Abstract
Herpesviruses infect nearly all humans and have long been implicated in autoimmune and chronic diseases, yet their immune interactions with host proteins have not been systematically characterized at population scale. We profiled immunoglobulin G reactivities to >4,600 herpesvirus peptides and >15,000 human proteins using multiplexed protein display in two Mass General Brigham Biobank cohorts (discovery n=1,289; replication n=763), with longitudinal electronic health record follow-up. We identified and replicated 3,943 FDR-significant associations across 93 autoantigens, including previously uncharacterized viral-autoantigen axes, such as PHLDA1 and ZNF550. Eleven autoantigens were predicted by viral peptide reactivities with >85% accuracy in independent validation; some exhibited shared viral-host sequence homology, consistent with possible molecular mimicry. Integrating immune reactivities with incident disease outcomes revealed virus-specific network architectures: cytomegalovirus formed the largest multimorbid network, Epstein-Barr virus converged on pleiotropic autoimmune hubs, and herpes simplex viruses formed smaller, partially overlapping autoreactive networks. These findings define a herpesvirus-autoantigen-disease network atlas and prioritize candidate viral-host immune axes for mechanistic investigation.