Possible Role of Retroviral Gene Expression in Multiple Sclerosis

Abstracts & Commentary

Synopsis: Syncytin’s proinflammatory properties in the nervous system demonstrate a novel role for an endogenous retrovirus protein, which may be a target for therapeutic intervention.

Source: Anthony JM, et al. Human Endogenous Retrovirus Glycoprotein-Mediated Induction of Redox Reactants Causes Oligodendrocyte Death and Demyelination. Nature Neurosci. 2004;10:1088-1095.

Anthony and colleagues studied the potential role of human endogenous retrovirus (HERV) gene products in triggering the inflammatory, demyelinating pathology of multiple sclerosis. The HERV envelope glycoprotein syncytin was found to be upregulated in the brain tissue from 3 patients with multiple sclerosis, both at the mRNA and protein level, particularly in areas of active demyelination. Transfection and expression of the syncytin envelope gene in glial cell cultures was shown to induce the production of oxidant molecules (nitric oxide) and inflammatory cytokines (interleukin-1) that were toxic to oligodendroglial cells. Rodents that were similarly transfected with syncytin in the corpus callosum showed oligodendroglial cell loss and increased microglial cells with hypertrophic astrocytes. In this animal model, the rodents with histopathological changes had associated neurological motor deficits, both of which could be prevented by the anti-oxidant ferulic acid.

During primate evolution over a million years ago, retroviruses invaded the genome and integrated to now account for up to 8% of human DNA. Most of the retroviral sequences are not expressed. However, some of these HERV sequences have retained functional regulatory sequences and open reading frames for expression, and may have a role in normal human physiology and disease. Syncytin is a 518-amino acid membrane glycoprotein that is highly expressed in the placenta, where it is involved in trophoblast cell fusion and syncytium formation. Syncytin appears to bind to an amino acid transporter receptor that also serves as a retrovirus receptor. There is evidence that retroviruses in humans and other animals (eg, HIV, HTLV-I, and lentiviruses) exert a variety of neuropathological effects, some by direct neurotoxic effects of the envelope protein, or by inducing a secondary host inflammatory immune response. Anthony and colleagues have found an association between the inflammatory pathology in multiple sclerosis and the expression of syncytin in the brain, and have developed an interesting animal model of disease which supports a specific therapeutic strategy with antioxidants. However, the presence of syncytin could be an epiphenomenon of inflammation, just as inflammation may be inducing a number of proteins, as well as certain herpes viruses, such as HHV-6, that have been demonstrated in brain lesions of multiple sclerosis patients. Further studies are needed to determine if blocking syncytin controls the inflammatory reaction, or whether B or T cell immune reactivity against syncytin, occurs in multiple sclerosis. —Brian R. Apatoff

Brian R. Apatoff, MD, PhD Associate Professor of Neurology, New York Presbyterian Hospital- Cornell Campus is Assistant Editor of Neurology Alert.