Comparative multi-omics of alphaherpesvirus latency-associated transcripts

• Applicant: Professor Dr. Daniel Depledge
• Subject Area: Virology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573123615

Alphaherpesviruses (αHVs) are a source of serious diseases in humans and animals. During infection, they establish lifelong latency from which they can periodically reactivate. Latent viruses are imperceptive to antivirals and vaccines, enabling recurrent disease and transmission. Moreover, the mechanisms governing latency and reactivation remain poorly understood, further limiting intervention efforts. A key feature of αHV latency is a generalized restriction of viral gene expression whereby only a subset of viral RNAs, termed latency-associated transcripts (LATs), are produced. Our research thus aims to understand how LATs interact with host cells during both productive and latent infections. Our prior work and new preliminary data indicate that αHV LATs are structurally more diverse than previously known. Here, we will test the hypothesis that structurally diverse αHV LATs share functional similarities. Our major objectives are to (i) delineate the architecture of the LAT loci encoded by 10 representative αHV spanning multiple genera across the evolutionary tree and (ii) identify unique and conserved functions of the HSV-1 LAT intron and VZV VLT lncRNAs. This will be achieved using a combination of advanced sequencing methodologies (i.e. nanopore direct RNA sequencing and small RNA sequencing), computational modelling, established RNA interactome capture approaches, recently developed human sensory neuron models of HSV and VZV latency (HD10.6 neurons), and our established use of target-enriched RNA sequencing and in situ analyses to validate our findings in latently-infected ganglia. Collectively, these studies will (i) generate comprehensive, high-resolution transcriptome and translatome annotations across all ten of the chosen αHV; (ii) reveal the higher order structures of LATs and their potential conservation among αHV; and (iii) identify both unique and conserved host processes regulated by HSV-1 LAT and VZV VLT, shedding light on their mechanisms of action. This knowledge will advance our understanding of herpesvirus latency and lay the groundwork for innovative strategies to target latent αHVs in humans and animals, ultimately reducing the global burden of herpesvirus-associated disease.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Partner Organisation: Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
• Cooperation Partner: Professor Werner Ouwendijk, Ph.D.