Study uncovers how HSV-1 disables the brain's antiviral defense

Infections caused by herpes simplex virus type 1 (HSV-1) can lead to HSV-1 encephalitis-a rare but deadly condition that inflames the brain. Despite decades of research, treatment options for this disease remain limited. HSV-1 has evolved alongside human hosts and developed strategies to evade immune responses, particularly in the brain. One key line of defense, the apolipoprotein B mRNA editing enzyme (APOBEC), a catalytic polypeptide-like family of proteins, can introduce mutations into viral DNA to prevent infection. However, HSV-1 is able to bypass this mechanism, with potentially life-threatening consequences.

To better understand this immune evasion, a new study led by Professor Yasushi Kawaguchi from the Division of Viral Pathogenesis, Department of Microbiology and Immunology at The Institute of Medical Science, The University of Tokyo, Japan, uncovers how HSV-1 disables the brain's antiviral defense-and how this defense can be restored. The study will be published in the journal Nature Microbiology on June 3, 2025, and offers a promising new therapeutic strategy for treating HSV-1 encephalitis by reactivating the host's intrinsic immune system.

The researchers identified a viral enzyme called uracil-DNA glycosylase (vUNG), which plays a key role in helping HSV-1 escape APOBEC1-mediated immunity. Once inside host cells, vUNG removes damaging mutations that APOBEC1 inserts into the viral genome, enabling HSV-1 to replicate freely in the brain.

But the team also discovered a way to disable this viral defense mechanism. By using a specially designed viral vector, the researchers were able to block vUNG activity, thereby restoring the protective effects of APOBEC1 and improving survival in infected mice. "Our study provides the first in vivo evidence, in the context of human pathogenic virus, that an intrinsic antiviral resistance of the infected host can be revived by blocking a viral evasion factor, pointing to a new therapeutic avenue based on reactivating intrinsic immunity," explains Prof. Kawaguchi.

To understand how HSV-1 survives in the brain, the team investigated the molecular mechanisms of viral evasion involving vUNG. They found that the enzyme becomes functional through phosphorylation at a specific amino acid-serine 302. To test this, they engineered a mutant form of HSV-1 with altered serine 302, making the virus unable to activate vUNG. Mice infected with this mutant version had lower levels of brain infection and improved survival, confirming that phosphorylation is essential for the immune-suppressing action of vUNG. More importantly, the absence of active vUNG allowed APOBEC1 to do its job: inserting mutations into the viral genome to halt its replication.

Inspired by this, the team developed a gene therapy approach using an adeno-associated virus (AAV) to deliver vUNG inhibitor (UGI), a protein that blocks vUNG. When mice received this AAV-UGI vector before exposure to HSV-1, they were far more likely to survive.

However, when the mice lacking APOBEC1 received this treatment, the protective effect vanished, solidifying the importance of the APOBEC1-vUNG interaction in the disease process.

"Our findings offer a potential new approach to treat herpes simplex virus encephalitis, a life-threatening disease with limited therapeutic options," says Prof. Kawaguchi. "By targeting the viral immune evasion mechanism, this research could contribute to the development of antiviral therapies that enhance the natural defenses in the body and improve patient outcomes in the near future."

This study not only reveals the stealth tactics HSV-1 uses to persist in the brain but also introduces a new therapeutic concept-targeting viral immune evasion rather than the virus itself. By restoring natural antiviral immunity, strategies like AAV-UGI could reduce the need for high-dose antiviral drugs, minimize side effects, and help prevent the emergence of drug-resistant strains. The approach may also have broader applications against other viruses that rely on similar immune evasion tactics.