From virus-host interactomics to perspectives in terms of drugability of protein-protein interactions

T presentation fall within the scope of an emerging discipline at the convergence of virology and systems biology. Since the completion of the human genome, it is commonly admitted that identifying protein interaction network (interactomes) gives key clues to understand how parts work together and thus to reach to a mechanistic understanding of the cell. Similarly, interactomes are also susceptible to provide a support to conceptualize the intricate relationships between virus-host proteins. We performed pioneering analyses to decipher virus-host interactomes (virhostomes), using high-throughput innovative approaches. In order to identify specific signatures, correlating interaction datasets, protein sequences and structural informations with pathogenic traits, we have developed a new strategy based on comparative interactomics which was applied to a broad spectrum of viruses from HPVs, HCV to Influenza virus. These interactomic datasets were generated by combining two orthogonal strategies: yeast two-hybrid and a newly designed high-throughput Gaussia princeps luciferase-based protein fragment complementation assay which can be declined in vivo on human cells as well as in vitro. Integrative analyses of the resulting virhostomes have highlighted a viral singularity characterized by a strong tendency to target highly central and interconnected cellular proteins. These “hubs” and “bottlenecks” proteins are enriched in essential proteins involved in critical cellular processes such as cell cycle control, cellular innate immunity, apoptosis, ubiquitin-proteasome pathway and cellular transport machinery. Furthermore, in order to monitor virus-host protein interaction in the course of infection, we adapted our split-luciferase assay to a transfection-infection or an infection only setting. This later approach was applied to influenza viruses with promising perspectives to identify new therapeutics.