There is convincing epidemiologic evidence that late Epstein Barr virus (EBV) primary infection/seroconversion is a risk factor for multiple sclerosis (MS) development. One meta-analysis found that all patients with MS had been infected with the virus from 5 to 20 years earlier. Despite decades of sucpicion and research, however, no studies have found evidence of expression of the EBV specific to MS, nor has the EBV been shown to be present in the brain. My colleagues and I have just published research1 that shows in vitro EBV activates potentially immunopathogenic and neuropathogenic proteins in cells deriving from blood (peripheral blood mononuclear cells) and brain (astrocytes). This, we think, could be a model for the missing link between the virus and the neurologic disease.
The Role of Retrovirus
Evidence for a potential virus involvement in MS pathogenesis is most consistent for EBV and for 2 human endogenous retroviruses from the W family (HERV-W)-multiple sclerosis–associated retrovirus (MSRV) and syncytin-1. Since 1998, we have been monitoring MS patients for expression of these viruses. Striking direct parallelisms have been found between MSRV positivity/load (in blood, spinal fluid, and brain samples) and temporal and clinical stages, as well as active/remission phases of the disease. MSRV positivity in spinal fluids increased with disease duration, and presence of the retrovirus in early MS was related to worse prognosis in the next 10 years. When we monitored patients receiving treatment, a major reduction of HERV-W/MSRV/syncytin-1 was detected in patients undergoing efficacious, current therapies.
Independent studies have shown that MSRVenv and syncytin-1 proteins share several biological features and are potentially neuropathogenic: they have pro-inflammatory and superantigenic properties, and have been shown to cause neurotoxic effects in vitro and in humanized or transgenic animal models.
EBV Impact on HERV-W/MSRV/sincytin-1
Based on these findings, a link between EBV and HERV-W/MSRV/syncytin-1 seemed possible to us. We performed in vitro experiments on cells from subjects expressing HERV-W/MSRV/syncytin-1, and on brain cells, either infecting them with the EBV or treating them with the major envelope protein of the EBV. We found that contact with this protein on the membrane of both cell types was sufficient to activate expression of the endogenous retrovirus.
These findings demonstrate for the first time that in vitro the EBV is able to activate HERV-W/MSRV/syncytin-1, in cells that are involved in MS pathogenesis and that are the target of EBV infection.
And, In vivo?
In vivo, pathogenic outcomes would depend on a range of host factors such as an abnormal reaction to a late EBV primary infection or a particular genetic background, or both. In the blood, HERV-W/MSRV/syncytin-1 activation by EBV might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, activation could trigger toxic mechanisms against oligodendrocytes that would induce inflammation, demyelination, and axonal damage. Astrocytes, in response to local stimulation by proinflammatory cytokines and other factors, might further activate HERV-W/MSRV/syncytin-1.
Our study suggests a possible co-factor model for MS pathogenesis that includes infection by the EBV as initial trigger of future MS, and HERV-W/MSRV/syncytin-1 as actual contributor to MS pathogenicity. We have yet to understand completely the mechanisms underlying the delay between infection with the virus and expression of MS symptoms. Complex, multifactorial diseases like MS take time, sometimes decades, to manifest. Each co-factor travels an individual course and we cannot predict the point in time when convergence will occur or when convergence will create illness.
1. Mameli G, Poddighe L, Mei A, Uleri E, Sotgiu S, et al. (2012) Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis. PLoS ONE. 2012;7(9):e44991. doi:10.1371/journal.pone.0044991. Available at: