難治性慢性活動性EBウイルス感染症を分子レベルで解明～高メチル化と体細胞変異の蓄積が重症化に関与することを発見、新たな治療の可能性も～

2025-11-04

2025-11-04 京都大学

京都大学の研究チームは、難治性の慢性活動性EBウイルス感染症(CAEBV)の重症化メカニズムを分子レベルで解明した。65例の患者検体を解析した結果、特にNK細胞型CAEBVではプロモーター領域のDNA高メチル化と、がん関連遺伝子の体細胞変異の蓄積が重症化に関与することを発見。これらの変化はウイルス感染細胞の増殖・生存を助長し、疾患悪化を招くことが示唆された。発見は、エピゲノム制御を標的とする新たな治療法の開発につながる可能性を持つ。

<関連情報>

マルチオミクス解析により⾼リスク NK 細胞型慢性活動性 EB ウイルス感染症のゲノム・エピゲノム異常の特徴を同定した Multiomics analysis reveals the genetic and epigenetic features of high-risk NK cell-type chronic active EBV infection

Ryo Akazawa,Takashi Mikami,Masaki Yamada,Itaru Kato,Hirohito Kubota,Satoshi Saida,Yoshinori Uchihara,Yuriko Ishikawa,Tatsuya Kamitori,Keiji Tasaka,Kiyotaka Isobe,Tomoya Isobe,Kazushi Izawa,Katsutsugu Umeda,Hidefumi Hiramatsu,Keita Jinnouchi,Masahiro Hirata,Masakazu Fujimoto,Tomoo Daifu,Hiroo Ueno,Seishiro Nodomi,Machiko Sawada,Hisanori Fujino,Katsuyoshi Koh,Mitsuteru Hiwatari,Motohiro Kato,Hiroaki Goto,Ikumi Katano,Ryoji Ito,Mamoru Ito,Nobuyuki Kakiuchi,Masahiro Marshall Nakagawa,Yuichi Shiraishi,Yoshitaka Honda,Hiroyuki Yoshitomi,Hideki Ueno,Maho Sato,Satoru Miyano,Hironori Haga,Akihisa Sawada,Ken-Ichi Imadome,Seishi Ogawa,Junko Takita
Blood Published:July 30, 2025
DOI:https://doi.org/10.1182/blood.2024026805

Key Points

We identified a high-risk subtype of NK cell-type CAEBV characterized by a high CpG island methylation pattern.
5-Azacytidine is effective against this subtype of NK cell-type CAEBV in vitro and in vivo, suggesting it is a novel potential therapy.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an orphan disease characterized by the proliferation and infiltration of EBV-infected T/natural killer (NK) cells into multiple organs. Although CAEBV is a heterogeneous disease with diverse clinical courses, its pathogenesis remains poorly understood. In this study, we explored the molecular mechanisms underlying CAEBV by performing a comprehensive multi-omics analysis, including genome, transcriptome, epigenome, and single-cell transcriptome and surface proteome analyses, of 65 CAEBV patients. Methylation analysis identified two distinct subtypes of NK cell-type CAEBV based on the CpG island methylator phenotype (CIMP). In CIMP-positive CAEBV, regions associated with enhancer of zeste homolog 2 binding sites and histone H3 lysine 27 trimethylation exhibited increased DNA hypermethylation, resulting in downregulation of tumor suppressor and anti-herpes virus genes. CIMP-positive CAEBV had a particularly poor prognosis and displayed a “neoplastic” phenotype with a DNA methylation pattern similar to that of extranodal NK/T-cell lymphoma, a higher tumor mutation burden, and frequent copy number alterations. In addition, both in vitro and in vivo functional assays demonstrated that 5-Azacytidine, a hypomethylating agent, was a potentially effective agent for high-risk CIMP-positive CAEBV. Finally, we established a method to effectively detect EBV-infected cells in single-cell analysis, suggesting that EBV-infected NK cells have tissue-resident properties and that innate and adaptive immunity to EBV is compromised in patients with CAEBV. The present findings provide insight into the complex molecular features of CAEBV and suggest potential molecular therapies.