Next Article in Journal
COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection
Next Article in Special Issue
Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease
Previous Article in Journal
Activatable Nanoparticles: Recent Advances in Redox-Sensitive Magnetic Resonance Contrast Agent Candidates Capable of Detecting Inflammation
Previous Article in Special Issue
Possibility of a New Indication for Amantadine in the Treatment of Bipolar Depression—Case Series Study
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Endogenous Retroviruses in Nervous System Disorders

1
Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, 06120 Halle (Saale), Germany
2
Department of Neurology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
3
Department of Surgical and Conservative Pediatrics and Adolescent Medicine, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2021, 14(1), 70; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010070
Submission received: 21 December 2020 / Revised: 11 January 2021 / Accepted: 13 January 2021 / Published: 16 January 2021
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)

Abstract

:
Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies.

1. Human Endogenous Retroviruses

Approximately 8% of human genomic DNA has high sequence similarity to retroviruses. These so-called human endogenous retroviral elements (HERV) are derived from exogenous retroviruses that have infected germ-line cells during evolution [1]. Once fixed in the population, these genetic elements were inherited as stable genetic components [1]. Some HERV display very high copy numbers, which might be the result of multiple germ line infections or reverse transcriptase-dependent amplification (retro-transposition) [2,3]. A phenomenon common to most HERV families, and particularly evident in HERV-K (HML-2), is their polymorphic nature, meaning that not all individuals have the same set of retroviruses at the same genomic sites. [4,5,6]. Such unfixed proviruses likely arose from divergence of retroviral copies, de novo insertions in the human population, or variable deletion of chromosomes [4,5,6]. As an example, HERV-K113 is present in a maximum of 30% of all individuals, showing a widespread geographic and racial variation [7,8].
Based on their similarity to exogenous viruses, the genomic structures of HERV possess the three viral genes gag (group specific antigens, encodes internal structural proteins), pol (encodes viral enzymes), and env (encodes the envelope protein), which are flanked by regulatory long terminal repeats (LTRs). Additional ERV-derived proteins, which are products of alternative splicing, include the regulatory rec and np9 proteins. However, most of the ERV open reading frames are mutated and cannot produce functional proteins or virions [9]. An earlier genome-wide search revealed only 29 env, 17 gag, and 13 pol open reading frames (ORF) longer than 500 codons, which possibly code for viral proteins, among a total of 38,000 retroviral ORFs examined [10]. The maintenance of ORFs in HERV genomes over many thousands of years of evolution suggests a functional role for these elements. However, an intact ORF alone is not sufficient for protein expression, since HERV are usually epigenetically silenced. Only if HERV become reactivated by intrinsic or extrinsic factors, can viral RNAs and proteins be produced. Their function is largely unknown, even though understanding of their importance has increased in recent years. Both the beneficial and detrimental effects of encoded viral proteins have been reported. Participation in normal physiological processes, such as placental development [11] and modulation of innate immunity [12], shall be mentioned here as examples. Independent of their protein-coding capacity, HERV are able to regulate neighboring genes by providing alternative promoters [13] or by altering the chromatin structure by binding co-repressor proteins like TRIM28 [14,15].
Emerging evidence suggests that members of the HERV-K, HERV-W, and HERV-H families have the potential to regulate immune function [16,17,18,19]. Hence, their aberrant expression has been linked to the development and progression of inflammatory and neurologic diseases, although causal links have yet to be established. In the present review, we will focus on the current state of knowledge on the association of HERV with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other nervous system disorders. Additionally, the potential of HERV as new therapeutic targets will be highlighted. First, however, a general overview is given of how HERV sequences can be reactivated, as this is a basic prerequisite for possible pathogenic effects.

