New Research Uncovers HSV-1's Mechanism of Genome Manipulation

A groundbreaking study has revealed that the herpes simplex virus type 1 (HSV-1), responsible for cold sores, not only invades human cells but also actively reshapes the three-dimensional architecture of the human genome to facilitate its replication. Published in Nature Communications on June 20, 2025, by researchers from the Center for Genomic Regulation (CRG) in Barcelona, the study presents the first evidence that HSV-1 deliberately alters the structure of host DNA within hours of infection.

According to Dr. Esther González Almela, the first author of the study, "HSV-1 is an opportunistic interior designer, reshaping the human genome with great precision and choosing which bits it comes into contact with. It's a novel mechanism of manipulation we didn't know the virus had to exploit host resources." This manipulation occurs rapidly, with the virus hijacking the host's RNA polymerase II enzyme soon after infection, which is crucial for synthesizing viral proteins.

The researchers discovered that HSV-1 employs host enzymes, particularly topoisomerase I, to access essential genetic machinery. Blocking this enzyme completely halted the virus's ability to rearrange the human genome, providing a potential new therapeutic target for controlling HSV-1 infections. Dr. Pia Cosma, a leading researcher at CRG, noted, "In cell culture, inhibiting this enzyme stopped the infection before the virus could make a single new particle. That gives us a potential new therapeutic target to stop infection."

The experimental approach combined super-resolution microscopy, which can visualize structures as small as 20 nanometers, with Hi-C techniques that map the interactions between various DNA segments within the nucleus. This innovative methodology allowed the scientists to observe the rapid onset of viral hijacking, which begins within the first hour of infection and leads to significant changes in chromatin structure.

Dr. Álvaro Castells García, co-first author of the study, remarked, "We always thought dense chromatin shut genes down, but here we see the opposite: stop enough transcription first and the DNA compacts afterwards. The relationship between activity and structure might be a two-way street."

The implications of this study extend beyond basic virology. With nearly four billion people worldwide infected with HSV-1, the findings represent a significant advancement in understanding how the virus operates and present a promising avenue for therapeutic interventions. HSV-1 is known for causing recurrent outbreaks and, in rare cases, severe complications such as blindness or life-threatening diseases in newborns and immunocompromised individuals.

Despite existing antiviral treatments, the emergence of drug-resistant HSV-1 strains underscores the urgency of developing new strategies to combat this widespread virus. The research team at CRG is optimistic that targeting the mechanisms revealed in this study could lead to more effective treatments, addressing the public health challenges posed by HSV-1.

In summary, this pioneering research sheds light on the intricate relationship between HSV-1 and the human genome, highlighting new potential avenues for therapeutic intervention. The study not only enhances our understanding of viral manipulation of host cellular machinery but also opens the door to innovative treatments for a condition that affects millions globally.