Multiple Sclerosis-associated Retrovirus Research Articles

Usefulness of Next-Generation Sequencing in Excluding Bovine Leukemia Virus as a Cause of Adult Camel Leukosis in Dromedaries.

Adult camel leukosis is an emerging hematological and neoplastic disease in dromedaries. It has been hypothesized that bovine leukemia virus (BLV) or its genetic variants may be associated with adult camel leukosis. In this study, we used next-generation sequencing (NGS) to detect all possible viruses in five lung samples from five dromedaries with histopathological evidence of adult camel leukosis and four tissue samples from two control dromedaries. A total throughput of 114.7 Gb was achieved, with an average of 12.7 Gb/sample. For each sample, all the pair-end 151-bp reads were filtered to remove rRNA sequences, bacterial genomes and redundant sequences, resulting in 1-7 Gb clean reads, of which <3% matched to viruses. The largest portion of these viral sequences was composed of bacterial phages. About 100-300 reads in each sample matched "multiple sclerosis-associated retrovirus", but manual analysis showed that they were only repetitive sequences commonly present in mammalian genomes. All viral reads were also extracted for analysis, confirming that no BLV or its genetic variants or any other virus was detected in the nine tissue samples. NGS is not only useful for detecting microorganisms associated with infectious diseases, but also important for excluding an infective cause in scenarios where such a possibility is suspected.

CancerHERVdb: Human Endogenous Retrovirus (HERV) Expression Database for Human Cancer Accelerates Studies of the Retrovirome and Predictions for HERV-Based Therapies.

In this study, we sought to create a database summarizing the expression of human endogenous retroviruses (HERVs) in various human cancers. HERVs are suitable therapeutic targets due to their abundance in the human genome, overexpression in various malignancies, and involvement in various cancer pathways. We identified articles on HERVs from PubMed and then prescreened and automatically categorized them using the portable document format (PDF) data extractor (PDE) R package. We discovered 196 primary research articles with HERV expression data from cancer tissues or cancer cell lines. HERV RNA and protein expression was reported in brain, breast, cervical, colorectal, endocrine, gastrointestinal, kidney/renal/pelvis, liver, lung, genital, oral cavity, pharynx, ovary, pancreas, prostate, skin, testicular, urinary/bladder, and uterus cancers, leukemias, lymphomas, and myelomas. Additionally, we discovered reports of HERV RNA-only overexpression in soft tissue cancers including heart, thyroid, bone, and joint cancers. The CancerHERVdb database is hosted in the form of interactive visualizations of the expression data and a summary data table at https://erikstricker.shinyapps.io/cancerHERVdb/. The user can filter the findings according to cancer type, HERV family, HERV gene, or a combination thereof and easily export the results with the corresponding reference list. In our report, we provide examples of potential uses of the CancerHERVdb, such as identification of cancers suitable for off-target treatment with the multiple sclerosis-associated retrovirus (MSRV)-Env-targeting antibody GNbAC1 (now named temelimab) currently in phase 2b clinical trials for multiple sclerosis or the discovery of cancers overexpressing HERV-H long terminal repeat-associating 2 (HHLA2), a newly emerging immune checkpoint. In summary, the CancerHERVdb allows cross-study comparisons, encourages data exploration, and informs about potential off-target effects of HERV-targeting treatments. IMPORTANCE Human endogenous retroviruses (HERVs), which in the past have inserted themselves in various regions of the human genome, are to various degrees activated in virtually every cancer type. While a centralized naming system and resources summarizing HERV levels in cancers are lacking, the CancerHERVdb database provides a consolidated resource for cross-study comparisons, data exploration, and targeted searches of HERV activation. The user can access data extracted from hundreds of articles spanning 25 human cancer categories. Therefore, the CancerHERVdb database can aid in the identification of prognostic and risk markers, drivers of cancer, tumor-specific targets, multicancer spanning signals, and targets for immune therapies. Consequently, the CancerHERVdb database is of direct relevance for clinical as well as basic research.

