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<p>Epstein–Barr virus (EBV) infects approximately 90–95% of the global population<sup><CitationRef CitationID="CR1">1</CitationRef>,<CitationRef CitationID="CR2">2</CitationRef></sup> and persists in B cells as a lifelong infection<sup><CitationRef CitationID="CR3">3</CitationRef></sup>. Previous EBV infection is associated with autoimmune and neoplastic disease<sup><CitationRef CitationID="CR4">4</CitationRef></sup>. Still, the biological basis of host control during EBV persistence remains unclear. Here we report the identification of non-genetic and genetic factors that are associated with EBV control during persistent infection. Using blood-based genome sequence data from 486,315 UK Biobank and&#xa0;336,123 All of Us participants, we identified short-read pairs mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. EBV read detection (EBVread<sup>+</sup>) reflects increased viral load in blood cells, as shown by orthogonal measurements, and was associated with HIV infection, immunosuppressive drug&#xa0;intake and current smoking. Genome-wide analyses of EBVread<sup>+</sup> identified strong associations at the major histocompatibility complex (MHC), including 54&#xa0;independent human leukocyte antigen (HLA) alleles of MHC classes I and II, and&#xa0;at 27 genomic regions outside MHC. Epistasis with distinct HLA alleles of MHC&#xa0;class I was observed at the <i>ERAP2</i> locus. Analysis of individuals with EBV-associated diseases<sup><CitationRef CitationID="CR4">4</CitationRef></sup> revealed a higher polygenic burden of EBVread<sup>+</sup> for HLA alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01) and at MHC class II in rheumatoid arthritis. Phenome-wide analyses identified a polygenic overlap of EBVread<sup>+</sup> with inflammatory bowel disease, hypothyroidism and type 1 diabetes. Our study establishes by-products of human genome sequencing as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.</p>

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Host control of persistent Epstein–Barr virus infection

  • 期刊论文

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  • 发表日期：

    2026年2月19日

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  • Axel Schmidt,
  • T. Madhusankha Alawathurage,
  • Friederike S. David,
  • Yosuke Ogawa,
  • Leonard Frach,
  • Sylvia Richter,
  • Merle Schaefer,
  • Carina M. Mathey,
  • Sabrina K. Henne,
  • Genta Nagao,
  • Hiromu Tanaka,
  • Shuhei Azekawa,
  • Ko Lee,
  • Naoki Fukunaga,
  • Junko Hamamoto,
  • Hiroki Kabata,
  • Katsunori Masaki,
  • Hirofumi Kamata,
  • Shinnosuke Ikemura,
  • Shotaro Chubachi,
  • Satoshi Okamori,
  • Hideki Terai,
  • Atsuho Morita,
  • Takanori Asakura,
  • Makoto Ishii,
  • Koichi Fukunaga,
