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
MS.
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.