Pregnancy Is Associated with Impaired Transcription of Human Endogenous Retroviruses and of TRIM28 and SETDB1, Particularly in Mothers Affected by Multiple Sclerosis

Accumulating evidence highlights the pathogenetic role of human endogenous retroviruses (HERVs) in eliciting and maintaining multiple sclerosis (MS). Epigenetic mechanisms, such as those regulated by TRIM 28 and SETDB1, are implicated in HERV activation and in neuroinflammatory disorders, including MS. Pregnancy markedly improves the course of MS, but no study explored the expressions of HERVs and of TRIM28 and SETDB1 during gestation. Using a polymerase chain reaction real-time Taqman amplification assay, we assessed and compared the transcriptional levels of pol genes of HERV-H, HERV-K, HERV-W; of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis associated retrovirus (MSRV); and of TRIM28 and SETDB1 in peripheral blood and placenta from 20 mothers affected by MS; from 27 healthy mothers, in cord blood from their neonates; and in blood from healthy women of child-bearing age. The HERV mRNA levels were significantly lower in pregnant than in nonpregnant women. Expressions of all HERVs were downregulated in the chorion and in the decidua basalis of MS mothers compared to healthy mothers. The former also showed lower mRNA levels of HERV-K-pol and of SYN1, SYN2, and MSRV in peripheral blood. Significantly lower expressions of TRIM28 and SETDB1 also emerged in pregnant vs. nonpregnant women and in blood, chorion, and decidua of mothers with MS vs. healthy mothers. In contrast, HERV and TRIM28/SETDB1 expressions were comparable between their neonates. These results show that gestation is characterized by impaired expressions of HERVs and TRIM28/SETDB1, particularly in mothers with MS. Given the beneficial effects of pregnancy on MS and the wealth of data suggesting the putative contribution of HERVs and epigenetic processes in the pathogenesis of the disease, our findings may further support innovative therapeutic interventions to block HERV activation and to control aberrant epigenetic pathways in MS-affected patients.

Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder.

Human endogenous retroviruses (HERVs) are relics of ancestral infections and represent 8% of the human genome. They are no longer infectious, but their activation has been associated with several disorders, including neuropsychiatric conditions. Enhanced expression of HERV-K and HERV-H envelope genes has been found in the blood of autism spectrum disorder (ASD) patients, but no information is available on syncytin 1 (SYN1), SYN2, and multiple sclerosis-associated retrovirus (MSRV), which are thought to be implicated in brain development and immune responses. HERV activation is regulated by TRIM28 and SETDB1, which are part of the epigenetic mechanisms that organize the chromatin architecture in response to external stimuli and are involved in neural cell differentiation and brain inflammation. We assessed, through a PCR realtime Taqman amplification assay, the transcription levels of pol genes of HERV-H, -K, and -W families, of env genes of SYN1, SYN2, and MSRV, as well as of TRIM28 and SETDB1 in the blood of 33 ASD children (28 males, median 3.8 years, 25–75% interquartile range 3.0–6.0 y) and healthy controls (HC). Significantly higher expressions of TRIM28 and SETDB1, as well as of all the HERV genes tested, except for HERV-W-pol, were found in ASD, as compared with HC. Positive correlations were observed between the mRNA levels of TRIM28 or SETDB1 and every HERV gene in ASD patients, but not in HC. Overexpression of TRIM28/SETDB1 and several HERVs in children with ASD and the positive correlations between their transcriptional levels suggest that these may be main players in pathogenetic mechanisms leading to ASD.

Epstein-Barr Virus Load Correlates with Multiple Sclerosis-Associated Retrovirus Envelope Expression.

pHERV-W ENV and syncytin-1, the envelope proteins of the human endogenous retrovirus W family (HERV-W), have been proposed as etiological factors for MS development. In addition, herpesviruses, such as the Epstein-Barr virus (EBV) and the human herpesvirus 6A/B (HHV-6A/B), have been also strongly associated with the disease. This work aims to study the possible link between viral loads and antibody titers against EBV and HHV-6A/B and the pHERV-W ENV/syncytin-1 protein/gene expression. For this purpose, we conducted a 12-month longitudinal study involving 98 RRMS patients. Peripheral blood samples were obtained from each patient. Serum antibody titers against EBV and HHV-6A/B were determined by ELISA, while viral loads were analyzed using qPCR. HLA MS-related alleles were also genotyped. pHERV-W ENV/syncytin-1 protein and gene expression levels in immune cells were assessed by flow cytometry and qPCR, respectively. We found that the 12-month variation of the pHERV-W ENV gene expression levels positively correlated with the variation of the EBV viral load, especially in those patients with high baseline EBV loads. Therefore, these results could support previous studies pointing to the transactivation of pHERV-W ENV by EBV. However, further studies are needed to better understand this possible relationship.

