Antiviral Antibody Epitope Selection is a Heritable Trait

Venkataraman, Thiagarajan; Valencia, Cristian; Mangino, Massimo; Morgenlander, William; Clipman, Steven J.; Liechti, Thomas; Valencia, Ana; Christofidou, Paraskevi; Spector, Tim; Roederer, Mario; Duggal, Priya; Larman, H. Benjamin

There is enormous variability in human immune responses to viral infections. However, the genetic factors that underlie this variability are not well characterized. We used VirScan, a high-throughput viral epitope scanning technology, to analyze the antibody binding specificities of twins and SNP-genotyped individuals. These data were used to estimate the heritability and identify genomic loci associated with antibody epitope selection, response breadth, and the control of Epstein-Barr Virus (EBV) viral load. We identified 4 epitopes of EBV that were heritably targeted, and at least two EBNA-2 binding specificities that were associated with variants in the MHC class-II locus. We identified an EBV serosignature that predicted viral load in white blood cells and was associated with genetic variants in the MHC class-I locus. Our study provides a new framework for identifying genes important for pathogen immunity, with specific implications for the genetic architecture of EBV humoral responses and the control of viral load.