Genetics Impact Immune Response to Herpes Simplex Virus


Novel mutations in the gene GTF3A impairs the innate immune response to herpes simplex virus 1.

Research into the way genetics affect the antiviral response to herpes simplex virus 1 (HSV-1) may help to avoid rare complications, such as herpes simplex encephalitis (HSE), according to a study published in Science Immunology.

HSV-1 is among the most common human pathogens and infects several billion people worldwide. In rare cases—1 in 250,000 to 500,000 individuals per year—HSV-1 can lead to HSE, predominantly in children younger than 3 years of age.

“Late diagnosis of HSE or lack of adequate antiviral therapy is associated with high mortality (~70%), and most survivors develop neurological sequelae,” the study authors wrote.

Researchers from Ghent University in Belgium and Cleveland Clinic’s Florida Research & Innovation Center (FRIC) studied genetic data from a 9-month-old patient with immunodeficiency who was hospitalized with HSE, which is a rare and life-threatening brain inflammation associated with HSV-1 infection. The investigators observed novel mutations in the gene GTF3A, which impairs the innate immune response.

These findings hold potential as a genetic marker that physicians may use to evaluate a patient’s risk of developing HSE, despite these mutations generally occurring rarely in the population, according to the study authors.

Many people are infected in childhood with the HSV-1 virus but the vast majority don’t suffer from HSE. The most common symptom of HSV-1 is oral cold sores, although many individuals do not show any symptoms. HSV-1 carries a greater risk for immunodeficient children and adults who are unable to control the virus well.

“Genetic and mechanistic analyses of uncommon viral diseases like herpes encephalitis are quite rare. In fact, the causes underlying severe herpes encephalitis are often unknown,” FRIC Scientific Director Michaela Gack, PhD, said in a press release. “This information provides us with invaluable insight into the fundamental molecular processes that govern our immune response and opens up opportunities for future research on severe disease outcomes.”

GTF3A mutations guide how cells respond to viral activity through the genetic makeup of a protein called TFIIIA, which is involved in helping human enzymes produce certain types of RNA that can determine specific functions inside cells, according to the study authors. They added that some RNAs can produce an anti-herpes viral immune response.

After testing cells with the mutations, it was found that because of defects in certain immunostimulatory RNAs, the mutated cells were more susceptible to HSV-1 infection and lost the ability to control the HSV-1 virus.

The study authors said the mutated gene is part of the body’s defense system that produces interferons to fight off viral infection. They noted that these findings show a critical layer of innate defense human cells use to control HSV-1 infections.

“Understanding the molecular processes underlying antiviral responses is key to treating or possibly preventing severe viral infections that change patients’ and families’ lives,” Gack said. “Our findings on critical immune defense proteins may translate into new therapies in the future.”


GTF3A mutations predispose to herpes simplex encephalitis by disrupting ...November 18, 2022. Science Immunology. Available at: Accessed December 5, 2022.

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