Evolution of antibody titres against Epstein\u2013Barr virus and human herpesvirus 6A/B and expression of multiple sclerosis-associated retrovirus in the serum of pregnant multiple sclerosis patients

Epstein–Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls—P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods.

Role of Viral Infections in Multiple Sclerosis Pathogenesis among Indian Population.

The role of viral infections in multiple sclerosis (MS) pathogenesis is unclear. Certain neurotropic viruses previously linked with MS among white population were studied including Epstein-Barr virus, human herpesvirus-6 (HHV-6) and MS-associated retrovirus (MSRV). Sixty-two MS patients (37 had a recent clinical relapse) and 65 controls with other neurological disorders were included. Blood and cerebrospinal fluid (CSF) samples were obtained and processed with the primary objective of determining whether there was intrathecal multiplication of viruses under study (EBV, HHV6 A and B and human endogenous retrovirus) or a breach in blood-brain barrier associated with viral presence in both peripheral blood and CSF. Evidence of breach in blood-brain barrier was seen in 86.5% of patients as evidenced by abnormal CSF/serum albumin index and or MRI. EBV nuclear antigen (EBNA1 IgG) was seen in 89% of MS patients and 58% controls (P = <0.001). However, HHV6 IgG was similar in both groups (85% versus 81%; P = 0.45). In affinity immunoblotting reaction intrathecal IgG synthesis against EBNA1 antigen was demonstrable in 26% (16/62) of patients and none against HHV6. A subset of patients showed significant elevation in mean copy number of plasma EBV DNA during relapse and there was a trend for the same among patients harboring HHV-6B. No evidence of isolated intrathecal viral presence or multiplication was seen. The results of our study suggest that viruses studied namely EBV and HHV6 have a role in triggering relapses through a peripheral mechanism, rather than a direct role through intrathecal multiplication.

The Relationship of the Mechanisms of the Pathogenesis of Multiple Sclerosis and the Expression of Endogenous Retroviruses.

Simple SummaryMultiple sclerosis is a neurodegenerative disease of the central nervous system, develops at an early age and often leads to a disability. The etiological cause of the disease has not been fully elucidated, and as a result, no effective treatment is available. This review summarizes the current knowledge about the relationship between the expression of human endogenous retroviruses and the pathogenesis of multiple sclerosis. The epigenetic mechanisms of transcriptional regulation, the role of transcription factors, cytokines, and exogenous viruses are also addressed in this review. The elucidation of the mechanisms of an increase in endogenous retrovirus expression in multiple sclerosis could help to develop therapeutic strategies and novel methods for early diagnosis and treatment of the disease.Two human endogenous retroviruses of the HERV-W family can act as cofactors triggering multiple sclerosis (MS): MS-associated retrovirus (MSRV) and ERVWE1. Endogenous retroviral elements are believed to have integrated in our ancestors’ DNA millions of years ago. Their involvement in the pathogenesis of various diseases, including neurodegenerative pathologies, has been demonstrated. Numerous studies have shown a correlation between the deterioration of patients’ health and increased expression of endogenous retroviruses. The exact causes and mechanisms of endogenous retroviruses activation remains unknown, which hampers development of therapeutics. In this review, we will summarize the main characteristics of human endogenous W retroviruses and describe the putative mechanisms of activation, including epigenetic mechanisms, humoral factors as well as the role of the exogenous viral infections.

PHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

Induction of Proinflammatory Multiple Sclerosis-Associated Retrovirus Envelope Protein by Human Herpesvirus-6A and CD46 Receptor Engagement.

