Human Endogenous Retrovirus and Neuroinflammation in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Abstract

BackgroundHuman endogenous retroviruses HERV-W encode a pro-inflammatory protein, named MSRV-Env from its original identification in Multiple Sclerosis. Though not detected in various neurological controls, MSRV-Env was found in patients with chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). This study investigated the expression of MSRV in CIDP and evaluated relevant MSRV-Env pathogenic effects.Methods50 CIDP patients, 19 other neurological controls (ONDs) and 65 healthy blood donors (HBDs) were recruited from two different countries. MSRV-env and -pol transcripts, IL6 and CXCL10 levels were quantified from blood samples. MSRV-Env immunohistology was performed in distal sensory nerves from CIDP and neurological controls biopsies. MSRV-Env pathogenic effects and mode of action were assayed in cultured primary human Schwann cells (HSCs).FindingsIn both cohorts, MSRV-env and -pol transcripts, IL6 positivity prevalence and CXCL10 levels were significantly elevated in CIDP patients when compared to HBDs and ONDs (statistically significant in all comparisons). MSRV-Env protein was detected in Schwann cells in 5/7 CIDP biopsies. HSC exposed to or transfected with MSRV-env presented a strong increase of IL6 and CXCL10 transcripts and protein secretion. These pathogenic effects on HSC were inhibited by GNbAC1, a highly specific and neutralizing humanized monoclonal antibody targeting MSRV-Env.InterpretationThe present study showed that MSRV-Env may trigger the release of critical immune mediators proposed as instrumental factors involved in the pathophysiology of CIDP. Significant MSRV-Env expression was detected in a significant proportion of patients with CIDP, in which it may play a role according to its presently observed effects on Schwann cells along with previously known effects on immune cells.Experimental results also suggest that a biomarker-driven therapeutic strategy targeting this protein with a neutralizing antibody such as GNbAC1 may offer new perspectives for treating CIDP patients with positive detection of MSRV-Env expression.Funding.

Human Endogenous Retroviruses in Neurological Diseases

“…CIDP cases [64], a recent study confirmed upregulated HERV-W expression in blood cells and peripheral nerve lesions of patients suffering from CIDP [80]. This investigation also showed TLR4-mediated effects of HERV-W Env protein on primary human Schwann cells.…”

Evolutionary Medicine of Retroviruses in the Human Genome

“…24 HERV env proteins are related to complex pathological disorders and can be one of the targets for therapeutic approach. 25 A monoclonal antibody against a HERV-W env protein is under clinical trial as a therapeutic approach for MS. 26,27 Upregulation of HERV-W was also reported in blood cells and peripheral nerve lesions of chronic inflammatory demyelinating polyradiculoneuropathy patients, and 28 In sporadic amyotrophic lateral sclerosis patients, env proteins of HERV-K are specifically expressed in cortical and spinal neurons and can cause cellular degeneration. 29 RT proteins encoded by the pol gene of HERV-K have been detected in brain and blood tissues, but transmission of amyotrophic lateral sclerosis has not yet been demonstrated.…”

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

“…Interestingly, it has already been evidenced that HERV-W-Env also displays direct pathogenic effects toward endothelial cells and Schwann cells of peripheral nerves (49,50). This raises questions regarding the comorbidities associated with T1D, such as diabetic vasculopathies and peripheral diabetic neuropathy.…”

“…GNbAC1 is a humanized IgG4 antibody grafted with the 6 complementarity-determining region (CDRs) of an HERV-W-Env-neutralizing clonal hybridoma directed against the HERV-W protein encoded by MSRV-env clone (GenBank, AF331500-1; https://www.ncbi.nlm.nih.gov/genbank/), produced in CHO cells as a recombinant antibody under GMP conditions for therapeutic use. These custom antibodies have already been tested and published in peer-reviewed publications (24,25,30,35,50). GN_mAb_Env04 does not recognize the same epitope that GN_mAb_Env03.…”