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.

Falling fowl of the chicken reference genome: pitfalls of studying polymorphic endogenous retroviruses.

High quality reference genomes have facilitated the study of endogenous retroviruses (ERVs). However, there are an increasing number of published works which assume the ERVs in reference genomes are universal; even those of evolutionarily recent integrations. Consequently, these studies fail to properly characterise polymorphic ERVs, and even propose biological functions for ERVs that may not actually be present in the genomes of interest. Here, I outline the pitfalls of three studies of chicken endogenous Avian Leukosis Viruses (ALVEs or "ev genes": the "original" ERVs), all confounded by the assumption that the reference genome provides a representative ALVE baseline.

Infectivity assessment of porcine endogenous retrovirus using high-throughput sequencing technologies.

Xenogenic cell-based therapeutic products are expected to alleviate the chronic shortage of human donor organs. For example, porcine islet cell products are currently under development for the treatment of human diabetes. As porcine cells possess endogenous retrovirus (PERV), which can replicate in human cells in vitro, the potential transmission of PERV has raised concerns in the case of products that use living pig cells as raw materials. Although several PERV sequences exist in the porcine genome, not all have the ability to infect human cells. Therefore, polymerase chain reaction analysis, which amplifies a portion of the target gene, may not accurately assess the infection risk. Here, we determined porcine genome sequences and evaluated the infectivity of PERVs using high-throughput sequencing technologies. RNA sequencing was performed on both PERV-infected human cells and porcine cells, and reads mapped to PERV sequences were examined. The normalized number of the reads mapped to PERV regions was able to predict the infectivity of PERVs, indicating that it would be useful for evaluation of the PERV infection risk prior to transplantation of porcine products.

Vitamin D, Epstein-Barr virus, and endogenous retroviruses in multiple sclerosis - facts and hypotheses.

The pathogenesis of multiple sclerosis (MS) remains poorly understood. Presumably, MS is caused by multiple environmental, epigenetic, and genetic factors. Among them, human endogenous retroviruses (HERVs), Epstein-Barr virus (EBV) and vitamin D have been suggested to play a role in the pathogenesis and course of MS. Because vitamin D can affect the immune system and infections, it can be hypothesized that there is a close interplay between vitamins, EBV and ERV in the pathogenesis of MS. Here, we summarize the important data on vitamin D, including polymorphisms in genes related to vitamin D metabolism, EBV and ERV, in the pathogenesis of MS and create hypotheses regarding their interactions. Data indicate that vitamin D has a strong impact on viral infections and interferes with EBV infection, while EBV is capable of activating silent ERVs. We believe that EBV could be the missing link between vitamin D and ERV in MS pathogenesis.

Activation of Endogenous Retrovirus, Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer's Disease.

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer's disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.

KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control.

Endogenous retroviruses (ERVs) have accumulated in vertebrate genomes and contribute to the complexity of gene regulation. KAP1 represses ERVs during development by its recruitment to their repetitive sequences through KRAB zinc-finger proteins (KZNFs), but little is known about the regulation of ERVs in adult tissues. We observed that KAP1 repression of HERVK14C was conserved in differentiated human cells and performed KAP1 knockout to obtain an overview of KAP1 function. Our results show that KAP1 represses ERVs (including HERV-T and HERV-S) and ZNF genes, both of which overlap with KAP1 binding sites and H3K9me3 in multiple cell types. Furthermore, this pathway is functionally conserved in adult human peripheral blood mononuclear cells. Cytosine methylation that acts on KAP1 regulated loci is necessary to prevent an interferon response, and KAP1-depletion leads to activation of some interferon-stimulated genes. Finally, loss of KAP1 leads to a decrease in H3K9me3 enrichment at ERVs and ZNF genes and an RNA-sensing response mediated through MAVS signaling. These data indicate that the KAP1-KZNF pathway contributes to genome stability and innate immune control in adult human cells.

Characterization of porcine endogenous retrovirus particles released by the CRISPR/Cas9 inactivated cell line PK15 clone 15.

