A new era in gammaherpesvirus transcriptomics: high-resolution profiling and model development

A recent article by Torma et al. (G. Torma, Á. Dörmő, Á. Fülöp, D. Tombácz, et al., mSystems 10:e01678-24, 2025, https://doi.org/10.1128/msystems.01678-24) presents the first high-resolution, long-read transcriptomic atlas of Caviid gammaherpesvirus 1 (CaGHV-1), offering insights into its transcriptional complexity. Using nanopore direct RNA and cDNA sequencing, the study maps transcription start sites, polyadenylation signals, alternative splicing, and upstream open reading frames (uORFs), revealing a landscape of coding and non-coding RNAs with pervasive transcriptional overlaps. These features underscore the evolutionary conservation of key regulatory mechanisms across gammaherpesviruses, notably replication and transcription activator (RTA)-mediated transcriptional control. By establishing CaGHV-1 as a promising model for Kaposi's sarcoma-associated herpesvirus (KSHV)-related disease, the work sets a foundation for studies of viral gene regulation, immune evasion, and pathogenesis, including bacterial artificial chromosomes (BACs) for genetic manipulation. Here, we discuss the advances in the study as well as how some limitations remain regarding read coverage biases, sequencing errors, and the uncharacterized functions of non-coding RNAs and emphasize the need for validation and functional assays. This study provides a valuable resource for understanding gammaherpesvirus biology and advancing translational research in viral pathogenesis and therapeutic development.