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Nat. Commun., 13 April 2026 | https://doi.org/10.1038/s41467-026-71896-w Herpes simplex virus 1 harboring poly(T) DNA sequences as a key ligand for AIM2 inflammasome activation and host defense

SuHyeon Oh^1,2†, Jueun Oh^1†, Kyeongchan Im^3†, Tae Hyoung Kim^4†, Jihye Lee^1†, Kihye Shin^5,6, Nabukenya Mariam³, Cheong Seok³, Jaewoo Park¹, GyeongJu Yu¹, Hayeon Kim¹, Suhyun Kim¹, Seyun Shin¹, Jinwoo Gil¹, Sehee Park⁷, Yoon-Seok Chung⁸, Daesik Kim³, Young Ki Choi^2*, Eui Tae Kim^4,5,6*, Joo Sang Lee^3,9*, SangJoon Lee^1,10*

¹Department of Biological Science, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea
²Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea
³Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea
⁴Department of Biomedicine & Drug Development, Jeju National University Graduate School, Jeju, Republic of Korea
⁵Department of Microbiology and Immunology, Jeju National University College of Medicine, Jeju, Republic of Korea
⁶Jeju Research Center for Natural Medicine, Jeju National University Core Research Institute, Jeju, Republic of Korea
⁷Division of Acute Viral Disease, Center for Emerging Virus Research, National Institute of Infectious Diseases, National Institute of Health, Cheongju, Republic of Korea
⁸Division of High-Risk Pathogens, Department of Laboratory Diagnosis and Analysis, Korea Disease Control and Prevention Agency, KDCA, Cheongju, Republic of Korea
⁹Department of Digital Health, Samsung Advanced Institute of Health Science and Technology and Department of Artificial Intelligence, Sungkyunkwan University, Suwon, Republic of Korea
¹⁰Graduate School of Health Science and Technology, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea

^†These authors have contributed equally
^*Correspondence: SangJoon Lee, Joo Sang Lee, Eui Tae Kim, Young Ki Choi

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.

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