The infection of human transplant recipients by porcine endogenous retrovirus (PERV) is a safety issue for xenotransplantation (XTx). CRISPR/Cas9 technology has enabled the generation of pigs free of functional PERVs, and the susceptibility of these animals to reinfection by PERVs remains unclear. To assess virological safety, we characterized a cell line in which PERVs have been inactivated by CRISPR/Cas9 (PK15 clone 15) for its susceptibility to infectious PERV. First, basal expression of PERV pol, the porcine PERV-A receptor (POPAR), and reverse transcriptase (RT) activity of PERV were determined. PK15 clone 15 cells were inoculated with PERV and monitored post infection for virus expression and RT activity. Particles were visualized by electron microscopy. Our data show that PK15 clone 15 cells still produce viral proteins that assemble to produce impaired viral particles. These virions have an irregular morphology that diverges from that of mature wild type. The particles are no longer infectious when tested in a downstream infection assay using supernatants of PK15 clone 15 cells to infect susceptible swine testis-IOWA (ST-IOWA) cells. The expression of POPAR was quantified to exclude the possibility that lack of susceptibility to reinfection, for PERV-A, is caused by absence of viral host receptor(s). PK15 and PK15 clone 15 cells do, in fact, express POPAR equally. PERV RT inactivation mediated by CRISPR/Cas9 does not compromise virus assembly but affects virion structure and proviral integration. The constitutive virion production seems to maintain cellular resistance to superinfection and possibly indicates a protective side effect of this specific CRISPR/Cas9 mediated RT inactivation.

Decellularized pig pulmonary heart valves-Depletion of nucleic acids measured by proviral PERV pol.

BACKGROUND: Decellularized human pulmonary heart valve (dhHV) scaffolds have been shown to be the gold standard especially for younger, adolescent patients. However, human heart valves are limited in availability. Xenogeneic decellularized pig heart valves (dpHV) may serve as alternative. METHODS: The efficacy of DNA reduction processes upon decellularization of heart valves from German Landrace pigs was analyzed by measurements of remaining nucleic acids including proviral porcine endogenous retrovirus (PERV) sequences. Porcine pulmonary heart valves (pPHV) were decellularized by three different protocols and further treated with DNaseI or Benzonase, at varying incubation times. DNA isolated from valve associated muscle (m), valve cusp (c), and pulmonary artery (pa) was monitored by PCR and qRT-PCR using GAPDH and the PERV polymerase (pol) for read-out. RESULTS: Decellularization of pPHV led to a significant reduction of DNA (>99%) which could be further significantly increased for (m) and (pa) by nuclease treatment, reducing proviral PERV pol from approximately 5 × 107 to 5 × 103  copies/mg in nuclease treated tissues. CONCLUSIONS: Both nucleases demonstrated comparable activities. But DNaseI revealed to be less consistent for PERV, especially at muscular tissue. Noteworthy, remaining proviral sequences are still detectable by PCR; however, due to the absence of the cellular replication machinery the production of infectious particles is not expected. Decellularization and nuclease treatment of pPHV is an efficient procedure to reduce the DNA content including PERV, thus represents a valuable option to increase virus safety independently from the source animal background.

Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer's disease?

HIV infection in the combination antiretroviral therapy (cART) era has become a chronic disease with a life expectancy almost identical to those free from this infection. Concomitantly, chronic diseases such as neurodegenerative diseases have emerged as serious clinical problems. HIV-induced cognitive changes, although clinically very diverse are collectively called HIV-associated neurocognitive disorder (HAND). HAND, which until the introduction of cART manifested clinically as a subcortical disorder, is now considered primarily cognitive disorder, which makes it similar to diseases like Alzheimer's (AD) and Parkinson's disease (PD). The pathogenesis involves either the direct effects of the virus or the effect of viral proteins such as Tat, Ggp120, and Nef. These proteins are either capable of destroying neurons directly by inducing neurotoxic mediators or by initiating neuroinflammation by microglia and astrocytes. Recently, it has become recognized that HIV infection is associated with increased production of the beta-amyloid peptide (Aß) which is a characteristic of AD. Moreover, amyloid plaques have also been demonstrated in the brains of patients suffering from HAND. Thus, the question arises whether this production of Aß indicates that HAND may lead to AD or it is a form of AD or this increase in Aß production is only a bystander effect. It has also been discovered that APP in HIV and its metabolic product Aß in AD manifest antiviral innate immune peptide characteristics. This review attempts to bring together studies linking amyloid precursor protein (APP) and Aß production in HIV infection and their possible impact on the course of HAND and AD. These data indicate that human defense mechanisms in HAND and AD are trying to contain microorganisms by antimicrobial peptides, however by employing different means. Future studies will, no doubt, uncover the relationship between HAND and AD and, hopefully, reveal novel treatment possibilities.

Human Endogenous Retroviruses and Type 1 Diabetes.