  • Yoshifumi Uwamino,
  • Sho Uchida,
  • Shunsuke Uno,
  • Tomoyasu Nishimura,
  • Naoki Hasegawa,
  • Emmy Yanagita,
  • Hiroshi Nishihara,
  • Junichi Sasaki,
  • Hiroshi Morisaki,
  • Toshiro Sato,
  • Yuko Kitagawa,
  • Yuta Matsubara,
  • Yohei Mikami,
  • Kosaku Nanki,
  • Takanori Kanai,
  • Ryuya Edahiro,
  • Yuya Shirai,
  • Kyuto Sonehara,
  • Daisuke Okuzaki,
  • Daisuke Motooka,
  • Masahiro Kanai,
  • Tatsuhiko Naito,
  • Kenichi Yamamoto,
  • Qingbo S. Wang,
  • Yasuhiro Kato,
  • Takayoshi Morita,
  • Shinichi Namba,
  • Ken Suzuki,
  • Yoko Naito,
  • Yu-Chen Liu,
  • Ayako Takuwa,
  • Fuminori Sugihara,
  • James B. Wing,
  • Shuhei Sakakibara,
  • Nobuyuki Hizawa,
  • Takayuki Shiroyama,
  • Satoru Miyawaki,
  • Yusuke Kawamura,
  • Akiyoshi Nakayama,
  • Hirotaka Matsuo,
  • Yuichi Maeda,
  • Takuro Nii,
  • Yoshimi Noda,
  • Takayuki Niitsu,
  • Yuichi Adachi,
  • Takatoshi Enomoto,
  • Saori Amiya,
  • Reina Hara,
  • Yuta Yamaguchi,
  • Teruaki Murakami,
  • Tomoki Kuge,
  • Kinnosuke Matsumoto,
  • Yuji Yamamoto,
  • Makoto Yamamoto,
  • Midori Yoneda,
  • Toshihiro Kishikawa,
  • Shuhei Yamada,
  • Shuhei Kawabata,
  • Noriyuki Kijima,
  • Masatoshi Takagaki,
  • Noah Sasa,
  • Yuya Ueno,
  • Motoyuki Suzuki,
  • Norihiko Takemoto,
  • Hirotaka Eguchi,
  • Takahito Fukusumi,
  • Takao Imai,
  • Munehisa Fukushima,
  • Haruhiko Kishima,
  • Hidenori Inohara,
  • Kazunori Tomono,
  • Kazuto Kato,
  • Meiko Takahashi,
  • Fumihiko Matsuda,
  • Haruhiko Hirata,
  • Yoshito Takeda,
  • Atsushi Kumanogoh,
  • Takanori Hasegawa,
  • Kunihiko Takahashi,
  • Tatsuhiko Anzai,
  • Satoshi Ito,
  • Yuji Uchimura,
  • Akifumi Endo,
  • Yasunari Miyazaki,
  • Takayuki Honda,
  • Tomoya Tateishi,
  • Shuji Tohda,
  • Naoya Ichimura,
  • Kazunari Sonobe,
  • Chihiro Tani Sassa,
  • Jun Nakajima,
  • Masumi Ai,
  • Ryuji Koike,
  • Akinori Kimura,
  • Satoru Miyano,
  • Tomomi Takano,
  • Kazuhiko Katayama,
  • Koji Okudela,
  • Ryunosuke Saiki,
  • Yasuhito Nannya,
  • Seishi Ogawa,
  • Takayoshi Hyugaji,
  • Eigo Shimizu,
  • Kotoe Katayama,
  • Seiya Imoto,
  • Yosuke Omae,
  • Katsushi Tokunaga,
  • Takafumi Ueno,
  • Yoshinori Fukui,
  • Hiroyuki Hayashi,
  • Yukihiro Yoshimura,
  • Natsuo Tachikawa,
  • Kazuhisa Takahashi,
  • Norihiro Harada,
  • Yuki Tanabe,
  • Toshio Naito,
  • Makoto Hiki,
  • Yasushi Matsushita,
  • Haruhi Takagi,
  • Ryousuke Aoki,
  • Ai Nakamura,
  • Sonoko Harada,
  • Hitoshi Sasano,
  • Takashi Ishiguro,
  • Taisuke Isono,
  • Shun Shibata,
  • Yuma Matsui,
  • Chiaki Hosoda,
  • Kenji Takano,
  • Takashi Nishida,
  • Yoichi Kobayashi,
  • Yotaro Takaku,
  • Noboru Takayanagi,
  • Soichiro Ueda,
  • Natsumi Yazaki,
  • Ai Tada,
  • Masayoshi Miyawaki,
  • Masaomi Yamamoto,
  • Eriko Yoshida,
