Viruses are entirely dependent on their hosts to reproduce. They ransack living cells for parts and energy and hijack the host's cellular machinery to make new copies of themselves. Herpes simplex virus-1 (HSV-1), it turns out, also redecorates, according to a new study in Nature Communications.
Researchers at the Centre for Genomic Regulation (CRG) in Barcelona have discovered the cold sore virus reshapes the human genome's architecture, rearranging its shape in three-dimensional space so that HSV-1 can access host genes most useful for its ability to reproduce.
"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," says Dr. Esther González Almela, first author of the study.
While other herpes viruses have been seen compacting and reshaping host chromosomes, it was unclear whether it was a side effect of the virus invading and setting up its own viral replication factories. The study is the first proof that HSV-1 reshapes the human genome deliberately and within hours of infection.
Crucially, the researchers found that blocking a single host enzyme, topoisomerase I, completely blocked HSV-1's ability to rearrange the human genome during infection, bringing the hostile takeover to a halt. The discovery represents a new potential strategy to control a virus which infects nearly four billion people worldwide.
"In cell culture, inhibiting this enzyme stopped the infection before the virus could make a single new particle," says ICREA Research Professor Pia Cosma, corresponding author of the study at the Centre for Genomic Regulation (CRG) in Barcelona. "That gives us a potential new therapeutic target to stop infection."
The researchers made the findings by combining super-resolution microscopy, an imaging technique which can see structures 20 nanometres wide, around 3,500 times thinner than a strand of hair, with Hi-C, a technique that reveals which bits of DNA are touching inside the nucleus. They used both techniques to gain new mechanistic insights into how HSV-1 hijacks human cells.
They found the hostile takeover begins within the first hour, with the virus hijacking the human RNA-polymerase II enzyme to help synthesise its own proteins. Topoisomerase I, an enzyme that snips DNA to release torsional stress, and cohesin, a structural protein, followed human RNA-polymerase II into the newly forming viral replication compartments.
Three hours after infection, most polymerase and a sizeable fraction of the other two factors had abandoned human genes. The wholesale theft causes transcription to collapse across the host genome, which in turn caused chromatin, the human genome's natural state inside cells, to be crushed into a dense shell just 30% of its original volume.
This was an unexpected finding, as the structure of chromatin is thought to dictate transcription. "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," says Dr. Álvaro Castells García, co-first author of the study.
Two in every three people under age 50 live with HSV-1. Once infected, people have the virus for life, though most cases are asymptomatic or manifest as recurrent cold sores. Rarely, the virus can cause blindness or life-threatening disease in newborns and immunocompromised people.
The findings of the study can help address the public health burden of HSV-1, which is considered a global health challenge because of its prevalence and ability to cause recurrent outbreaks. Though treatments are available to manage symptoms, drug-resistant strains are on the rise, and there is no cure
