Abstract

Herpes simplex virus type 1 (HSV-1) infection remains a major global health challenge, yet the mechanisms underlying strain-specific innate immune responses are poorly understood. Here, we show that distinct HSV-1 strains differentially activate the absent in melanoma 2 (AIM2) inflammasome. The HF strain robustly induces AIM2-dependent inflammasome activation, whereas the F and KOS strains elicit minimal responses despite comparable infection efficiency. We demonstrate that this difference is driven by viral genomic features rather than replication capacity. Genomic analyses identify a poly(T) DNA sequence within the UL25-UL26 intergenic region that is enriched in the HF strain. Deletion of a 14-mer poly(T) sequence markedly impairs inflammasome activation, cytokine release, and host protection in vivo, whereas introduction of a poly(T) tract into the F strain is sufficient to confer AIM2 activation and enhanced host defense. Furthermore, poly(T)-mediated AIM2 activation is length-dependent, conserved in human macrophages, and requires a cGAS-STING-IRF1 licensing axis. Together, these findings identify viral poly(T) DNA as a key determinant of strain-specific AIM2 inflammasome activation and reveal how viral genomic variation shapes innate immune recognition.

A research team, led by Professor SangJoon Lee from the Department of Biological Sciences at UNIST has identified a specific viral DNA sequence that triggers the body’s innate immune system, offering new insights into viral detection mechanisms and potential avenues for immunomodulatory therapies.

In collaboration with Professor Joo Sang Lee from Sungkyunkwan University, Professor Eui Tae Kim from Jeju National University, and Director Young Ki Choi from the Korea Virus Research Institute at the Institute for Basic Science (IBS), the team demonstrated that a repetitive poly(T) sequence within the genome of herpes simplex virus type 1 (HSV-1) functions as a molecular barcode recognized by the innate immune sensor AIM2.

HSV-1 infects about 67% of the global population and remains dormant in nerve cells, evading immune detection. Upon reactivation, it infects epithelial cells, provoking inflammation as part of the host’s defense. The study revealed that AIM2, a pivotal immune sensor in macrophages, detects the virus by recognizing poly(T) tracts—regions of repeated thymine (T) nucleotides—in its DNA.

Importantly, immune activation was shown to depend on both the presence and length of this poly(T) sequence: longer repeats elicited stronger inflammatory responses and induced apoptosis in infected cells. Strains lacking the sequence or with fewer than 20 thymine bases elicited minimal immune activity. Introducing the poly(T) sequence into less responsive strains restored immune detection, with increased length correlating to heightened responses.

These findings were confirmed in animal models, where viruses containing the poly(T) motif triggered inflammation and suppressed viral replication, while those without it led to unchecked proliferation and more severe disease outcomes.

Further genomic analysis revealed that similar poly(T) repeats are conserved across various pathogenic viruses—including orthopoxviruses, adenoviruses, and coronaviruses—indicating a shared mechanism of immune recognition.

“This study demonstrates that innate immune sensors recognize viral genomes with greater specificity than previously thought,” said Professor Lee. “Targeting these sensing pathways, rather than the viruses themselves, may offer innovative therapeutic options. Our research provides a foundation for developing immunomodulatory treatments for infectious diseases.”

He added, “Given the conservation of this sequence across multiple viruses associated with severe illnesses, understanding its role could help link viral genomic features to disease severity and inform the design of targeted therapies.”

Published in Nature Communications on April 13, the study was supported by multiple funding agencies, including the National Research Foundation of Korea (NRF), the Korea Health Industry Development Institute (KHIDI), the Ministry of Health and Welfare (MOHW), the Institute for Basic Science (IBS), the Circle Foundation, and Yuhan Corporation.

Journal Reference

SuHyeon Oh, Jueun Oh, Kyeongchan Im, et al., "Herpes simplex virus 1 harboring poly(T) DNA sequences as a key ligand for AIM2 inflammasome activation and host defense," Nat. Commun., (2026).