Project A1: Lucio Fortelny, doctoral researcher (MD)

Human herpesviruses remain highly prevalent pathogens, with infection rates of up to 95% of the adult population worldwide. While remaining latent in the long term, they can cause severe and life-threatening disease in immunocompromised individuals, particularly transplant recipients. Current antiviral therapies - most prominently acyclovir and related nucleoside analogs - are limited by narrow antiviral activity spectra, viral drug resistance, and sometimes secondary target effects such as toxicity. This project aimed to explore novel experimental therapeutic strategies by combining direct-acting with host-directed antivirals to enhance efficacy and broadness of the antiviral spectrum

The project started with a retrospective analysis of diagnostic data, referring to clinical virus submissions to the University Hospital Erlangen, to identify the most clinically relevant alpha-, beta-, and gamma-herpesviruses. A 10-year diagnostic synopsis of data led to a categorization of human herpesviruses in distribution and pathogenesis. Subsequently, selected compounds have been experimentally evaluated for antiviral potency and cytotoxicity using reporter-based infection assays. To systematically assess pharmacological drug interactions, we employed two established synergy-quantification frameworks: the Loewe Additivity Fixed-Dose and Bliss Independence Checkerboard Assays. These complementary approaches enabled precise characterization of synergistic, additive, or antagonistic drug interactions, whereby a focus on the Loewe Assay was given in this thesis.

By integrating virological profiling, mechanistic assay systems, and quantitative synergy modeling, this project aims were defined to identify broad and highly synergistic antiviral combinations. Such host-directed/direct-acting dual strategies may provide a promising, forthcoming path towards more effective and safer treatment options against severe herpesviral infections.