Host control of persistent Epstein–Barr virus infection
- 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
2026-02-19
Epstein–Barr virus (EBV) infects approximately 90–95% of the global population 1,2 and persists in B cells as a lifelong infection 3 . Previous EBV infection is associated with autoimmune and neoplastic disease 4 . 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 diseases 4 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.