Sleepers inside Cell Nuclei
Virologists from Freie Universität unlock the tricks of herpes viruses
Mar 07, 2018
Do you have herpes? Most likely, yes! Even those who do not suffer from the annoying lip blisters known as cold sores, which are caused by the herpes simplex virus, are probably infected – like more than 90 percent of the world’s population – with one of the other eight human herpes viruses.
Anyone who has ever had chickenpox or suffered from roseola as an infant or toddler, with its attendant rosy-colored rash, still carries those viruses. They’re there to stay – for the rest of the person’s life.
Varicella zoster, for example, stores its genetic material in human nerve cells. Thirty, 50, or even 70 years later, when chickenpox is only a distant memory, the virus can become active again. Stress can be enough to “wake up” the pathogens. When that happens, they migrate along nerve pathways to the skin, where they trigger the extremely painful rash known as shingles. It’s bad for the patient, but good for the virus. Infectious particles spread easily to others, so the virus can extend its reach.
Virologist Benedikt Kaufer, a professor at the Department of Veterinary Medicine at Freie Universität Berlin, specializes in herpes viruses in humans and animals. Together with colleagues, he has discovered just how refined the viruses’ approach is. “It was previously accepted that all herpes viruses store their genetic material as a circular genome inside the host’s cells. But some pathogens manage to build their DNA directly into the ends of our chromosomes – the telomeres.” Using artificially introduced green fluorescent proteins, the researchers can even visualize virus DNA inside the chromosomes.
Herpes viruses that cause roseola have now even been found in sperm samples. “It is assumed that one percent of the world population must carry these viruses in every cell of the body – and pass them along to their offspring.” And that brings up a whole new set of questions. What diseases does this cause? And what symptoms do people who carry the virus in their genetic material have?
Together with Amr Aswad, who will shortly be coming to Freie Universität from Oxford on an Einstein International Postdoctoral Fellowship to establish new bioinformatic and molecular biology methods at the Institute of Virology, Kaufer aims to investigate how, exactly, the gene integration takes place. They also aim to study what changes take place in the virus genome when this herpes virus enters “sleep mode.”
The herpes virus group is a huge one. Alongside the nine human species, there are about 200 other known herpes viruses that affect animals. Horses, dogs, cats, mice – there is hardly any animal family that doesn’t have its own herpes viruses. Humans cannot become infected with animal viruses, because the pathogens are highly host-specific.
Still, though, they are important to us when it comes to the health of livestock. Marek’s disease (GaHV-2), for example, causes paralysis and tumors in chickens. It hides in T cells, which it can transform into cancer cells. Solid tumors form shortly afterward, affecting the breast muscle, kidneys, and spleen, among other areas. Unvaccinated chickens face certain death when infected. Kaufer studies this disease as an example of herpes in animals.
Kaufer wants to know what makes GaHV-2 a killer, since the virus has grown steadily more aggressive over the past several decades. German chickens have generally been immunized against this disease since back in the 1960s. “It was the first vaccination that could protect an animal from cancer,” Kaufer says. But the virus stepped up its efforts and evolved. Ten years later, some strains managed to leap the “immunization hurdle.” The result? Once again, thousands of chickens died in just a short time. Billions of laying hens and breeding animals have been immunized worldwide in the meantime. The vaccine is now in its third generation.
But what makes the virus so successful? “Unlike flu viruses, GaHV-2 does not change its surface structures. We are studying whether mutations in certain genes are responsible for the rising virulence. There are a number of indications that this is the case,” Kaufer says.
Marek’s disease is well documented, which means the virologists have access to samples from all of the various virulence stages and can analyze and compare gene sequences. Kaufer is focusing in particular on the oncogene meq. “It affects the cell cycle in infected cells, preventing cell death. If you remove meq from the genome, the virus loses these functions, and no more tumors form.”
But Kaufer also wants to know how far GaHV-2 can go from here. With that in mind, he uses chemicals that can trigger mutations to accelerate the virus’s evolution in the lab. “This gives us a large number of new virus varieties in just a short time. Some of them cannot multiply at all anymore, while others are likely to be even more aggressive, giving us clues to where GaHV-2 might go from here. ” The researchers aim to use these new findings to generate new vaccine candidates, thereby ensuring that animals can be protected in the future.
Luckily, very few herpes viruses contain cancer genes. The vast majority of them have no interest at all in stimulating cell division in the host, as cancer genes do. Like varicella zoster, they have found a quiet place to sleep instead. After all, lying dormant is the simplest strategy to ensure the survival of their genes. With luck, it might work for 70 or 80 years, since nerve cells typically do not die until the human organism does.
A new shingles vaccine is currently in the final stages of clinical trials, incidentally. It will prevent the reactivation of the viruses, at which point people will hopefully be able to say: Sleep tight, varicella – forever!
Benedikt Kaufer, Ph.D., Professor ofVirology, Department of Veterinary Medicine, Freie Universität Berlin, Tel.: +49 30 838 51936, Email: firstname.lastname@example.org