ClinicSpeak & CrowdSpeak: why is EBV so important in MS?

More about our crowdfunding initiative. #ClinicSpeak #CrowdFunding #MSBlog #MSResearch

"Did you know that if you develop infectious mononucleosis (IM) due to Epstein-Barr virus (EBV) infection you are more than twice as likely to develop MS than if you acquire EBV without any symptoms (asymptomatic EBV infection)? Even more impressive is that people who don't get infected with EBV are protected from getting MS. In addition, if you have been tested and shown to be EBV negative and then go onto develop MS you alway get infected with EBV prior to developing MS. These epidemiological insights are the main pillars supporting EBV as the likely cause of MS. What we don't know is how EBV causes MS at a molecular level. Does EBV simply trigger the disease and then have nothing to do with ongoing MS disease activity (the hit and run theory)? Is ongoing EBV infection central to driving MS disease activity (the direct viral hypothesis)? Does EBV trigger another virus to act, for example HERVs (human endogenous retroviruses) (the dual-viral hypothesis)? Does EBV simply act as an essential cofactor in driving autoimmunity (the danger or co-stimulatory signal autoimmune hypothesis)? Does EBV immortalise autoimmune B-cells that drive MS disease activity (B cell hypothesis)?"

"The only way to test these different hypotheses is to do experiments. As there is no good animal model of EBV and MS we need to do these experiments in pwMS. One could argue that the effectiveness of anti-CD20 therapy in MS would suggest that the B-cell is where the money is. However, this may not necessarily be the case. Anti-CD20 therapy depletes B-cells and hence we can't be confident that it is working via an anti-EBV mechanism. This is why we want to test drug(s) that specifically target EBV. If we are able to inhibit EBV replication in the body of pwMS and show it shuts down MS disease activity then this would go a long way to support the direct viral and/or dual viral hypotheses. Sadly, we still don't have a small molecule anti-viral drug that has been licensed to treat EBV infection. Reasons for this are complex and relate to how Pharm works. We are trying to convince Pharma that IM is a worthwhile disease to treat and if they develop anti-EBV drugs there will be a market for them. Despite this we have circumstantial evidence that an old anti-herpes drug is capable of suppressing EBV infection. We now want to test this in pwMS. Before doing this we need show that it is capable of inhibiting EBV pwMS and to find out what dose is required to do this. Once we have answered these two questions we will be able to design a study to test this drug in pwMS."

"We know that people infected with EBV intermittently shed EBV in their saliva. This shedding is due to active EBV infection in the salivary glands. We can use this shedding to test whether or not this anti-viral drug works against EBV. Before doing the trial we need to know how many pwMS shed virus on their saliva and how long they shed virus for in serial samples collected over months. Evidence exist from studies in healthy people that EBV shedding is intermittent and seasonal (see abstract below and figures). What we need is this information from pwMS."

EBV shedding in saliva of normal people. Figure from Ling et al. J Infect Dis. 2003 May 15;187(10):1571-80. 

"The good news is that we can answer this question quickly from a saliva samples collected as part of an another study that was measuring stress hormones. We now want to process these samples ASAP so that we can use the data for power calculations for our proposed dose-finding studies of our anti-viral drug. This is why we are asking you to help us raise the money to do the lab work for this study ASAP. I sincerely hope you can help. If everyone who visited this site donated £1 each time they visited we would raise the money we need in 1 or 2 days. I would like to thank all our supporters who have already donated so kindly; things are going well. Thank you."

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"If this work inspires you in any way please send the link to anyone you know who has a personal link with MS. I can't tell you how important it is for us not give up on the viral hypothesis of MS."

Ling et al. The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study. J Infect Dis. 2003 May 15;187(10):1571-80. 

Humans are infected with viruses that establish long-term persistent infections. To address whether immunocompetent individuals control virus reactivation globally or independently and to identify patterns of sporadic reactivation, we monitored herpesviruses and polyomaviruses in 30 adults, over 14 months. Epstein-Barr virus (EBV) DNA was quantitated in saliva and peripheral blood mononuclear cells (PBMCs), cytomegalovirus (CMV) was assayed in urine, and JC virus (JCV) and BK virus (BKV) DNAs were assayed in urine and PBMCs. All individuals shed EBV in saliva, whereas 67% had >or=1 blood sample positive for EBV. Levels of EBV varied widely. CMV shedding occurred infrequently but occurred more commonly in younger individuals (P<.03). JCV and BKV virurias were 46.7% and 0%, respectively. JCV shedding was age dependent and occurred commonly in individuals >or=40 years old (P<.03). Seasonal variation was observed in shedding of EBV and JCV, but there was no correlation among shedding of EBV, CMV, and JCV (P>.50). Thus, adults independently control persistent viruses, which display discordant, sporadic reactivations.

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