Herpes Simplex Virus-1 Manipulates Human DNA to Enhance Infection

The herpes simplex virus-1 (HSV-1) has demonstrated a remarkable ability to manipulate the human genome, according to a recent study published in *Nature Communications* on June 20, 2025. Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have uncovered that HSV-1 actively reshapes the architecture of human DNA within hours of infection, allowing the virus to access vital host genes necessary for its reproduction.

The study, led by Dr. Esther González Almela, revealed that HSV-1 acts as an "opportunistic interior designer," rearranging the genome’s three-dimensional structure to optimize its chances of replicating. This manipulation is not merely a byproduct of viral invasion; it is a deliberate strategy employed by the virus to exploit host cellular resources. “It’s a novel mechanism of manipulation we didn’t know the virus had,” Dr. González Almela stated.

Historically, while other herpes viruses have shown the ability to compact and alter host chromosomes, the exact mechanism and intention behind this restructuring remained largely speculative until now. The CRG study provides the first conclusive evidence that HSV-1 reshapes human DNA purposefully and swiftly after infection.

One of the critical findings of the research is the role of topoisomerase I, an enzyme crucial for managing DNA's structural tension. The researchers found that inhibiting this enzyme completely halted HSV-1's ability to rearrange the human genome during infection. Dr. Pia Cosma, an ICREA Research Professor at CRG and the corresponding author of the study, emphasized the therapeutic potential of targeting this enzyme: “In cell culture, inhibiting this enzyme stopped the infection before the virus could make a single new particle.” This discovery opens new avenues for potential treatments for HSV-1, which currently affects nearly four billion people worldwide.

The researchers employed advanced techniques, including super-resolution microscopy and Hi-C, to gain insights into how HSV-1 commandeers human cells. They observed that the viral takeover begins within the first hour of infection, with the virus hijacking the human RNA polymerase II enzyme to synthesize its proteins. Following this, the virus also recruits topoisomerase I and cohesin, a structural protein, into the viral replication compartments, leading to a dramatic collapse in transcription across the host genome.

This collapse compresses chromatin—the form in which DNA is packaged in cells—into a denser state, reducing its volume to just 30% of its original size. This finding challenges previous assumptions about the relationship between chromatin structure and gene expression. “We always thought dense chromatin shut genes down, but here we see the opposite: stop enough transcription first and the DNA compacts afterwards,” noted Dr. Álvaro Castells García, co-first author of the study.

HSV-1 is particularly prevalent, with two out of every three individuals under the age of 50 carrying the virus. While many infections are asymptomatic, the virus can lead to severe complications, including blindness in rare cases. The implications of this study are significant, as they could reshape public health approaches to managing HSV-1, especially in light of rising drug-resistant strains and the absence of a definitive cure.

The findings underscore the urgent need for continued research into innovative therapeutic strategies to combat HSV-1, particularly as the virus remains a global health challenge due to its widespread prevalence. The potential to target topoisomerase I provides a promising new direction in the quest for effective treatments against this pervasive virus.