PURPOSE OF THE REVIEW: The aim of this review is to discuss recent data pointing at an involvement of human endogenous retroviruses (HERVs) in type 1 diabetes (T1D) onset and progression. RECENT FINDINGS: The envelope protein of HERV-W family, named HERV-W-Env, was detected in pancreata from T1D patients and was shown to display pro-inflammatory properties and direct toxicity toward pancreatic beta cells. The etiopathogenesis of T1D remains elusive, even if conventional environmental viral infections have been recurrently involved. Nonetheless, a new category of pathogens may provide the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. A number of studies have now shown that HERV sequences, which are normally inactivated or repressed in the human genome, could be activated by environmental viruses. Thus, if similarly activated by viruses associated with T1D, disregarded HERV genes may underlie T1D genetic susceptibility. Moreover, once expressed, HERV elements may display broad pathogenic properties, which identify them as potential new therapeutic targets.

Expression profile of human porcine endogenous retrovirus A receptors (HuPAR-1, HuPAR-2) and transcription factor activator protein-2γ (TFAP-2C) genes in infected human fibroblasts-Model in vitro.

BACKGROUND: Xenotransplantation of porcine tissues raises concerns, especially in the context of the potential interspecies transmission of porcine endogenous retroviruses (PERVs). To date, the possibility of PERV infections of various human cells has been confirmed in vitro. PERVs infect cells coupling viral Env protein with adequate functional receptor on the surface of the host cell. So far, two PERV-A receptors have been described in humans: HuPAR-1 and HuPAR-2. TFAP-2C was described as one of the transcription factors engaged in the expression of HuPAR-2. METHODS: Bacterial LPS, well known as a strong inflammation inducer, was used in this study to stimulate changes of the expression profile of inflammation-related genes in human cells in vitro. The aim of the study was to investigate the expression profile of HuPAR-1 and HuPAR-2 and TFAP-2C genes in human NHDF cells treated with LPS and/or infected with PERVs from PK15 cells. PERV infection and expression was confirmed by qPCR and RTqPCR. The expression of HuPAR-1, HuPAR-2, and TFAP-2C genes was studied using HGU 133A 2.0 microarrays and RTqPCR. RESULTS: NHDF cells expressed both HuPAR-1 and HuPAR-2 genes with a higher expression of HuPAR-1. LPS down-regulated the expression of HuPAR-1 and TFAP-2C in NHDF cells, but had no effect on HuPAR-2 expression. These changes induced by LPS were more pronounced in the presence of PERV infection. CONCLUSION: As reported previously, treatment of NHDF cells with LPS decreased PERV-A provirus integration and increased PERV-A mRNA expression. PERV infection alone did not modulate the expression of HuPAR-1, HuPAR-2, and TFAP-2C. This is the first study analyzing the expression profile of HuPAR-1, HuPAR-2, and TFAP-2C in NHDF cells treated by LPS and/or infected by PERVs.

Endogenous Retroviruses Activity as a Molecular Signature of Neurodevelopmental Disorders.

Human endogenous retroviruses (HERVs) are genetic elements resulting from relics of ancestral infection of germline cells, now recognized as cofactors in the etiology of several complex diseases. Here we present a review of findings supporting the role of the abnormal HERVs activity in neurodevelopmental disorders. The derailment of brain development underlies numerous neuropsychiatric conditions, likely starting during prenatal life and carrying on during subsequent maturation of the brain. Autism spectrum disorders, attention deficit hyperactivity disorders, and schizophrenia are neurodevelopmental disorders that arise clinically during early childhood or adolescence, currently attributed to the interplay among genetic vulnerability, environmental risk factors, and maternal immune activation. The role of HERVs in human embryogenesis, their intrinsic responsiveness to external stimuli, and the interaction with the immune system support the involvement of HERVs in the derailed neurodevelopmental process. Although definitive proofs that HERVs are involved in neurobehavioral alterations are still lacking, both preclinical models and human studies indicate that the abnormal expression of ERVs could represent a neurodevelopmental disorders-associated biological trait in affected individuals and their parents.

Susceptibility of Human Endogenous Retrovirus Type K to Reverse Transcriptase Inhibitors.

Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV type K (HERV-K) HML-2 (HK2) family contains proviruses that are the most recent entrants into the human germ line and are transcriptionally active. In HIV-1 infection and cancer, HK2 genes produce retroviral particles that appear to be infectious, yet the replication capacity of these viruses and potential pathogenicity has been difficult to ascertain. In this report, we screened the efficacy of commercially available reverse transcriptase inhibitors (RTIs) at inhibiting the enzymatic activity of HK2 RT and HK2 genomic replication. Interestingly, only one provirus, K103, was found to encode a functional RT among those examined. Several nucleoside analogue RTIs (NRTIs) blocked K103 RT activity and consistently inhibited the replication of HK2 genomes. The NRTIs zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), and the nucleotide RTI inhibitor tenofovir (TDF), show efficacy in blocking K103 RT. HIV-1-specific nonnucleoside RTIs (NNRTIs), protease inhibitors (PIs), and integrase inhibitors (IIs) did not affect HK2, except for the NNRTI etravirine (ETV). The inhibition of HK2 infectivity by NRTIs appears to take place at either the reverse transcription step of the viral genome prior to HK2 viral particle formation and/or in the infected cells. Inhibition of HK2 by these drugs will be useful in suppressing HK2 infectivity if these viruses prove to be pathogenic in cancer, neurological disorders, or other diseases associated with HK2. The present studies also elucidate a key aspect of the life cycle of HK2, specifically addressing how they do, and/or did, replicate.IMPORTANCE Endogenous retroviruses are relics of ancestral virus infections in the human genome. The most recent of these infections was caused by HK2. While HK2 often remains silent in the genome, this group of viruses is activated in HIV-1-infected and cancer cells. Recent evidence suggests that these viruses are infectious, and the potential exists for HK2 to contribute to disease. We show that HK2, and specifically the enzyme that mediates virus replication, can be inhibited by a panel of drugs that are commercially available. We show that several drugs block HK2 with different efficacies. The inhibition of HK2 replication by antiretroviral drugs appears to occur in the virus itself as well as after infection of cells. Therefore, these drugs might prove to be an effective treatment by suppressing HK2 infectivity in diseases where these viruses have been implicated, such as cancer and neurological syndromes.

The 2017 IXA Presidential Lecture: Recent developments in xenotransplantation.

The last few years have seen significant progress in xenotransplantation. Porcine xenograft survival in preclinical models continues to improve, accompanied by the adjustment of immunosuppression to more clinically realistic levels. The rapid uptake of CRISPR/Cas9 technology has accelerated the generation of new knock-in and knockout pigs, including animals null for the endogenous retrovirus PERV. This brief review presents a personal view of recent developments in the field.

Porcine endogenous retroviruses: Quantification of the copy number in cell lines, pig breeds, and organs.

BACKGROUND: Porcine endogenous retroviruses (PERVs) may pose a risk of xenotransplantation using porcine cells, tissues, or organs. PERVs are integrated in the genome of all pigs, and some can infect certain human cells. The copy number of PERVs in different pig breeds has been determined by using different methods, with varying results. METHODS: To determine the PERV copy number in pig cell lines and in animals, a new method, droplet digital polymerase chain reaction (ddPCR) was used. DNA was isolated from pig cell lines (PK15 and PTK75 cells), from Aachen, Göttingen, and Black minipigs, and from genetically modified and non-modified German landrace pigs. Primers specific for the polymerase gene (pol) were used for the ddPCR. RESULTS: The median copy number of integrated proviruses was found between 46 and 70 copies in three different PK15 cell lines, 49 copies in PTK75 cells, 64 copies in Göttingen minipigs, 69 copies in Aachen minipigs, 117 copies in Black minipigs, and 59 copies in genetically modified pigs generated for xenotransplantation. PERV copy numbers varied between different organs from a single pig, indicating proviral amplification. The study also revealed that different PK15 cell lines from different laboratories which had been used as virus source for infection experiments carry different PERV copies. Furthermore, different copy numbers of cellular reference genes (GAPDH, ACTB) were detected in different cell lines and pigs. CONCLUSION: The determination of the PERV copy number using ddPCR extended previous data showing differences between the pig breeds and between different organs of a single animal. The determination of PERV copy numbers can be used to select animals less likely to transmit PERVs during xenotransplantation. In addition, this method will be of special value when PERV proviruses are to be inactivated by CRISPR/Cas9.

Examining the potential for porcine-derived islet cells to harbour viral pathogens.

With an onus on safety in the potential use of porcine islet cells as a treatment for diabetes, the use of animals lacking exogenous pathogens is clearly important and multilevel screening strategies have been presented on testing animals and the product. In this study, we wished to investigate whether islet cells indeed harboured the same viral pathogens of concern in the source animal. PMBC and islet cells from both adult and neonatal source animals were directly compared and tested for PCMV, PLHV, PCV2, PPV and HEV using both molecular and serological assays. Adult PBMC were found positive for all viruses with the exception of PCV2 and HEV. Neonatal PBMC were only found positive for PCMV and HEV. All animals were found negative for HEV antibodies. Interestingly, islet cells were negative for all viruses tested regardless of status in the animal-derived PBMC. Given that other laboratories have demonstrated the lack of virus detection during the culture of islets, this study also demonstrates that the hygiene status of the herd may not reflect the status of the product. This is important for establishing guidelines for any risk evaluation and mitigation process utilised during product manufacture.

Assessment of porcine endogenous retrovirus transmission across an alginate barrier used for the encapsulation of porcine islets.

