Background: Some of the strongest associations with MS onset are for human herpesviruses, particularly Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6). Their role in MS clinical course is less clear, however.

Methods: Prospective cohort of 198 persons with clinically definite MS, followed 2002–5, and serum samples obtained from all subjects at study entry to measure anti-HHV-6 and anti-EBV (Epstein–Barr nuclear antigen [EBNA] and viral capsid antigen [VCA]) IgG titers. Association with relapse evaluated using survival analysis; association with disability/progression evaluated using linear regression or multilevel mixed-effects linear regression.

Results: For the 145 persons with relapsing–remitting MS followed beyond one review, anti-HHV-6 IgG titer was positively associated with the hazard of relapse with a dose-dependent trend (p = 0.003), not affected by adjustment for anti-EBV IgG titers, neither of which were independently associated with relapse. There was no significant association between anti-human herpesvirus IgG titers and baseline-measured disability scores, or change in disability scores; however, anti-HHV-6 IgG titers were 2.8 times higher among progressive-course females than progressive-course males.

Discussion: These findings suggest that, in addition to a potential etiological role in MS, HHV-6 infection or the immune response to HHV-6 antigens may have an effect on the risk of MS relapses and possibly on progressive courses of MS. The observed effect was directly related to anti-HHV-6 IgG titers and may indicate that either HHV-6 infection or factors associated with an altered humoral immune response to HHV-6 may have an effect on MS clinical course. Anti-HHV-6 IgG titer may be a useful prognostic factor in relapsing–remitting MS clinical course.