Study shows how HSV-1 disables the brain's antiviral defenses

Study shows how HSV-1 disables the brain's antiviral defenses

Infections caused by herpes simplex virus type 1 (HSV-1) can lead to HSV-1 encephalitis A, a rare but fatal disease 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. A key line of defense, 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 can bypass this mechanism with potentially life-threatening consequences.

To better understand this immune education, a new study by Professor Yasushi Kawaguchi from the Division of Viral Pathogenesis, Department of Microbiology and Immunology at the Institute of Medicine, University of Tokyo, Japan, studies how HSV-1 deactivates the brain's antiviral defenses and how these defenses can be restored. The study is published in the journalNatural microbiologyon June 3, 2025 and provides a promising new therapeutic strategy to treat HSV-1 encephalitis by reactivating the host's intrinsic immune system.

The researchers identified a viral enzyme called uracil-DNA glycosylase (Vung) that plays a key role in helping HSV-1 evade APOBEC1-mediated immunity. Once in host cells, Vung eliminates harmful mutations that Apobec1 inserts into the viral genome, allowing HSV-1 to replicate freely in the brain.

But the team also discovered a way to deactivate this viral defense mechanism. By using a specially designed viral vector, the researchers were able to block vung activity, restoring the protective effects of APOBEC1 and improving survival in infected mice. “Our study provides the first in -vivo“Explains Prof. Kawaguchi.

To understand how HSV-1 survives in the brain, the team studied the molecular mechanisms of viral evasion using Vung. They found that the enzyme becomes functional through phosphorylation at a specific amino acid serine 302. To test this, they constructed a mutated form of HSV-1 with altered serine 302, which prevented the virus from activating Vung. Mice infected with this mutant version had lower levels of brain infection and improved survival, confirming that phosphorylation is essential for Vung's immunosuppressive effects. More importantly, the lack of an active virus allows APOBEC1 to do its job: insert mutations into the viral genome to stop 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 the mice received this AAV-UG vector before being exposed to HSV-1, they were far more likely to survive.

When mice lacking APOBEC1 received this treatment, the protective effect disappeared, solidifying the importance of the APOBEC1-Vung interaction in the disease process.

“Our results provide a potential new approach to the treatment of herpes simplex virus encephalitis, a life-threatening disease with limited therapeutic options“says Prof. Kawaguchi.”By targeting the viral immune resistance mechanism, this research could contribute to the development of antiviral therapies that enhance the body's natural defenses and improve patient outcomes in the near future. “

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

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