Innovative Approach to Boost Brain Immunity Against HSV-1 by Targeting Viral Enzymes

Herpes simplex virus type 1 (HSV-1) can cause severe brain inflammation known as HSV-1 encephalitis, which can be fatal if untreated. Despite ongoing research, therapeutic options remain limited. A recent study by researchers at the University of Tokyo has uncovered new insights into how the virus evades the brain’s natural immune defenses, and how this process can potentially be reversed.

HSV-1 has developed mechanisms to bypass the brain’s antiviral proteins, notably the APOBEC family, which normally introduce mutations into viral DNA to prevent infection. The virus counters this by deploying a viral enzyme called uracil-DNA glycosylase (vUNG), which repairs mutations caused by APOBEC1, enabling the virus to replicate unchecked in brain tissue.

The research team focused on the role of vUNG and found that its activity depends on phosphorylation at the amino acid serine 302. When they engineered a mutant virus where this phosphorylation site was altered, vUNG activity was disrupted, leading to reduced viral proliferation and increased survival in infected mice. This confirmed that blocking vUNG restores the effectiveness of the host’s antiviral response.

Importantly, the team developed a gene therapy approach using an adeno-associated virus (AAV) vector to deliver an inhibitor of vUNG, known as UGI. When administered to mice prior to infection, this therapy significantly improved survival rates. The findings demonstrated that inhibiting viral evasion strategies can reactivate the host’s intrinsic immunity, offering a promising new avenue for treatment.

This breakthrough highlights the potential of targeting viral immune evasion proteins, rather than the virus itself, to manage HSV-1 infections. Such strategies could reduce reliance on high-dose antivirals, minimize side effects, and prevent the development of drug resistance. Moreover, this approach could be expanded to other neurotropic viruses employing similar immune escape tactics.

Overall, the study emphasizes the importance of intrinsic immunity in combating brain infections and paves the way for innovative therapies that harness the body’s natural defenses to fight viral diseases more effectively.

Source: https://medicalxpress.com/news/2025-06-viral-enzymes-brain-immunity-hsv.html