Viruses are notorious for evading man-made drugs, but they are powerless against a rare mutation in the gene ISG15. A person who possesses this mutation is better at fighting off most (if not all) of the viruses that plague humankind—but probably fewer than one person in 10 million has it. Dusan Bogunovic of the Icahn School of Medicine at Mount Sinai thinks it may be possible to develop a drug that mimics this mutation. If he is right, he may be on the verge of developing a pill that will temporarily bestow the ability to fight off a virus—any virus—without getting sick. The medication should also grant the person who takes it lifelong immunity to any strain encountered while on the drug (unless the virus mutates, as the flu does). To figure out how the mutation suppresses viruses and how a drug might imitate it, Bogunovic and his team recruited six people with this defect, sequenced their DNA, and isolated blood and skin cells from several of them. The researchers then exposed skin cells from three of the people to multiple viruses, including influenza and herpes. After 24 hours, their cells contained orders of magnitude fewer copies of viral particles than normal cells. The reason, the team explained this past May in Nature Communications, is that the ISG15 mutation knocks out a function that helps to dampen inflammation. Inflammation helps the body fight viruses, so these people “are just a little more ready than you or I for the virus that infects them,” Bogunovic says. As a result, their body fights invading viruses and develops immunity before the virus can replicate enough to make them sick. Bogunovic wants to find a drug that can mimic the effects of the ISG15 mutation. “By tuning our system ever so slightly, we could tame the first burst of infection,” he explains. Bogunovic’s group is now screening 16 million compounds in search of a promising antiviral drug. Once it finds candidates, it will need to fine-tune their chemistries, perform toxicology and animal tests, and, finally, run human clinical trials. Success is by no means guaranteed. Some people with the ISG15 mutation have occasional seizures and the beginnings of lupuslike autoimmunity; any drug would need to avoid such side effects (the researchers say taking the drug short term may help with that). Bogunovic is currently in negotiations to start a biotech company based on his research. “Nothing is impossible,” he says. “It’s a process, but I think a very exciting one.”
To figure out how the mutation suppresses viruses and how a drug might imitate it, Bogunovic and his team recruited six people with this defect, sequenced their DNA, and isolated blood and skin cells from several of them. The researchers then exposed skin cells from three of the people to multiple viruses, including influenza and herpes. After 24 hours, their cells contained orders of magnitude fewer copies of viral particles than normal cells. The reason, the team explained this past May in Nature Communications, is that the ISG15 mutation knocks out a function that helps to dampen inflammation. Inflammation helps the body fight viruses, so these people “are just a little more ready than you or I for the virus that infects them,” Bogunovic says. As a result, their body fights invading viruses and develops immunity before the virus can replicate enough to make them sick.
Bogunovic wants to find a drug that can mimic the effects of the ISG15 mutation. “By tuning our system ever so slightly, we could tame the first burst of infection,” he explains. Bogunovic’s group is now screening 16 million compounds in search of a promising antiviral drug. Once it finds candidates, it will need to fine-tune their chemistries, perform toxicology and animal tests, and, finally, run human clinical trials. Success is by no means guaranteed. Some people with the ISG15 mutation have occasional seizures and the beginnings of lupuslike autoimmunity; any drug would need to avoid such side effects (the researchers say taking the drug short term may help with that). Bogunovic is currently in negotiations to start a biotech company based on his research. “Nothing is impossible,” he says. “It’s a process, but I think a very exciting one.”