2. Regulation of HERV Expression

To ensure genomic stability and integrity, HERV are usually transcriptionally silent. This is accomplished by DNA methylation and histone modifications [20,21,22,23]. The majority of endogenous retroviral sequences are located in chromosomal regions with repressive, heterochromatic chromatin architecture leading to low transcriptional activity in most cell types [21]. This “epigenetic corset” is established during embryogenesis. However, in early embryonic stages, which are characterized by global hypomethylation, precise regulation of retroviral sequences seems to be involved in physiologic processes such as the induction of viral restriction pathways [24] and the differentiation of stem cells. For instance, neural differentiation involves tight control of HERV-H RNAs via death-associated protein 5 (DAP5, also known as novel APOBEC-1 target 1, NAT1) and the terminal uridyltransferase TUT7 [25]. Similarly, the down-regulation of highly expressed HERV-K (HML-2) envelope protein in pluripotent stem cells results in dissociation of the stem cell colonies and increased differentiation along neuronal pathways [26].
If the epigenetic control machinery becomes impaired, endogenous retroviral sequences can be activated and become transcriptionally active [27,28]. This is particularly evident in cancer because DNA methylation in cancer cells is often severely impaired. As a consequence, the activity of many HERV, particularly HERV-K, is frequently elevated in tumors like melanoma, breast cancer, and astrocytoma (reviewed in [29]). In contrast, development-specific demethylation in placental tissue leads to the physiologically required expression of HERV during placentogenesis. Syncytin-1, the envelope protein of the HERV-W family member HERVWE1, was shown to contribute to the formation of the syncytiotrophoblast by its membrane fusogenic capacity and seems to also be involved in maternal immune tolerance towards the fetus [30,31].
Additional to epigenetic mechanisms, environmental factors such as caffeine and aspirin are supposed to be regulators of HERV expression [32], although in vivo evidence for this is still lacking. In particular, infections with exogenous viruses represent potent triggers of HERV activation. Thus, transactivation of HERV by human immunodeficiency virus 1 (HIV-1), hepatitis B virus (HBV), human T-lymphotropic virus 1 (HTLV-1), and influenza A virus has been described [33,34,35,36]. For example, the HIV-1 transactivator of transcription (Tat) protein can induce the expression of HERV in lymphocytes and astrocytes through regulation of the nuclear factor kappa B (NFκB) pathway, the nuclear factor of activated T cells (NFAT) pathway, and the toll-like receptor 4 (TLR4) pathway [37,38]. In accordance with that, HIV-1 infected patients show increased antibody titers against the transmembrane unit of HERV-K (HML-2) envelope protein, which decrease with antiviral treatment [39]. The transactivator protein Tax of HTLV-1 increases, similar to HIV-1 Tat, the promoter activity of HERV-K, HERV-W, HERV-H, and HERV-E members in T cells [35]. Herpesviruses including Epstein–Barr virus (EBV) [18,40,41], herpes simplex virus 1 (HSV-1) [42,43,44], and human cytomegalovirus [45] have also been reported to induce HERV transactivation. As a probably important example, the EBV glycoprotein gp350 triggers transcription of the HERV-K18 env gene in resting B cells after binding to the EBV receptor CD21 [41]. The same gp350 stimulates HERV-W Env protein expression in astrocytes through the NFκB pathway [46]. Interestingly, since EBV infection is an important risk factor for the development of MS, HERV are discussed as the missing link between EBV infection and disease onset [47]. Additional information on the virus-associated regulation of HERV elements is provided in a recent review by Chen et al. [48]. Infections with other pathogens including Toxoplasma gondii were shown to induce a wide range of HERV elements in the Ewing sarcoma cell line SK-N-MC [49]. Inflammatory conditions per se, such as interferon gamma (IFNγ) and other proinflammatory cytokines, were shown to induce HERV expression in vitro [50,51]. It is not yet clear whether HERV occur as a consequence or as a cause of inflammatory processes. For this reason, the interaction of HERV with the immune system is being intensively investigated, especially in the context of diseases such as multiple sclerosis.

3. Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system resulting in progressive neurodegeneration and neurological disability. The onset usually occurs between the ages of 20 and 40 and is often evidenced by a clinically isolated syndrome (CIS), i.e., a first episode of neurological symptoms caused by inflammation or demyelination [52]. The type of symptomatology is diverse and depends on the affected central nervous system regions; common early signs include vision problems, weakness or fatigue, and balance problems. MS can typically be divided into three clinical types: (i) Relapsing-remitting MS (RRMS), which is characterized by discrete relapses with intermediate periods of remission. Relapses manifest themselves in new or worsening symptoms with underlying active brain lesions with lymphocytic inflammation. (ii) Secondary progressive MS (SPMS) typically develops 10–15 years after RRMS onset, characterized by a slowly progressive disease course with dominant neurodegeneration. (iii) Primary progressive MS (PPMS) is characterized by gradually increasing disability from the onset of the disease involving a dominant neural system, such as lower limb weakness and spasticity; 5–15% of MS patients show a PPMS onset.
White matter lesions incidentally found by magnetic resonance imaging (MRI) in individuals without a clinical history of demyelinating attacks or any other cause of white matter lesions (radiologically isolated syndrome, RIS) indicate that MS begins before the first clinical symptoms become apparent [53,54]. The early clinical course is marked by relapses from which symptomatic recovery is usually complete. Transition from RRMS to SPMS is subtle with relapses occurring on a low background level of progression, before progression becomes dominant. This gradual clinical disease development is consistent with rather continuous pathological changes. At the beginning of the disease, inflammation is suggested as the driving force, while the progressive phase is dominated by neurodegenerative processes. Nevertheless, cognitive impairment and progressive MRI-detectable atrophy occur in early MS, suggesting that neurodegeneration is already present from clinical onset.
The pathological hallmarks of MS are focal inflammatory lesions characterized by primary demyelination in the white and grey matter of the CNS. Oligodendrocyte damage and demyelination originate in the periphery with the activation of self-reactive T cells that infiltrate in the CNS across a disintegrating blood–brain barrier [55]. In active lesions, activated microglia or macrophages, mainly CD8-positive cytotoxic T-lymphocytes, and fewer CD4-positive helper T cells, B cells, and plasma cells can be found [56]. The inflammatory process is accompanied by the activation of astrocytes leading to the formation of astroglial scars [55,57]. Acute axonal damage is most prominent in the early stages of RRMS and SPMS, whereas in PPMS, axon degradation is more constant [58]. Whether axonal damage occurs as a consequence or independently of demyelination is subject to controversial discussion [59].
Extensive remyelination can be frequently observed during the early stages of RRMS [60]. However, recurrent inflammatory attacks and the failure of myelin repair during later progressive phases of the disease ultimately lead to permanent de-myelinization. There is currently no causal therapy for MS. Treatment is designed to reduce inflammatory processes and prevent the progression of symptoms.
Although the cause of MS remains unclear, it is believed that a combination of genetic and environmental factors influences disease susceptibility. Studies with siblings of affected individuals and monozygotic twins indicate a strong genetic component [61,62]. The human major histocompatibility complex (MHC) region on chromosome 6p21 was identified early as the strongest genetic locus for MS [63,64]. More recent genome-wide association studies uncovered more than 200 implicated genetic risk variants, including 110 non-MHC genetic loci [65,66,67], which all confer small increases in disease risk. Moreover, genetic differences between RRMS and PPMS have been identified [68]. The association of different HERV loci and MS risk will be discussed below. The multifactorial character of MS becomes particularly evident in studies showing that the individual risk of disease in genetically predisposed individuals increases when they are additionally exposed to environmental risk factors [69,70,71,72]. Such factors include low vitamin D levels, lack of sun exposure, female sex, EBV infection, obesity during adolescence, and smoking [69]. Among these factors, infection with EBV is considered the strongest risk factor, as the risk of developing MS increases 15-fold with EBV infection in childhood and 30-fold with infection in adolescence compared with uninfected individuals [73]. Moreover, there is a higher frequency of EBV seropositivity in MS patients compared to controls [74] and the beneficial effects of EBV-specific T cell therapy in MS have been demonstrated [75]. Several mechanistic hypotheses addressing the etiologic role of EBV in MS exist and are summarized in a recent review [76].