  • Reina Hayashi,
  • Tomoki Nagasaka,
  • Sawako Arai,
  • Yutaro Kaneko,
  • Kana Sasaki,
  • Etsuko Tagaya,
  • Masatoshi Kawana,
  • Ken Arimura,
  • Yasushi Nakano,
  • Yukiko Nakajima,
  • Ryusuke Anan,
  • Ryosuke Arai,
  • Yuko Kurihara,
  • Yuko Harada,
  • Kazumi Nishio,
  • Tetsuya Ueda,
  • Masanori Azuma,
  • Ryuichi Saito,
  • Toshikatsu Sado,
  • Yoshimune Miyazaki,
  • Ryuichi Sato,
  • Yuki Haruta,
  • Tadao Nagasaki,
  • Yoshinori Yasui,
  • Yoshinori Hasegawa,
  • Akihiro Noda,
  • Yusei Fukushima,
  • Reina Kitagawa,
  • Yoshikazu Mutoh,
  • Tomoki Kimura,
  • Tomonori Sato,
  • Reoto Takei,
  • Satoshi Hagimoto,
  • Yoichiro Noguchi,
  • Yasuhiko Yamano,
  • Hajime Sasano,
  • Sho Ota,
  • Yasushi Nakamori,
  • Kazuhisa Yoshiya,
  • Fukuki Saito,
  • Tomoyuki Yoshihara,
  • Daiki Wada,
  • Hiromu Iwamura,
  • Syuji Kanayama,
  • Shuhei Maruyama,
  • Takashi Yoshiyama,
  • Ken Ohta,
  • Hiroyuki Kokuto,
  • Hideo Ogata,
  • Yoshiaki Tanaka,
  • Kenichi Arakawa,
  • Masafumi Shimoda,
  • Takeshi Osawa,
  • Hiroki Tateno,
  • Isano Hase,
  • Shuichi Yoshida,
  • Shoji Suzuki,
  • Miki Kawada,
  • Hirohisa Horinouchi,
  • Fumitake Saito,
  • Keiko Mitamura,
  • Masao Hagihara,
  • Junichi Ochi,
  • Tomoyuki Uchida,
  • Rie Baba,
  • Daisuke Arai,
  • Takayuki Ogura,
  • Hidenori Takahashi,
  • Shigehiro Hagiwara,
  • Shunichiro Konishi,
  • Ichiro Nakachi,
  • Koji Murakami,
  • Mitsuhiro Yamada,
  • Hisatoshi Sugiura,
  • Hirohito Sano,
  • Shuichiro Matsumoto,
  • Nozomu Kimura,
  • Yoshinao Ono,
  • Hiroaki Baba,
  • Yusuke Suzuki,
  • Sohei Nakayama,
  • Keita Masuzawa,
  • Hidefumi Koh,
  • Tadashi Manabe,
  • Yohei Funatsu,
  • Fumimaro Ito,
  • Takahiro Fukui,
  • Keisuke Shinozuka,
  • Sumiko Kohashi,
  • Masatoshi Miyazaki,
  • Tomohisa Shoko,
  • Takashi Inoue,
  • Takahiro Asami,
  • Toshiyuki Hirano,
  • Keigo Kobayashi,
  • Hatsuyo Takaoka,
  • Kazuyoshi Watanabe,
  • Naoki Miyazawa,
  • Yasuhiro Kimura,
  • Reiko Sado,
  • Hideyasu Sugimoto,
  • Akane Kamiya,
  • Naota Kuwahara,
  • Akiko Fujiwara,
  • Tomohiro Matsunaga,
  • Yoko Sato,
  • Takenori Okada,
  • Yoshihiro Hirai,
  • Hidetoshi Kawashima,
  • Atsuya Narita,
  • Kazuki Niwa,
  • Yoshiyuki Sekikawa,
  • Koichi Nishi,
  • Masaru Nishitsuji,
  • Mayuko Tani,
  • Junya Suzuki,
  • Hiroki Nakatsumi,
  • Takashi Ogura,
  • Hideya Kitamura,
  • Eri Hagiwara,
  • Kota Murohashi,
  • Hiroko Okabayashi,
  • Takao Mochimaru,
  • Shigenari Nukaga,
  • Ryosuke Satomi,
  • Yoshitaka Oyamada,
  • Nobuaki Mori,
  • Tomoya Baba,
  • Yasutaka Fukui,
  • Mitsuru Odate,
  • Shuko Mashimo,
  • Yasushi Makino,
  • Kazuma Yagi,
  • Mizuha Hashiguchi,
  • Junko Kagyo,
  • Tetsuya Shiomi,
  • Satoshi Fuke,
  • Hiroshi Saito,
  • Tomoya Tsuchida,
  • Shigeki Fujitani,