The aberrant expression of human endogenous retrovirus (HERV) elements of the HERV-W family has been associated with different diseases, including multiple sclerosis (MS). In particular, the expression of the envelope protein (Env) from the multiple sclerosis-associated retrovirus (MSRV), a member of HERV-W family and known for its potent proinflammatory activity, is repeatedly detected in the brain lesions and blood of MS patients. Furthermore, human herpesvirus 6 (HHV-6) infection has long been suspected to play a role in the pathogenesis of MS and neuroinflammation. We show here that both HHV-6A and stimulation of its receptor, transmembrane glycoprotein CD46, induce the expression of MSRV-Env. The engagement of extracellular domains SCR3 and SCR4 of CD46-Cyt1 isoform was required for MSRV-env transactivation, limiting thus the MSRV-Env induction to the CD46 ligands binding these domains, including C3b component of complement, specific monoclonal antibodies, and both infectious and UV-inactivated HHV-6A, but neither HHV-6B nor measles virus vaccine strain. Induction of MSRV-Env required CD46 Cyt-1 singling and was abolished by the inhibitors of protein kinase C. Finally, both membrane-expressed and secreted MSRV-Env trigger TLR4 signaling, displaying thus a proinflammatory potential, characteristic for this viral protein. These data expand the specter of HHV-6A effects in the modulation of the immune response and support the hypothesis that cross-talks between exogenous and endogenous viruses may contribute to inflammatory diseases and participate in neuroinflammation. Furthermore, they reveal a new function of CD46, known as an inhibitor of complement activation and receptor for several pathogens, in transactivation of HERV env genes, which may play an important role in the pathogenesis of inflammatory diseases.

Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses.

The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS-associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis.

Monitoring the Transcriptional Activity of Human Endogenous Retroviral HERV-W Family Using PNA Strand Invasion into Double-Stranded DNA

In the presented assay, we elaborated a method for distinguishing sequences that are genetically closely related to each other. This is particularly important in a situation where a fine balance of the allele abundance is a point of research interest. We developed a peptide nucleic acid (PNA) strand invasion technique for the differentiation between multiple sclerosis-associated retrovirus (MSRV) and ERVWE1 sequences, both molecularly similar, belonging to the human endogenous retrovirus HERV-W family. We have found that this method may support the PCR technique in screening for minor alleles which, in certain conditions, may be undetected by the standard PCR technique. We performed the analysis of different ERVWE1 and MSRV template mixtures ranging from 0 to 100% of ERVWE1 in the studied samples, finding the linear correlation between template composition and signal intensity of final reaction products. Using the PNA strand invasion assay, we were able to estimate the relative ERVWE1 expression level in human specimens such as U-87 MG, normal human astrocytes cell lines and placental tissue. The results remained in concordance with those obtained by semi-quantitative or quantitative PCR.

The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis

Two human endogenous retroviruses of the HERV-W family are proposed as multiple sclerosis (MS) co-factors: MS-associated retrovirus (MSRV) and ERVWE1, whose env proteins showed several potentially neuropathogenic features, in vitro and in animal models. Phase II clinical trials against HERV-Wenv are ongoing. HERV-W/MSRV was repeatedly found in MS patients, in striking parallel with MS stages, active/remission phases, and therapy outcome. The HERV-Wenv protein is highly expressed in active MS plaques. Early MSRV presence in spinal fluids predicted worst MS progression 10 years in advance. Effective anti-MS therapies strongly reduced MSRV/Syncytin-1/HERV-W expression. The Epstein–Barr virus (EBV) activates HERV-W/MSRV in vitro and in vivo, in patients with infectious mononucleosis and controls with high anti-EBNA1-IgG titers. Thus, the two main EBV/MS links (infectious mononucleosis and high anti-EBNA1-IgG titers) are paralleled by activation of HERV-W/MSRV. It is hypothesized that EBV may act as initial trigger of future MS, years later, by activating MSRV, which would act as direct neuropathogenic effector, before and during MS.

Multiple sclerosis-associated retrovirus, Epstein-Barr virus, and vitamin D status in patients with relapsing remitting multiple sclerosis.

The relationship between infections and autoimmune diseases is complex and there are several reports highlighting the role of human endogenous retroviruses (HERVs) in these patients. The levels of multiple sclerosis-associated retrovirus (MSRV)-type DNA of Env gene was measured in peripheral blood mononuclear cells from 52 patients with relapsing-remitting multiple sclerosis (RRMS) and 40 healthy controls using specific quantitative PCR (qPCR) analysis. Furthermore, we analyzed the status of HERV-W/MSRV in these patients with regards to both EBV (DNA load and anti-EBNA1 IgG antibody) and vitamin D concentration. MSRV DNA copy number were significantly higher in RRMS patients than healthy controls (P < 0.0001). Interestingly, an inverse correlation was found between MSRV DNA copy number and serum vitamin D concentration (P < 0.01), but not for EBV load or anti-EBNA-1 IgG antibody.