BACKGROUND: Subcutaneous implantation of a macroencapsulated patch containing human allogenic islets has been successfully used to alleviate type 1 diabetes mellitus (T1DM) in a human recipient without the need for immunosuppression. The use of encapsulated porcine islets to treat T1DM has also been reported. Although no evidence of pathogen transfer using this technology has been reported to date, we deemed it appropriate to determine if the encapsulation technology would prevent the release of virus, in particular, the porcine endogenous retrovirus (PERV). METHODS: HEK293 (human epithelial kidney) and swine testis (ST) cells were co-cultured with macroencapsulated pig islets embedded in an alginate patch, macroencapsulated PK15 (swine kidney epithelial) cells embedded in an alginate patch and free PK15 cells. Cells and supernatant were harvested at weekly time points from the cultures for up to 60 days and screened for evidence of PERV release using qRT-PCR to detect PERV RNA and SG-PERT to detect reverse transcriptase (RT). RESULTS: No PERV virus, or evidence of PERV replication, was detected in the culture medium of HEK293 or pig cells cultured with encapsulated porcine islets. Increased PERV activity relative to the background was not detected in ST cells cultured with encapsulated PK15 cells. However, PERV was detected in 1 of the 3 experimental replicates of HEK293 cells cultured with encapsulated PK15 cells. Both HEK293 and ST cells cultured with free PK15 cells showed an increase in RT detection. CONCLUSIONS: With the exception of 1 replicate, there does not appear to be evidence of transmission of replication competent PERV from the encapsulated islet cells or the positive control PK15 cells across the alginate barrier. The detection of PERV would suggest the alginate barrier of this replicate may have become compromised, emphasizing the importance of quality control when producing encapsulated islet patches.

Pan-vertebrate comparative genomics unmasks retrovirus macroevolution.

Although extensive research has demonstrated host-retrovirus microevolutionary dynamics, it has been difficult to gain a deeper understanding of the macroevolutionary patterns of host-retrovirus interactions. Here we use recent technological advances to infer broad patterns in retroviral diversity, evolution, and host-virus relationships by using a large-scale phylogenomic approach using endogenous retroviruses (ERVs). Retroviruses insert a proviral DNA copy into the host cell genome to produce new viruses. ERVs are provirus insertions in germline cells that are inherited down the host lineage and consequently present a record of past host-viral associations. By mining ERVs from 65 host genomes sampled across vertebrate diversity, we uncover a great diversity of ERVs, indicating that retroviral sequences are much more prevalent and widespread across vertebrates than previously appreciated. The majority of ERV clades that we recover do not contain known retroviruses, implying either that retroviral lineages are highly transient over evolutionary time or that a considerable number of retroviruses remain to be identified. By characterizing the distribution of ERVs, we show that no major vertebrate lineage has escaped retroviral activity and that retroviruses are extreme host generalists, having an unprecedented ability for rampant host switching among distantly related vertebrates. In addition, we examine whether the distribution of ERVs can be explained by host factors predicted to influence viral transmission and find that internal fertilization has a pronounced effect on retroviral colonization of host genomes. By capturing the mode and pattern of retroviral evolution and contrasting ERV diversity with known retroviral diversity, our study provides a cohesive framework to understand host-virus coevolution better.

Transposable Elements (Human Endogenous Retroviruses) in Cancer.

Transposable elements (TEs) have shown a great significance in regulatory elements research, being responsible for different types of cancers. They are divided into three classes on the basis of their mode of transposition, structural properties, and their homology with DNA sequence. In evaluating their role in cancers and other pathologies, researchers have found extensive evidence of their involvement. TEs can also be used as genetic markers for cancers and help in identifying potential therapeutic targets. There have been advancements in the management of hepatocellular carcinoma using TEs as regulatory components involved in the cancer's pathogenesis.

Human endogenous retroviruses and multiple sclerosis: Causation, association, or after-effect?

From the early days of MS discovery, infections have been proposed as a possible cause of the disease. In the last three decades, an association between human endogenous retrovirus expression and MS has been further investigated and confirmed. Nevertheless, the role of such retroviruses in the disease needs clarification. In this review, we introduce MSRV/HERV-W and describe its association with MS. We then summarize the evidence for the involvement of MSRV/HERV-W in the aetiology and progression of MS and its possible role as biomarker and drug target. Biological mechanisms for HERV effects in MS may involve the activation of innate immune pathways by the envelope protein of MSRV (MSRVEnv). In addition to in vitro and experimental studies, further insight on how HERVs may influence immune-mediated pathology in MS may also come from the use of antiretroviral treatments in patients.