Retroviral Elements

Retroviral Elements, Genetic Susceptibility and Infectious

Triggers: Converging Data Suggesting an Integrative Pathogenic Concept in

Multiple Sclerosis and Possible Common Points with Schizophrenia

H. Perron

Different groups have observed retrovirus particle (RVP)

production in cell cultures from patients with multiple sclerosis (MS). This in

vitro production appeared relatively specific for MS versus healthy controls,

but was likely to be enhanced or activated by infectious triggers such as

Herpesviruses (e.g. HSV, EBV…).  Independent molecular analysis of

retroviral RNA associated with RVP revealed two different genetic families of

endogenous retroviral elements (HERV): MSRV/HERV-W and RGH/HERV-H.

Interestingly, these sequences were detected by mutually

exclusive primers in RT-PCR amplifications.  Surprisingly, these two HERV

families both contain a proviral copy inserted in chromosome 7q21-22 region at

about 1Kb of distance of each other.  In addition to this tandem RGH/HERV-W

proviruses, another HERV-W copy is located within a T-cell alpha-delta receptor

(TCR) gene on chromosome 14q21 region.  Surprisingly, these two insertion

sites correspond to genetic loci independently identified as potentially

associated with genetic susceptibility to MS.  Moreover, TCR alpha

chain  genetic determinants have also been reported to be statistically

associated with MS.

A plausible role for infectious agents triggering a

co-activation of this chromosome 7q HERV tandem (replicative retrovirus and/or

other virus and/or intracellular bacteria) and, eventually, other HERV copies

must therefore be considered.  A genetic polymorphism of particular HERV

copies and the production of pathogenic molecules (gliotoxin and superantigen)

possibly associated with retroviral expression are also likely to be relevant in


An integrative concept of pathogenic “chain-reaction”

in MS involving several step-specific pathogenic “agents” and

“products” somewhat interacting with particular genetic elements would

federate most partial data obtained on MS, including retroviral expression.

Considering this concept and known animal models involving a

genetic regulation of retroviral–or even non-retroviral infection by endogenous

retroviral (ERV) haplotypes, the recently proposed role of retroviral elements

such as MSVR in schizophrenia might involve a genetic susceptibility associated

with particular MSRV/HERV-W haplotypes.  Previous theories associating

retrotransposable elements and chromosome X in schizophrenia should therefore be

re-evaluated taking the numerous MSRV/HERV-W elements on chromosome X into

account.  Nonetheless, somatic recombinations limited to a limited number

of cells within a given individual caused by de novo retrotransposition or by

all infectious homologous strain, are also possible and could provide

non-conventional genetic abnormalities.  In these conditions, the ?

viro-genetic ? contribution of particular retroviral elements in schizophrenia

could also be considered as participating to another pathogenic ? chain reaction

? having common points with MS but different input and outcome.