Host control of persistent Epstein–Barr virus infection

Epstein–Barr virus (EBV) infects approximately 90–95% of the global population^1,2 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.