The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis.

BackgroundThe interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS.ObjectiveTo perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients.MethodsMedline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association.Results43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W (MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF.ConclusionsThis systematic review and meta-analysis shows an association between expression of HERVs, and in particular the HERV-W family, and MS.

The application of strand invasion phenomenon, directed by peptide nucleic acid (PNA) and single-stranded DNA binding protein (SSB) for the recognition of specific sequences of human endogenous retroviral HERV-W family.

The HERV-W family of human endogenous retroviruses represents a group of numerous sequences that show close similarity in genetic composition. It has been documented that some members of HERV-W-derived expression products are supposed to play significant role in humans' pathology, such as multiple sclerosis or schizophrenia. Other members of the family are necessary to orchestrate physiological processes (eg, ERVWE1 coding syncytin-1 that is engaged in syncytiotrophoblast formation). Therefore, an assay that would allow the recognition of particular form of HERV-W members is highly desirable. A peptide nucleic acid (PNA)-mediated technique for the discrimination between multiple sclerosis-associated retrovirus and ERVWE1 sequence has been developed. The assay uses a PNA probe that, being fully complementary to the ERVWE1 but not to multiple sclerosis-associated retrovirus (MSRV) template, shows high selective potential. Single-stranded DNA binding protein facilitates the PNA-mediated, sequence-specific formation of strand invasion complex and, consequently, local DNA unwinding. The target DNA may be then excluded from further analysis in any downstream process such as single-stranded DNA-specific exonuclease action. Finally, the reaction conditions have been optimized, and several PNA probes that are targeted toward distinct loci along whole HERV-W env sequences have been evaluated. We believe that PNA/single-stranded DNA binding protein-based application has the potential to selectively discriminate particular HERV-W molecules as they are at least suspected to play pathogenic role in a broad range of medical conditions, from psycho-neurologic disorders (multiple sclerosis and schizophrenia) and cancers (breast cancer) to that of an auto-immunologic background (psoriasis and lupus erythematosus).

A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs).

Although multiple sclerosis (MS) is one of the most common central nervous system diseases in young adults, little is known about its etiology. Several human endogenous retroviruses (ERVs) are considered to play a role in MS. We are interested in which ERVs can be identified in the vicinity of MS associated genetic marker to find potential initiators of MS. We analysed the chromosomal regions surrounding 58 single nucleotide polymorphisms (SNPs) that are associated with MS identified in one of the last major genome wide association studies. We scanned these regions for putative endogenous retrovirus sequences with large open reading frames (ORFs). We observed that more retrovirus-related putative ORFs exist in the relatively close vicinity of SNP marker indices in multiple sclerosis compared to control SNPs. We found very high homologies to HERV-K, HCML-ARV, XMRV, Galidia ERV, HERV-H/env62 and XMRV-like mouse endogenous retrovirus mERV-XL. The associated genes (CYP27B1, CD6, CD58, MPV17L2, IL12RB1, CXCR5, PTGER4, TAGAP, TYK2, ICAM3, CD86, GALC, GPR65 as well as the HLA DRB1*1501) are mainly involved in the immune system, but also in vitamin D regulation. The most frequently detected ERV sequences are related to the multiple sclerosis-associated retrovirus, the human immunodeficiency virus 1, HERV-K, and the Simian foamy virus. Our data shows that there is a relation between MS associated SNPs and the number of retroviral elements compared to control. Our data identifies new ERV sequences that have not been associated with MS, so far.

