Investigation of the BKPyV life cycle and antiviral mechanisms of BKPyV-specific inhibitors in relevant in vitro models

https://grk2771.de/projects/project-p7/

Human Polyomaviruses (PyV) are highly prevalent and establish a lifelong asymptomatic persistence in the healthy immunocompetent host1,2. However, under immunosuppression, these viruses can reactivate, causing life-threatening infections (e.g. BKV caused PyV associated nephropathy, PVAN) due to uncontrolled viral replication1. Currently, no specific antiviral treatment is available This lack of effective therapeutics is partly due to the lack of small animal models and the availability of only poor surrogate in vitro/in vivo systems. We have recently identified 16 small molecule inhibitors, C1-16, against BKV using a phenotypic high throughput screen (Kraus et al., unpublished). For the further development of these inhibitors, it is essential to have an understanding of their cellular target structure and/or which part of the viral life cycle they inhibit.

Within this project we will gain a better understanding of the BKV the life cycle in relevant infection systems (e.g. primary cells and organoids). We will use these previously identified antiviral compounds in terms of their interference with essential host structures for viral reproduction (transport vesicles, nuclear uptake, replication compartments or vesicle dependent egress). Furthermore, we will characterize specific viral inhibitors at the molecular and structural level.

The project uses organoids and primary cells as infection models and BKV inhibitor characterization. It applies confocal live cell microscopy to follow BKV entry/ spread. Furthermore, the project takes advantage of X-ray crystallography to characterize inhibitor/target interaction.

References

Chong S, Antoni M, Macdonald A, Reeves M, Harber M, Magee CN (2019) BK virus: Current understanding of pathogenicity and clinical disease in transplantation. Rev Med Virol 29:e2044. Abstract

Theiss JM, Günther T, Alawi M, Neumann F, Tessmer U, Fischer N, Grundhoff A (2015) A Comprehensive Analysis of Replicating Merkel Cell Polyomavirus Genomes Delineates the Viral Transcription Program and Suggests a Role for mcv-miR-M1 in Episomal Persistence. PLoS Pathog 11:e1004974. Abstract

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