  • Mumon Takita,
  • Daiki Morikawa,
  • Toru Yoshida,
  • Takehiro Izumo,
  • Minoru Inomata,
  • Naoyuki Kuse,
  • Nobuyasu Awano,
  • Mari Tone,
  • Akihiro Ito,
  • Yoshihiko Nakamura,
  • Kota Hoshino,
  • Junichi Maruyama,
  • Hiroyasu Ishikura,
  • Tohru Takata,
  • Toshio Odani,
  • Masaru Amishima,
  • Takeshi Hattori,
  • Yasuo Shichinohe,
  • Takashi Kagaya,
  • Toshiyuki Kita,
  • Kazuhide Ohta,
  • Satoru Sakagami,
  • Kiyoshi Koshida,
  • Kentaro Hayashi,
  • Tetsuo Shimizu,
  • Yutaka Kozu,
  • Hisato Hiranuma,
  • Yasuhiro Gon,
  • Namiki Izumi,
  • Kaoru Nagata,
  • Ken Ueda,
  • Reiko Taki,
  • Satoko Hanada,
  • Kodai Kawamura,
  • Kazuya Ichikado,
  • Kenta Nishiyama,
  • Hiroyuki Muranaka,
  • Kazunori Nakamura,
  • Naozumi Hashimoto,
  • Keiko Wakahara,
  • Sakamoto Koji,
  • Norihito Omote,
  • Akira Ando,
  • Nobuhiro Kodama,
  • Yasunari Kaneyama,
  • Shunsuke Maeda,
  • Takashige Kuraki,
  • Takemasa Matsumoto,
  • Koutaro Yokote,
  • Taka-Aki Nakada,
  • Ryuzo Abe,
  • Taku Oshima,
  • Tadanaga Shimada,
  • Masahiro Harada,
  • Takeshi Takahashi,
  • Hiroshi Ono,
  • Toshihiro Sakurai,
  • Takayuki Shibusawa,
  • Yoshifumi Kimizuka,
  • Akihiko Kawana,
  • Tomoya Sano,
  • Chie Watanabe,
  • Ryohei Suematsu,
  • Hisako Sageshima,
  • Ayumi Yoshifuji,
  • Kazuto Ito,
  • Saeko Takahashi,
  • Kota Ishioka,
  • Morio Nakamura,
  • Makoto Masuda,
  • Aya Wakabayashi,
  • Hiroki Watanabe,
  • Suguru Ueda,
  • Masanori Nishikawa,
  • Yusuke Chihara,
  • Mayumi Takeuchi,
  • Keisuke Onoi,
  • Jun Shinozuka,
  • Atsushi Sueyoshi,
  • Yoji Nagasaki,
  • Masaki Okamoto,
  • Sayoko Ishihara,
  • Masatoshi Shimo,
  • Yoshihisa Tokunaga,
  • Yu Kusaka,
  • Takehiko Ohba,
  • Susumu Isogai,
  • Satoru Fukuyama,
  • Yoshihiro Eriguchi,
  • Akiko Yonekawa,
  • Keiko Kan-o,
  • Koichiro Matsumoto,
  • Kensuke Kanaoka,
  • Shoichi Ihara,
  • Kiyoshi Komuta,
  • Yoshiaki Inoue,
  • Shigeru Chiba,
  • Kunihiro Yamagata,
  • Yuji Hiramatsu,
  • Hirayasu Kai,
  • Koichiro Asano,
  • Tsuyoshi Oguma,
  • Yoko Ito,
  • Satoru Hashimoto,
  • Masaki Yamasaki,
  • Yu Kasamatsu,
  • Yuko Komase,
  • Naoya Hida,
  • Takahiro Tsuburai,
  • Baku Oyama,
  • Minoru Takada,
  • Hidenori Kanda,
  • Yuichiro Kitagawa,
  • Tetsuya Fukuta,
  • Takahito Miyake,
  • Shozo Yoshida,
  • Shinji Ogura,
  • Shinji Abe,
  • Yuta Kono,
  • Yuki Togashi,
  • Hiroyuki Takoi,
  • Ryota Kikuchi,
  • Shinichi Ogawa,
  • Tomouki Ogata,
  • Shoichiro Ishihara,
  • Arihiko Kanehiro,
  • Shinji Ozaki,
  • Yasuko Fuchimoto,
  • Sae Wada,
  • Nobukazu Fujimoto,
  • Kei Nishiyama,
  • Mariko Terashima,
  • Satoru Beppu,
  • Kosuke Yoshida,
  • Osamu Narumoto,
  • Hideaki Nagai,
  • Nobuharu Ooshima,
  • Mitsuru Motegi,
  • Akira Umeda,
  • Kazuya Miyagawa,
