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.
Overall, these findings highlight the power of reactivating the body’s own defenses and shine a spotlight on intrinsic immunity as a promising target in the fight against neurotropic viral infections.
***
Reference
Authors: Akihisa Kato1, 2, 3, 4, 17, Hayato Harima 17,18, Yuji Tsunekawa5, Manabu Igarashi6, 7, Kouichi Kitamura8, Kousho Wakae8, Tomoaki Nishiyama9, 10, Satoru Morimoto11, Toru Suzuki12, Hiroko Kozuka-Hata13, Masaaki Oyama13, Daisuke Motooka14, Mizuki Watanabe18, Kousuke Takeshima1, Yuhei Maruzuru1, 2, 3, Naoto Koyanagi1, 2, 3, Hideyuki Okano11, Toshifumi Inada12, Takashi Okada5, Masamichi Muramatsu8, 15, and Yasushi Kawaguchi1, 2, 3, 16
DOI: 10.1038/s41564-025-02026-3
Affiliations:
1. Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Japan
2. Department of Infectious Disease Control, The Institute of Medical Science, The University of Tokyo, Japan
3. Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Japan
4. PRESTO, Japan Science and Technology Agency, Japan
5. Division of Molecular and Medical Genetics, The Institute of Medical Science, The University of Tokyo, Japan
6. Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Japan
7. International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Japan
8. Department of Virology II, National Institute of Infectious Diseases, Japan
9. Research Center for Experimental Modeling of Human Disease, Kanazawa University, Japan
10. School of Science, University of Toyama, Japan
11. Keio University Regenerative Medicine Research Center, Keio University, Japan
12. Division of RNA and Gene Regulation, The Institute of Medical Science, The University of Tokyo, Japan
13. Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Japan
14. Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Japan
15. Department of Infectious Disease Research, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Japan
16. Pandemic Preparedness, Infection and Advanced Research Center, The University of Tokyo, Japan
17. Laboratory of Veterinary Public Health, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Japan
18. Pathology, Immunology and Microbiology, Graduate School of Medicine, The University of Tokyo, Japan
About The Institute of Medical Science, The University of Tokyo
The Institute of Medical Science, The University of Tokyo (IMSUT), established in 1892 as the Institute of Infectious Diseases and renamed IMSUT in 1967, is a leading research institution with a rich history spanning over 127 years. It focuses on exploring biological phenomena and disease principles to develop innovative strategies for disease prevention and treatment. IMSUT fosters a collaborative, interdisciplinary research environment and is known for its work in genomic medicine, regenerative medicine, and advanced medical approaches like gene therapy and AI in healthcare. It operates core research departments and numerous specialized centers, including the Human Genome Center and the Advanced Clinical Research Center, and is recognized as Japan’s only International Joint Usage/Research Center in life sciences.
About Professor Yasushi Kawaguchi from The Institute of Medical Science, The University of Tokyo
Professor Yasushi Kawaguchi is a virologist at The Institute of Medical Science, The University of Tokyo. Prof. Kawaguchi is an expert in the pathogenic mechanisms of herpes viruses. Since completing his PhD in Veterinary Medical Sciences (1995) from The University of Tokyo, he has built over 25 years of research experience, with over 240 publications in reputed national and international journals. He has received prestigious awards for his exemplary work in virology, including the 2024 Toyoichi Otawara Award (Chemotherapy and Serum Therapy Institute) and the 2021 Hideyo Noguchi Memorial Medical Prize.
Funding information
This study was supported by Grants for Scientific Research and Grant-in-Aid for Scientific Research (S) (20H05692) from the Japan Society for the Promotion of Science (JSPS), grants for Scientific Research on Innovative Areas (21H00338, 21H00417, 22H04803) and a grant for Transformative Research Areas (22H05584) from the Ministry of Education, Culture, Science, Sports and Technology of Japan, a PRESTO grant (JPMJPR22R5) from Japan Science and Technology Agency (JST), grants (JP20wm0125002, JP22fk0108640, JP22gm1610008, JP223fa627001, JP23wm0225031, JP23wm0225035) from the Japan Agency for Medical Research and Development (AMED), grants from the International Joint Research Project of the Institute of Medical Science, the University of Tokyo and grants from the Takeda Science Foundation, the Cell Science Research Foundation, the MSD Life Science Foundation, the Uehara Memorial Foundation, and the Mitsubishi Foundation.
END