Herpes Simplex Virus-1 Manipulates Human Genome Architecture, but a Key Enzyme Can Halt Its Effects

Recent research has uncovered that the herpes simplex virus-1 (HSV-1), known primarily for causing cold sores, has a sophisticated ability to reshape the human genome during infection. Conducted by scientists at the Center for Genomic Regulation (CRG) in Barcelona and published in Nature Communications, the study reveals that HSV-1 actively reconfigures the three-dimensional structure of host DNA to access genes that promote its replication. This process involves the virus acting as an 'interior designer,' deliberately reorganizing the host genome with precision.

The scientists used advanced techniques such as super-resolution microscopy, capable of visualizing structures as thin as 20 nanometers, and Hi-C, which maps DNA contact points inside the nucleus. They observed that within just one hour of infection, the virus hijacks the host’s transcription machinery, including RNA-polymerase II, along with enzymes like topoisomerase I and structural proteins like cohesin, to facilitate viral gene synthesis.

As the infection progresses, by around three hours, the virus-driven machinery abandons human genes, leading to a collapse in host gene transcription. This collapse results in chromatin—the complex of DNA and proteins—becoming densely packed, reducing its volume to just 30% of its original size. Interestingly, this was an unexpected finding, as previously it was thought that chromatin density dictated gene activity. Instead, the study suggests that reduced transcriptional activity leads to chromatin compaction, indicating a bidirectional relationship.

Crucially, the researchers discovered that inhibiting a single host enzyme, topoisomerase I, completely prevented HSV-1 from restructuring the genome in cell cultures, effectively halting the viral life cycle before new particles could form. This points to a potential new therapeutic target for controlling HSV-1 infections, which are highly prevalent worldwide, with two in three individuals under age 50 carrying the virus. Although treatments exist to manage symptoms, there is currently no cure, and drug-resistant strains are becoming more common.

These findings were achieved by combining super-resolution microscopy with Hi-C, providing deep mechanistic insights into how HSV-1 manipulates human cellular processes. The research underscores the virus's complex strategy of genome manipulation, offering new avenues for antiviral development aimed at enzymes like topoisomerase I, to combat recurrent herpes infections effectively.