  • Hisato Shimada,
  • Mayu Endo,
  • Yoshiyuki Ohira,
  • Masafumi Watanabe,
  • Sumito Inoue,
  • Akira Igarashi,
  • Masamichi Sato,
  • Hironori Sagara,
  • Akihiko Tanaka,
  • Shin Ohta,
  • Tomoyuki Kimura,
  • Yoko Shibata,
  • Yoshinori Tanino,
  • Takefumi Nikaido,
  • Hiroyuki Minemura,
  • Yuki Sato,
  • Yuichiro Yamada,
  • Takuya Hashino,
  • Masato Shinoki,
  • Hajime Iwagoe,
  • Hiroshi Takahashi,
  • Kazuhiko Fujii,
  • Hiroto Kishi,
  • Masayuki Kanai,
  • Tomonori Imamura,
  • Tatsuya Yamashita,
  • Masakiyo Yatomi,
  • Toshitaka Maeno,
  • Shinichi Hayashi,
  • Mai Takahashi,
  • Mizuki Kuramochi,
  • Isamu Kamimaki,
  • Yoshiteru Tominaga,
  • Tomoo Ishii,
  • Mitsuyoshi Utsugi,
  • Akihiro Ono,
  • Toru Tanaka,
  • Takeru Kashiwada,
  • Kazue Fujita,
  • Yoshinobu Saito,
  • Masahiro Seike,
  • Hiroko Watanabe,
  • Hiroto Matsuse,
  • Norio Kodaka,
  • Chihiro Nakano,
  • Takeshi Oshio,
  • Takatomo Hirouchi,
  • Shohei Makino,
  • Moritoki Egi,
  • Andreas J. Forstner,
  • Alexander T. Dilthey,
  • Anne-Katrin Pröbstel,
  • Kaan Boztug,
  • Markus M. Nöthen,
  • Ho Namkoong,
  • Yukinori Okada,
  • Eva C. Beins,
  • Kerstin U. Ludwig

摘要

Epstein–Barr virus (EBV) infects approximately 90–95% of the global population1,2 and persists in B cells as a lifelong infection3. Previous EBV infection is associated with autoimmune and neoplastic disease4. Still, the biological basis of host control during EBV persistence remains unclear. Here we report the identification of non-genetic and genetic factors that are associated with EBV control during persistent infection. Using blood-based genome sequence data from 486,315 UK Biobank and 336,123 All of Us participants, we identified short-read pairs mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. EBV read detection (EBVread+) reflects increased viral load in blood cells, as shown by orthogonal measurements, and was associated with HIV infection, immunosuppressive drug intake and current smoking. Genome-wide analyses of EBVread+ identified strong associations at the major histocompatibility complex (MHC), including 54 independent human leukocyte antigen (HLA) alleles of MHC classes I and II, and at 27 genomic regions outside MHC. Epistasis with distinct HLA alleles of MHC class I was observed at the ERAP2 locus. Analysis of individuals with EBV-associated diseases4 revealed a higher polygenic burden of EBVread+ for HLA alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01) and at MHC class II in rheumatoid arthritis. Phenome-wide analyses identified a polygenic overlap of EBVread+ with inflammatory bowel disease, hypothyroidism and type 1 diabetes. Our study establishes by-products of human genome sequencing as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.