The Epstein-Barr virus (EBV) transcription factor Epstein-Barr Nuclear Antigen 2 (EBNA2) can regulate gene expression depending on multiple sclerosis (MS) risk alleles, likely promoting viral infection, a new study in Australia found.

“This is consistent with the concept that these MS risk loci affect MS risk through altering the response to EBNA2,” the researchers wrote. They concluded that their findings support the role of EBV in MS pathogenesis and suggest that targeting EBV and EBNA2 could reduce their effects on the pathogenesis of the disease.

Previous research has shown that an EBV infection may be necessary for MS to develop, with almost all MS patients being seropositive for the virus. The authors of the present study have previously identified 6 MS risk loci colocated with EBNA2 binding sites in B-cells infected by EBV.

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To address whether EBNA2 binds at these MS risk loci in an allele-dependent manner and regulates gene expression, the researchers devised an allele-specific chromatin immunoprecipitation polymerase chain reaction assay to assess EBNA2 allelic preference. They also treated EBV-infected B-cells with a peptide inhibitor of EBNA2. They explained, “Inhibiting EBNA2 function would alter gene expression at these loci if it was mediated by EBNA2.”

They found that EBNA2 binding was indeed dependent on the risk allele for 5 of 6 MS risk loci. Treatment with a peptide inhibitor of EBNA2 significantly changed the expression of 5 genes. These were TRAF3, CD40, CLECL1, TNFAIP8, and TNFRSF1A. Four of these genes (TRAF3, CD40, CLECL1, and TNFRSF1A) are also involved in other autoimmune diseases associated with EBV and lymphocyte numbers.


Keane JT, Afrasiabi A, Schibeci SD, Swaminathan S, Parnell GP, Booth DR. The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype. EBioMedicine. Published online September 3, 2021. doi:10.1016/j.ebiom.2021.103572