Immunopathogenicity of MSRV envelope targeting brain macrophages

S, R&D Neuroimmunologie, Chemin de L’Orme, 69280 March L’Etoile, France; **INSERM

U548, Immunologie cellulaire et moléculaire,

Following

isolation in Leptomeningeal cell cultures from patients with Multiple Sclerosis

–MS- a novel retroviral element was identified and denominated “multiple

sclerosis associated retroviral element” –MSRV-. Its discovery led to the

subsequent identification of a genetically related family of human endogenous

retroviruses (HERV-W), which entered the germ line of primates at the level of

African monkeys, in which it should be named ERV-W. The peculiar nature of such

retroviral families comprising multiple endogenous copies in the genome of

animal species, made it impossible to set up tools for large epidemiological

studies as for, e.g., classical  exogenous retroviruses in humans-HTLV or HIV-,

and therefore to quickly elucidate an eventual link between MSRV and MS

pathogenesis  and/or aetiology. We thus focused on the study of eventual

pathogenic properties of MSRV retroviral particles, as detected in disease,

which would be compatible with pro-inflammatory and dysimmune mechanisms

In a

collaborative study with  Dr Monique Lafon  (Institut Pasteur, Paris) and Dr 

Patrice Marche  (INSERM/CEA, Grenoble), we have evidenced pro-inflammatory and

superantigen-like effects of MSRV virions purified from MS cultures and could

attribute these effects to its envelope protein. In a parallel collaboration

with  Pr JL Touraine (Faculté Laënnec, Lyon) , we have set up an human-animal

hybdrid model (SCID mice grafted with a functional human lymphoid system), which

confirmed in vivo the extremely potent immunopathogenicity of MSRV virions and

their ability to induce massive pro-inflammatory cytokine production resulting

severe immunopathogenic effects. The effects observed in this model are

interpreted as a « systemic » version of MSRV immunopathogenic effects, which

would be limited to focal areas when MSRV expression is reactivated in disease

Elsewhere, the

independent publications confirming the detection of MSRV in MS sera and the

clinical significance of its early detection in CSF provide renewed evidence

that this novel concept in MS is emerging from the past confusion towards an

In the

Sardinian studies, other neurological diseases such as “chronic inflammatory

demyelinating polyneuropathy” (CIDP) were over-represented and obviously

influenced the figures obtained in “neurological controls”-though remaining

significantly different from MS results. Interestingly, it corroborated our

unpublished data on a plausible association between CIDP and MSRV, in addition

to MS. This may also be the case for certain patients with schizophrenia -SCZ,

thus suggesting a role for MSRV in several neurological or psychiatric diseases,

probably with a common pathogenic pathway. This would be likely to consist in

the pro-inflammatory effects of MSRV envelope protein, which, in addition to

inflammatory demyelinating diseases, could also be relevant in SCZ: such

inflammatory phenomena in a “grey matter” context, were reported in to

contribute to neurotoxicity and were detected in SCZ, with interesting data on

Today, the

belief that MSRV would be “the virus causing MS” -as many opinion leaders are

still expecting a unique “causative agent” in MS-, is the best way to

Models such as

HTLV-1 causing either “Adult T-cell leukaemia”, either “tropical spastic

praparesis, either certain types of polymyositis or arthritis, but more

often…nothing at all, appear more relevant for understanding the concept of a

The role of

co-factors in HIV-associated diseases is another contribution to the

understanding of how a particular disease may result from, and be

tissue-targeted by, the combination of two pathogens: HHV-8 and HIV-1 in

The

contribution of the “endogenous retroviral genotype” is much more difficult to

illustrate in human diseases, since we are indeed building knowledge in humans

today. An insight into animal immunovirology of mouse mammary tumour virus (MMTV),

could nonetheless evidence the pathogenic role of transmissible and pathogenic

Since the

presence of circulating virions in MS, the relationship with disease outcome and

the direct pathogenicity of MS circulating virions have now been evidenced,

blocking pro-inflammatory effects of MSRV Envelope protein in diseases

associated with circulating MSRV virions has a good probability to have positive

Our therapeutic

strategy therefore focuses on potential inhibitors of MSRV-Env mediated