Beyond chromatin: how neuronal transcription controls HSV-1 latency

What is it about?

Herpes Simplex Virus 1 (HSV-1) causes lifelong infections by remaining dormant in neurons, a state known as latency. Traditionally it was thought that during latency the viral genome existed in a tightly knotted structure, blocking important cellular enzymes from most viral genes, thereby precluding their expression. Using a human neuronal model (LUHMES), our study shows that human neurons naturally restrict viral gene expression and genome replication compared to non-neuronal cells. Surprisingly, during latency, the viral genome is quite active transcriptionally. We show transcription initiation on almost all viral genes during latency, and most surprisingly, at higher levels than during acute infection in the same cells. This demonstrates that rather than keeping the genome silent, neurons block these newly produced viral transcripts from further processing, precluding their accumulation as stable functional mRNAs.

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Photo by Viktor Forgacs on Unsplash

Photo by Viktor Forgacs on Unsplash

Why is it important?

Understanding HSV-1 latency is challenging because animal models yield too few latently infected neurons for detailed molecular analysis. Using precision nuclear run-on sequencing (PRO-seq) in a human neuronal model (LUHMES), our study provides a high-resolution map of transcription during viral latency. We challenge the long-held belief that latent herpes simplex virus 1 genomes are mostly transcriptionally silent. Instead, we discover that cellular machinery initiates transcription on nearly all viral genes, but neurons maintain latency by blocking these transcripts at downstream checkpoints such as promoter-proximal pausing and elongation. This insight shifts our fundamental understanding of herpesvirus latency and highlights post-transcriptional checkpoints as potential targets for therapeutic intervention or reactivation therapies.

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