Retroviral Elements Associated with Superantigens and Neurotoxins: Learnings From Our Research in Multiple Sclerosis and Possible Avenue of Research in Neurological Diseases





Herve Perron, Ph.D. bioMérieux S.A.

Lyon, France

A common point to a number of human

diseases in which no precise etiology has been identified despite

decades of research efforts, is outlined by epidemiological data

and experimental models suggesting the contribution of

“environmental factors” among which viruses might play

a major role. In parallel, another common point is the obvious

contribution of the human genotypes to an increased risk and/or

to disease severity. Several autoimmune, neurodegenerative and

psychiatric diseases are concerned by these observations. Among

them, multiple sclerosis (MS) may represent a prototypic example

in which viruses and host’s genetics have long been studied.

The recent identification of retroviral

RNA sequences (MSRV) associated with extracellular virions

detectable in the plasma, the CSF, and in some cell cultures from

patients with MS, as well as of a cytotoxic factor targeting

glial cells (gliotoxin) detected in parallel will be analysed. In

the light of the different aetiopathogenic hypotheses for the

disease and of our preliminary observations, a working hypothesis

could rely upon an initial co-expression of a gliotoxic molecule

and of a retroviral superantigen in, e.g., a perivascular

macrophage. Blood brain barrier (BBB) disruption would occur

after perivascular astrocyte death caused by the first molecule

and disproportionate inflammation, and dysregulation of

autoreactive lymphocytes would result from superantigenic

stimulation of T-cells entering the brain parenchyma through an

open BBB. Retroviral expression may itself result from

infection(s) by viral co-factors such as herpesviruses, which we

have shown to be transactivators of our first retroviral isolate

(LM7) in MS. Since MSRV is closely related to a family of human

endogenous retroviruses (HERV), its expression could result from

an endogenous haplotype present in MS-susceptible individuals and

be induced by co-factors, as well as from an eventual, exogenous

retroviral strain remaining latent in rare CNS cells. Though all

regions from a potential MSRV genome have been sequenced from

particle-associated RNA, the correct proviral clone at the origin

of these retroviral particles remains to be identified but is

strongly hampered by the presence of numerous homologous HERV

copies in DNA.

Similar data with other retroviruses which

were recently published concerning autoimmune diseases such as

diabetes 1, Sjögren’s syndrome and systemic lupus, could

prefigurate a broader concept for the role of such retroviruses

in the aetiopathogenesis of autoimmune diseases. However, in

non-autoimmune diseases, existing models suggest that retroviral

expression in the CNS, though mostly defective and resulting from

complex interactions, can also generate cytotoxic molecules

which, either directly or indirectly through cytopathic effects

in glial cells, cause neurological diseases.

Therefore, the perspectives opened by the

concept of a retroviral aetiopathogenesis involving endogenous

and/or exogenous retroviruses encoding or inducing potent

cytopathogenic molecules in CNS diseases are considerable, but

require increased and concerted research in order to evaluate

their reliability.