Over the years, a number of infectious agents have been implicated as potential role players in the development of MS. Today, attention focuses primarily on HHV-6A, HHV-6B, Epstein Barr virus (EBV), Varicella Zoster Virus (VZV), Chlamydia pneumonia (Cpn) and human endogenous retroviruses (HERVs). Since these viruses and pathogens are also known to potentiate each other, it is possible that there are many infections involved in a chain reaction, resulting in an autoimmune process that continues long after the initial infections have passed. An excellent review on HHV-6 & MS was published in 2014 by Leibovitch & Jacobson.
Below are a few highlighted findings from the literature on the proposed relationship between HHV-6 and MS
- HHV-6A/B IgG correlates with relapse and progression in MS (Ortega-Madueno 2014)
- HHV-6A lytic antigen is target of HHV-6 specific oligcolonal bands in MS (Alenda 2014)
- HHV-6A infection causes persistent neuroinflammation via TLR9 in CD46 transgenic mice (Reynaud 2014)
- HHV-6 IgG but not EBV antibody titers predict relapse in multiple sclerosis (Simpson 2012)
- MS patients have increased prevalence and titer of IgG antibodies reactive to HHV-6 U94/REP Protein (Ben Fredj 2013)
- Marmosets inoculated with HHV-6A exhibit neurologic symptoms similar to those observed in patients with multiple sclerosis (Leibovitch 2013)
- HHV-6 DNA is found in the plasma and serum of 25-30% of MS patients, but not in controls (Garcia Montojo 2014, Alvarez-Lafuente 2008, Hollsberg 2005)
- HHV-6 IgG but not EBV antibody titers predict relapse in multiple sclerosis (Simpson 2012)
- MS patients have increased prevalence and titer of IgG antibodies reactive to HHV-6 U94/REP Protein (Ben Fredj 2013
- Marmosets inoculated with HHV-6A exhibit neurologic symptoms similar to those observed in patients with multiple sclerosis (Leibovitch 2013)
- HHV-6 DNA is found in the plasma and serum of 25-30% of MS patients, but not in controls (Garcia Montojo 2011, Alvarez-Lafuente 2008, Hollsberg 2005)
- HHV-6 specific intrathecal antibodies have been observed in MS patients but not healthy controls (Derfuss 2005, Ferro 2012)
- HHV-6 & EBV reactive oligoclonal bands have been found in nearly 1/3 of MS patients, but rarely among patients with other neurological syndromes (Virtanen 2011, Virtanen 2013)
- More HHV-6 DNA is found in MS patient serum during exacerbations than during relapses (Behzad-Behbahani 2011, Alvarez-Lafuente 2006, Alvarez-Lafuente 2004)
- HHV-6A reactivation has been linked to two genes associated with an increased risk for MS: IRF5 and MHC2TA rs4774C (Dominguez-Mozo 2012, Garcia-Montojo 2011)
- HHV-6 serum DNA levels diminish with interferon beta treatment and patients who do not clear their HHV-6 infection during interferon therapy have a poor prognosis (Garcia-Montojo 2011)
- More HHV-6 DNA is found in MS plaques than in non-affected white matter by immunohistochemistry and FISH in local tissue PCR (Goodman 2003)
- Lymphoproliferative response to HHV-6A: 67% of MS patients have significant lymphocyte response to HHV-6 vs. 32% of controls (Soldan 2000)
- T-cells reacting with myelin basic protein cross-react with HHV-6 and EBV synthetic peptides (Cheng 2012)
Etiological Theories
“Molecular mimicry” involving HHV-6 has been proposed as one mechanism by which the autoimmune process could be triggered and eventually progress toward the development of MS. One study showed that certain residues on the HHV-6 genome are identical to residues of myelin basic protein. Importantly, both T-cells and antibody responses to this peptide sequences were found elevated in MS patients (Tejada-Simon 2003). Moreover, in vitro infection of glial precursor cells was found to impair cell replication and increase the expression of oligodendrocyte markers, suggesting that HHV-6 infection of the CNS may influence the neural repair mechanism (Dietrich 2004).
In addition, it is known that the binding of HHV-6 to its primary cellular receptor CD46 can bias the cytokine profile of specific T-cell responses, which could in turn contribute to the CNS tissue damage observed in MS (Yao 2010). Furthermore, the leading theory of CMV-induced autoimmunity in transplant patients is that cell surface proteins from CMV-infected tissues are incorporated into the viral envelope of CMV, inducing graft-versus-host disease post transplant. Similarly, an argument could be made that myelin proteins from infected oligodendrocytes could become incorporated into the HHV-6A envelope as they enter and leave the cell, thus inducing the CNS autoimmunity observed in conditions such as MS and CFS.
Limiting Factors
One of the obstacles preventing further study of HHV-6A in serum of MS patients is that current commercial assays are not sensitive enough to detect the virus in cases of low-grade chronic infection (See Testing). However, four studies in the late 1990s (when such an assay was briefly available), showed dramatic differences between patients with MS and controls without MS. Studies using assays that differentiate between active and latent virus have shown an exceptionally strong association between HHV-6A and MS. We now know that due to the high level of latent virus found in controls, active infection should be measured by looking for HHV-6 DNA in cell free serum or plasma. Thanks to the advent of more sensitive detection technologies such as ddPCR, assays are now in development that will be able to effectively identify active HHV-6A infection in MS patients.
HHV-6A as a potential treatment target for MS patients
Once active HHV-6A infections can be diagnosed in MS patients through the use of more sensitive assays in commercial laboratories, MS may become treatable to some degree through the use of antiviral and immune modulators in properly identified patients. Such treatment has the potential to drastically improve CNS function in patients with MS symptoms attributable to HHV-6A viremia. At the 2013 International Conference on HHV-6 & 7, several groups met to discuss this issue, and agreed that a clinical trial of HHV-6A antiviral therapy for the treatment of MS patients is warranted and urgently needed. These groups are now focused on organizing such a trial.