MS disease activity not associated with peripheral HHV-6 or EBV reactivation

Where is EBV acting in the causal pathway of MS? Early vs. Late? Central vs. Peripheral? #MSBlog #MSResearch

"The study below did not show any link between peripheral blood and viral titres to EBV and HHV-6 antigens and peripheral blood viral loads and disease course (relapses or disease progression). What can we conclude from this study? Does this mean that EBV and HHV-6 are unrelated to disease activity? The main problem with the anti-EBV serology is that they did not include antibodies to EBV nuclear antigen-1 or EBNA-1. The latter is the antigen that is responsible of keeping EBV in its latent state. Most of the studies showing a positive correlation between EBV and MS disease activity have been with this latent antigen. This study focused on antigens expressed when the virus is in its lytic phase; it may notbe lytic EBV infection that is driving the disease. With regard to viral loads the investigators have also only focused on the peripheral blood compartment. These viruses may be active in other compartments, for example the saliva and central nervous system (CNS). One confounder that has not been taken into account are DMTs. I can't find any reference in the paper to how many study subjects were on for example, interferon-beta. This is important; IFN-beta is an anti-viral and it may suppress viral activity in the peripheral compartment. Does this paper disprove the viral hypothesis? No! What it does say is that antibody titres to lytic antigens are not associated to MS disease activity and the peripheral blood is probably not the compartment to be looking at for viral activity."


Epub: Simpson et al. EBV & HHV6 reactivation is infrequent and not associated with MS clinical course. Acta Neurol Scand. 2014 Jun 3. doi: 10.1111/ane.12268.

BACKGROUND: Among the environmental factors associated with MS causation, some of the strongest associations are with EBV, and to a lesser extent human herpesvirus 6 (HHV6). Associations with clinical course are less conclusive, however.

METHODS: We evaluated serum anti-EBV-EA-R IgG and anti-HHV6 IgM, and EBV and HHV6 viral load (VL) for their associations with relapse, disability, and progression in disability in a prospective cohort of 198 participants with clinically definite MS.

RESULTS: Anti-EBV-EA-R IgG was detected in 81.8% of cases at study entry, and titres remained essentially unchanged during the study. Anti-HHV6 IgM was detected in only one participant, and EBV-VL (29%) and HHV6-VL (1.8%) were detected in a minority of samples, and where detected levels were low. Our previously demonstrated association between anti-HHV6 IgG and relapse hazard was not affected by adjustment for parameters of reactivation. We found no evidence that any of the viral markers were associated with disability or progression in disability. In relation to relapse, only EBV-VL was positively associated, although this was strongly influenced by a single individual.

CONCLUSION: Using a prospective cohort design, we found no convincing evidence that reactivation parameters of EBV or HHV6 were associated with subsequent MS relapse hazard or progression in disability, confirming previous findings, and indicating that herpes virus reactivation is not an important driver of relapse or disability in this established MS population.

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