Viruses lack any life on their own; they need to invade living cells to thrive. The herpes simplex virus type 1 (HSV-1) is certainly no exception.
Primarily recognized for causing cold sores, HSV-1 often lurks silently in the majority of people. However, within our cells, this virus performs some remarkable alterations to DNA.
A recent study featured in the journal Nature Communications reveals that HSV-1 does more than just hijack the cellular mechanisms of its host. It actually modifies the three-dimensional structure of the human genome, allowing the virus to tap into specific genes that facilitate its replication.
According to Dr. Esther González Almela, “HSV-1 acts like an opportunistic interior designer, shaping the human genome with precision and deciding which parts to interact with.”
This alteration is not accidental but a deliberate strategy. The virus begins to reconfigure DNA connections within hours of entering the body, creating an environment that’s ideal for its replication.
Understanding herpes HSV-1 – the basics
HSV-1 infects a large portion of the global population, with estimates suggesting that more than two-thirds of individuals under 50 harbor the virus.
Typically, people contract HSV-1 in childhood through nonsexual means, like sharing utensils or engaging in close interactions.
For many, the virus stays dormant in nerve cells, reactivating intermittently due to stress, illness, or a weakened immune system.
Even though the physical symptoms are often mild, the stigma associated with herpes can create anxiety and emotional distress, particularly when outbreaks occur.
In some rare instances, HSV-1 can lead to more serious issues, causing genital herpes through oral-genital contact and raising sexual health concerns.
Additionally, HSV-1 can cause encephalitis, a potentially fatal brain inflammation, particularly in infants or those with compromised immune systems.
How the herpes virus controls DNA
Within an hour of entering a cell, HSV-1 seizes control of the host’s RNA polymerase II (RNAP II), an enzyme that typically transcribes RNA from human DNA. Instead, it reroutes RNAP II to replicate its own genes.
To support this process, Topoisomerase I (TOP1) enters the fray, relieving DNA tension, and cohesin, which assists in DNA folding, rushes toward the viral genome. Collectively, these enzymes enable the formation of viral replication compartments (VRCs).
Inside these compartments, human gene expression significantly slows. RNAP II and TOP1 forsake host DNA, resulting in chromatin—the compact form of DNA—collapsing to roughly 30% of its usual volume.
VRCs proliferate quickly, pushing host DNA to the nucleus’s outer edges, leading to a steep decline in human gene activity. Before long, viral RNA fills the cell.
Surprising turns in genome folding
Cohesin participates in forming short loops close to viral DNA, although much of its regular function diminishes. Some loops of host DNA are lost, while others remain intact. The virus specifically rewires certain loops to enhance genes that benefit it.
Interestingly, despite this manipulation, chunks of the human genome manage to preserve their structure. A/B compartments—larger segments of active or dormant DNA—remain more or less unaffected, indicating that chromatin can maintain its overall architecture, even when under viral attack.
Additionally, HSV-1 doesn’t seem to depend on altering chemical markers like H3K27me3 or H3K9me3; it keeps these epigenetic marks intact while physically altering the DNA’s shape and location.
Dr. Álvaro Castells García from Southern Medical University in Guangzhou, China, pointed out, “We always thought that dense chromatin silences genes, but what we see here is different: stop sufficient transcription first, and then the DNA compacts. The connection between activity and structure may be more complex than we thought.”
One enzyme blocks the virus
The research team identified a crucial flaw in the virus’s strategy. By inhibiting just one host enzyme, TOP1, they completely halted HSV-1’s genome restructuring. Without TOP1, VRCs couldn’t take shape, which meant the virus couldn’t create new particles.
“In cell culture, blocking this enzyme prevented the infection from producing a single new particle,” stated Professor Pia Cosma.
This discovery positions TOP1 as a potential target for new therapies. With such a large percentage of people under 50 carrying HSV-1, a treatment like this could be significant.
The herpes virus rewires DNA
The researchers employed advanced technology to reveal HSV-1’s methods. Super-resolution microscopy enabled them to discern features as small as 20 nanometers, while Hi-C analysis clarified which DNA segments were in contact.
The viral genome tends to associate with regions that are active and rich in genes within human DNA. These connections might be instrumental in activating the genes the virus relies on.
Throughout the course of the infection, clusters of the HSV-1 genome maintain a stable size, with RNAP II closely binding to them while cohesin binds more loosely. This equilibrium supports sustained replication.
The findings suggest that HSV-1 doesn’t merely invade; it thoroughly reorganizes human cells with precision. Despite there being no cure for HSV-1 at present, this study sheds light on a potential strategy for future treatments.
If we can prevent the virus from altering human DNA early in the infection, there’s a chance we could stop its spread, which could lead to new therapeutic options.
The study appears in the journal Nature Communications.
