Herpes simplex virus type 1 alters the structure of the human genome during infection by hijacking the cell’s transcription machinery, new research shows.

Using high-resolution imaging and genomic techniques, scientists detailed how the virus disrupts normal gene expression by reorganizing host DNA and sequestering essential transcription enzymes.

Herpes simplex virus type 1 (HSV-1), a DNA virus that establishes lifelong infections, actively replicates during its lytic phase by forming viral replication compartments (VRCs) in the nucleus. These compartments are hubs of viral gene activity and sites of profound structural changes in host DNA.

One of the earliest changes observed was widespread chromatin condensation. Chromatin shifted from a loosely organized, active state to a compacted structure at the nuclear periphery that was detectable within 1 hour postinfection and intensified over time.

By eight hours postinfection, more than 70% of the nuclear area lacked host DNA, which had moved to the nuclear edges. This change coincided with redistribution of RNA polymerase II (RNAP II), the enzyme that initiates transcription. Normally dispersed throughout the nucleus, RNAP II became increasingly concentrated in VRCs and rendered much of the human genome transcriptionally inactive.

The virus required host RNAP II and topoisomerase I (TOP1) for replication. Investigators found that viral genomes consistently colocalized with RNAP II and cohesin, a protein complex involved in organizing chromatin loops. These interactions allowed HSV-1 to redirect transcriptional resources toward viral gene expression.

Inhibition of TOP1 fully blocked HSV-1 infection but blocking viral DNA replication did not prevent chromatin compaction. This finding indicated that transcription machinery hijacking—not replication alone—was essential for reprogramming host cells.

Further analyses showed that while overall chromatin compartmentalization was preserved, the architecture of topologically associating domains (TADs) and chromatin loops was extensively altered. New loops formed during infection were larger and repositioned compared with those in uninfected cells. The fact that "chromatin compartments are maintained in the highly compacted human genome" is "remarkable," the authors noted, led by Esther González-Almela, PhD, and Alvaro Castells-Garcia, PhD, and indicates "that the overall 3D spatial organization of chromatin is resilient to major physical reshaping induced by HSV-1."

The viral genome preferentially associated with gene-rich regions of host DNA, particularly within transcriptionally active compartments. These regions contained genes involved in transcription, RNA export, and protein synthesis. Although global host transcription was suppressed, these specific genes were upregulated, suggesting targeted manipulation by the virus.

Through super-resolution microscopy and chromosome conformation capture, the investigators mapped HSV-1’s reorganization of nuclear architecture. They discovered how HSV-1 exploits host structural and transcriptional systems to support viral replication and identified TOP1 as a potential therapeutic target.

This research provides detailed insight into how HSV-1 reshapes the host genome and may inform antiviral strategies that prevent the virus from gaining control of the cell’s transcriptional machinery.

The authors reported no conflicts of interest.

Source: Nature Communications