Host control of persistent Epstein–Barr virus infection

Epstein-Barr virus (EBV) infects ≈90-95% of the global population^1,2 and persists in B cells as a life-long infection³. Prior 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 (GS) 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 HLA-alleles of MHC class 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 GS as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.