Human endogenous retrovirus W in brain lesions: Rationale for targeted therapy in multiple sclerosis

Background objectiveAttempts to identify a causative agent of Multiple Sclerosis (MS) among environmental viruses have consistently failed suggesting that development of MS is a result from gene-environment interactions. A new pathogenic player within human genes, a human endogenous retrovirus (HERV) was identified from MS cells, named MS-associated retrovirus element (MSRV) and unveiled homologous multicopy HERVs (HERV-W). As independent studies revealed biological features of HERV-W on immune-mediated inflammation and on remyelinating cells, the present study characterized the presence of HERV-W envelope protein (MSRV-Env) at the cellular level, in different MS lesion stages to extend and validate previous studies. MethodsImmunohistological analysis of HERV-W envelope cellular expression in different lesion stages from a cohort of MS brains versus controls, using well-characterized and highly specific monoclonal antibodies. ResultsHERV-W envelope protein was detected in all MS brains and quite essentially in lesions. Immunohistochemistry showed dominant expression in macrophages and microglia, coinciding with areas of active demyelination, spread over the active lesions, or limited to the rim of active microglia in chronic active lesions or in few surviving astrocytes of inactive plaques. Weak expression was seen in MS normal appearing white matter. In active plaques, few lymphoid cells and astrocytes were also stained. This HERV-W expression was not observed in control brains. InterpretationHERV-W was expressed in demyelinated lesions from MS brains, which were all positive for this endogenous pathogenic protein. Pronounced HERV-W immunoreactivity in active MS lesions was intimately associated with areas of active demyelination throughout the successive stages of lesion evolution in MS brains. Based on its pathogenic potential, this HERV-W (MSRV) endogenous toxin thus appears to be a novel therapeutic target in MS. It also has a unique positioning as an early and lifelong expressed pathogenic agonist, acting upstream the pathways in which dysregulated physiological effectors are usually targeted by present therapeutic strategies for MS.

Multiple Sclerosis between Genetics and Infections: Human Endogenous Retroviruses in Monocytes and Macrophages.

The etiology of multiple sclerosis (MS) is still unknown, but there is strong evidence that genetic predisposition associated with environmental factors can trigger the disease. An estimated 30 million years ago, exogenous retroviruses are thought to have integrated themselves into human germ line cells, becoming part of human DNA and being transmitted over generations. Usually such human endogenous retroviruses (HERVs) are silenced or expressed at low levels, but in some pathological conditions, such as MS, their expression is higher than that in the healthy population. Three HERV families have been associated with MS: HERV-H, HERV-K, and HERV-W. The envelope protein of MS-associated retrovirus (MSRV) from the HERV-W family currently has the strongest evidence as a potential trigger for MS. In addition to expression in peripheral immune cells, MSRV is expressed in monocytes and microglia in central nervous system lesions of people with MS and, through the activation of toll-like receptor 4, it has been shown to drive the production of proinflammatory cytokines, reduction of myelin protein expression, and death of oligodendrocyte precursors. In conclusion, the association between HERVs and MS is well documented and a pathological role for MSRV in MS is plausible. Further studies are required to determine whether the presence of these HERVs is a cause or an effect of immune dysregulation in MS.

Treatment Against Human Endogenous Retrovirus: A Possible Personalized Medicine Approach for Multiple Sclerosis

Human endogenous retroviruses (HERV) represent about 8% of the human genome. Some of these genetic elements are expressed in pathological circumstances. A HERV protein, the multiple sclerosis-associated retrovirus (MSRV) envelope protein (MSRV-Env), is expressed in the blood and active brain lesions of multiple sclerosis (MS) patients. It possesses pro-inflammatory and myelinotoxic properties. The patterns of expression and pathogenic properties of MSRV-Env make it a relevant drug target for MS therapeutics-in particular for preventing neurodegeneration, a key component of progressive forms of MS. An immunoglobulin G4 monoclonal antibody (mAb), called GNbAC1, has been developed to neutralize this pathogenic target. After showing neutralizing effects in vitro and in mouse models of MS, GNbAC1 is now in phase II clinical development. MSRV-related biomarkers such as MSRV-Env and MSRV polymerase (MSRV-Pol) gene transcripts are overexpressed in the blood and cerebrospinal fluid of patients with MS. These biomarkers may have prognostic value for long-term MS evolution, and their transcription levels in blood decline during treatments with GNbAC1, which has also been reported in patients administered reference MS drugs such as natalizumab or interferon-β. GNbAC1 as a new MSRV-Env-antagonist mAb could be a specific and causal treatment for MS, with a particular application for progressive forms of the disease. For possible use in companion diagnostic tests, MSRV-associated biomarkers could open the door to a personalized therapeutic approach for MS.