Background: Multiple sclerosis (MS) is an autoimmune disease characterised by demyelination of the central nervous system, thought to be triggered by environmental factors in genetically susceptible individuals. Seropositivity, timing and clinical manifestation of Epstein-Barr virus (EBV) infection are significant risk factors for MS. EBV transactivates an MS-associated human endogenous retrovirus, HERV-W, with in vitro toxicity to myelin-producing cells. As part of the International MS Genetics Consortium, we have defined over 110 common genetic variants associated with MS (Nature, 2011; Nature Genetics 2013), confirming the prime role of the immune system in inherited susceptibility. Apart from the HLA genes, interaction between MS risk variants and EBV has not been well-characterised. Aim: To investigate immune pathways in which MS risk genes may promote cellular activity of EBV and the transactivated retrovirus, HERV-W. Methods: MS risk genes CD40, EOMES, and TBX21; and RPS6 (regulated by MS risk gene RPS6KB1) were chosen based on differential expression in whole blood in MS. Genotype was determined by RT-PCR; gene expression by RNASeq; and cell-surface expression by flow cytometry. Results and Discussion: The MS risk variant of CD40 was expressed at lower levels in whole blood. CD40 competes with its EBV functional mimic LMP1 for intracellular signalling molecules, eg TRAF3. We hypothesise that lower expression of the CD40 MS risk variant allows greater LMP-1 signalling. Lower whole blood EOMES and TBX21 gene expression reflected lower proportions of, and gene expression in NK and CD8 memory subsets in MS: key mediators of the anti-EBV immune response. RPS6, expressed at higher levels in MS, was correlated with HERV-W expression; future work will examine effect of RPS6KB1 genotype. Conclusion: Several MS risk genes interact with EBV pathways in immune cells, supporting a model in which these confer increased susceptibility to EBV-mediated cellular events.