linked to this, the functionality and interplay of immune evasion proteins to prevent recognition of infected somatic cells by CD8 T-lymphocytes is investigated. Using BAC-mutagenesis to modify the HCMV genome, a systematic analysis of the molecular mechanisms of the interference of the virus with CTL-recognition is performed. The galK-counterselection method, recently adapted for HCMV in our laboratory provides an extremely useful tool to modify the viral genome for this purpose. Of particular interest here is the impact of immune evasion on the exogenous introduction and cross-presentation of viral antigens. As could be shown by our group and others, exogenous uptake of structural proteins from viral particle provides one major pathway, how infected organ cells are sensitized against CTL-attack in the face of immune evasion. In this respect, the impact of the intracellular transport of viral antigens on their presentation on the surface of infected cells is critical in order to optimize vaccine approaches. These studies will not only focus on recognition of infected organ cells or professional antigen presenting cells; our group will also use a unique cell culture latency model for HCMV, established in our laboratory to study antigen presentation during latent and reactivated infection. Furthermore, the molecular mechnisms of particle morphogenesis during HCMV infection will be studied to optimize conditions for the production of a vaccine, based on subviral particles termed Dense Bodies (DB).
The results gathered in these basic science projects will then be highly valuable for the second major focus of the programme, which deals with the usage of DB as a vaccine (see Figure 1). Antigenically optimized particles (recDB) will be developed to provide immunotherapeutic strategies against HCMV reactivation in the course of solid organ or hematopoietic cell transplantation and for the prevention of prenatal infection. Of particular interest for testing of vaccine candidates will be the establishment of a preclinical challenge model for HCMV in mice. The use of recDB as vaccine shall also be tested on the clinical level. For this, a network of collaborations with clinical colleagues and partners from the pharmaceutical industry will have to be established to design studies for the phase I/II clinical testing of a DB-based vaccine on the translation level. The extraordinary properties of DB will be further used to develop a vaccine platform for chronic viral infections, such as Hepatitis C Virus or HIV.