FOR 5200:  Disrupt - Evade - Exploit: Gene expression and host response programming in DNA virus infection (DEEP-DV)

• Subject Area: Medicine ; Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 443644894

Gene expression is a fundamental process controlled by a complex network of regulatory factors. Nuclear replicating DNA viruses typically cause chronic infections and depend on these complex host networks for their own gene expression. Simultaneously, they need to manipulate regulatory networks to avoid clearance and create a favorable environment for chronic viral infection. Failure or success at controlling gene expression networks ultimately determines whether the initial infection becomes abortive, or proceeds to a productive or persistent phase. Viral reservoirs associated with chronic infections can take different forms. Through continuous cycles of replication and re-infection, a productive persistence can be established. In contrast, a so-called non-productive persistence is based on the establishment of certain cell populations in which no or only very low virus production takes place. Regardless of which specific form of viral persistence is employed, successful establishment of viral reservoirs requires sophisticated mechanisms to counteract antiviral host responses and viral gene expression programs tailored to the environment within a given target cell. In this context, the central focus of the DEEP-DV consortium is to study the dedicated strategies employed by newly infecting DNA viruses to disrupt, evade, or exploit nuclear gene expression networks to achieve the desired infection outcome. The central hypothesis is that such viral strategies may vary depending on the specific nuclear environment and state of the host cell. However, there will be commonalities and as-of-yet undefined shared principles that are important across diverse nuclear DNA virus species and even across families. This is especially true for antiviral host responses and nuclear repressor complexes that have to be evaded or exploited by newly incoming viral genomes. DEEP-DV will investigate the early events of nuclear DNA virus infection to define these principles. Importantly, while such mechanisms are usually interrogated in a single viral system, the projects in DEEP-DV investigate different DNA viruses of the herpes-, polyoma- and adenovirus families. Since these viruses are evolutionarily ancient, and have co-evolved with their host over millions of years, we expect that the joint endeavor proposed here is ideally suited to uncover above principles. DEEP-DV brings together scientists with strong virological expertise, firm command of state of the art experimental methodologies (e.g. genome, transcriptome and epigenome analytics, RNP proteomics, single cell technologies and advanced imaging methods), and profound experience with bioinformatic data analysis. This endeavor seeks to open up new possibilities to understand and, ultimately, control acute and chronic DNA virus infections.

• DFG Programme: Research Units

Projects

• Control of HCMV transcription through compositional tuning of PML-nuclear bodies (Applicant Bosse, Jens Bernhard )
• Coordination Funds (Applicant Brinkmann, Melanie )
• Herpesvirus-Chromatin-Programmierung während der De-Novo-Infektion (Applicants Grundhoff, Adam ;  Viejo-Borbolla, Abel )
• Integrative functional genomics of DNA virus infections (Applicant Friedel, Caroline )
• Mechanistic insights into modulation of type I interferon transcription by tegument proteins of cytomegalovirus and its impact on viral transcription (Applicant Brinkmann, Melanie )
• Regulation and Herpes simplex virus 1 counter-regulation of transcriptional bursting kinetics in the early type I interferon response (Applicants Dölken, Lars ;  Erhard, Florian )
• Role of the intercellular heterogeneity, epigenetics and viral factors in the decision between lytic replication and latency of human herpesvirus 6 (Applicant Kaufer, Ph.D., Benedikt Bertold )
• Shaping of viral gene expression and replication patterns by host responses during early infection with human polyomaviruses (Applicant Fischer, Nicole Brigitte )
• Spatiotemporal control of human cytomegalovirus transcriptional silencing during lytic and latent infection (Applicant Stamminger, Thomas )
• Spatiotemporal regulation of host/viral chromatin remodeling complexes by Human Adenovirus (HAdV) determinants during early infection (Applicant Schreiner, Sabrina )
• The role of RNA-binding proteins regulating transcription in HSV-1-infected cells and organoids (Applicant Landthaler, Markus )

• Spokesperson: Professorin Dr. Melanie Brinkmann