The project will focus on four distinct human cytomegalvirus(HCMV)-related research areas:
- the molecular biology of gene transcription
- the pathogenesis of HCMV infection and diseases
- the improvement and standardisation of diagnostic methods
- the improvement of antiviral therapy and the investigation of mechanisms of resistance
To study the function and mechanism of action of HCMV gene products antisense RNA expression vectors specific for the immediate early genes 1 and 2, the major early beta2.7kb transcript as well as the pp65 tegument protein will be used. The highly complex problem of pathogenesis of HCMV infection and disease will be tackled experimentally with three major questions: 1) How does HCMV infection influence host cell functions? 2) Is the genetic diversity between different virus isolates sufficient to allow evasion of an effective immune response? 3) Is viral load in the infected host related to tissue tropism and HCMV disease? The cruicial point concerning diagnosis in the clinical setting is the differentiation of active HCMV infection and HCMV disease as well as indication for antiviral therapy. The two sensitive methods developed in recent years (PCR and antigenemia assay) suffer from lack of standardisation, which is essential. Internal and external quality control will be developed and implemented in the clinics, which will allow comparison of data between different centres in Europe. The diagnostic data will be related to severity of HCMV disease and will be used to evaluate early antiviral treatment and to monitor therapeutic response. Currently two drugs, ganciclovir and forscarnet, are licensed for treatment of HCMV disease. Life-long treatment, as is required in AIDS-patients with HCMV infections, results in the emergence of resistant viruses. The project focuses on the development of new antiviral strategies for treatment and mechanisms of resistance. A large number of new compounds will be screened for antiviral activity and the mode of action of these and already existing drugs will be elucidated.