3.1. HERV-W in MS

In line with a possible virus-associated etiology of MS, the involvement of HERV represents an additional piece of the puzzle in this multifactorial and heterogeneous disease. Over the past 30 years, concurrent studies by several investigators have consistently suggested a relationship between HERV and the development of MS.
The first observation of retroviral particles of presumed endogenous origin in MS patients dates back to the early 1990s [77]. The cDNA sequences derived from particle-associated RNA were then assigned to a “multiple sclerosis-associated retrovirus” (MSRV). Merely a decade later, it was discovered that MSRV belongs to the HERV-W family [78]. HERV-W is a multicopy family with about 650 loci in the human genome [79]. Most of these loci are coding-deficient due to their evolutionary age [80]. However, more than 100 HERV-W loci were found to be transcribed in the human brain [79], although it cannot be excluded that some of these transcripts are caused by recombination events in vitro [81]. Other investigators identified seven transcribed HERV-W env loci in peripheral blood mononuclear cells (PBMC) [82]. Among 13 reported HERV-W loci with full-length env genes, only the HERVWE1 locus on chromosome 7q21.2 codes for a complete HERV-W envelope protein called syncytin-1 [82]. ERVWE2 on chromosome Xq22.3 encodes an incomplete HERV-W env of unknown function [83]. Since there is no counterpart to the initially named MSRV envelope protein (GenBank sequence AF331500) in the human genome, the origin of MSRV env remains open [82,84]. Based on the assumption that reverse transcriptase can switch templates during in vitro PCR amplification [81], recombination of different HERV-W env loci transcripts was proposed [82]. The origin of different published MSRV sequences involving recombination of transcripts from up to six different HERV-W loci is discussed in more detail by Grandi et al. [84]. Other possible explanations for the discrepancy in HERV-W genomic sequences found by various investigators include unfixed copies of HERV-W that are present only in a certain percentage of the population, and the occurrence of somatic recombination events that cannot be detected in unaffected cells [81,85,86].
HERV-W proteins have been found to be physiologically expressed in the normal brain with unknown function [87,88]. Increased amounts of HERV-W RNA, DNA, proteins, virions, and antibodies directed against HERV-W peptides in the blood, cerebrospinal fluid (CSF), and/or brain of MS patients have been associated with disease etiology. HERV-W env has been detected in the brains of MS patients, particularly in macrophages and microglia in lesions, but not in healthy controls [89]. Similarly, active MS lesions show an accumulation of HERV-W gag in axonal structures and endothelial cells as well as specific expression of HERV-W env in macrophages and microglia cells [87,89,90,91]. Additionally, HERV-W env is elevated on the surface of B cells and monocytes [92,93,94]. Concerning seroreactivity, higher antibody titers against HERV-W env have been identified in patients with active MS compared to patients with stable MS [92], patients with neuromyelitis optica spectrum disorder [95,96], or healthy controls [97,98].
There are several studies that report increased copy numbers of HERV-W pol and env DNA or RNA in the blood (PBMC or serum/plasma) and/or CSF in patients with MS compared to control groups (healthy controls or patients with other neurological diseases) [90,99,100,101,102,103,104]. In this context, the presence of the MRSV in the CSF seems to be associated with disability accumulation and a higher rate of relapses in MS patients in a 10-year follow-up study in a Sardinian cohort [105]. Interestingly, one study found an inverse correlation between MSRV DNA copy numbers and vitamin D concentration in RRMS patients [106]. Although all mentioned studies report increased HERV-W viral loads when comparing MS patients with healthy controls, not all MS patients tested positive for HERV-W/MSRV RNA or anti-HERV-W env antibodies [95,100,107]. Consequently, the detection of HERV-W alone is not sufficient to distinguish MS patients from healthy individuals or patients with other neurological disorders. The variable expression of HERV in MS patients may rather reflect a differential regulation of inherited HERV copies in the genome. Thus, more detailed studies are still needed to determine the applicability of HERV-W as a diagnostic marker in MS.
The hypothesis that HERV-W is a driving factor in the development of MS is further challenged by studies reporting no association between HERV-W yields and the disease. For example, the relative transcript levels of investigated HERV-W elements in PBMC or the brain did not differ significantly between MS patients and controls [79,82] and no HERV-W was detected in the cerebrospinal fluid of MS patients using PCR [108]. Ruprecht and colleagues reported the absence of antibodies and T-cell reactivity against MSRV env and gag proteins in MS patients, respectively [109]. This might be due to self-tolerance to HERV as autoantigens in the investigated subjects. The positive seroreactivity against HERV-W mentioned above [92,95,96,97,98] referred to specific HERV-W peptides being antigenic and leading to a rather low response amplitude, which is consistent with variations in “natural autoantibodies” when corresponding tolerated antigens are released (cell death, tissue damage) or abnormally expressed (HERVs) [110]. Therefore, Ruprecht’s observations do not contradict the other studies. Another study reports syncytin-1 encoding RNA to be increased in MS brains compared to non-MS patients, but not in CSF and plasma [111]. Most of these studies do not consider the treatment effects on HERV formation and persistence. It was shown that interferon-beta (IFN-β) treatment reduces MSRV levels in the plasma of MS patients below detection limits after three months of treatment [112]. Likewise, elevated antibody titers against HERV-W env in MS patients decreased after IFN-β treatment [97]. This may explain in part the absence of HERV-W in other investigations. However, the complex genomic distribution of HERV-W elements leads to limitations in the comparability of studies, since it often remains unclear from which genetic locus the investigated protein or nucleic acid originates. Despite these limitations, a meta-analysis of 12 studies performed by Morandi and colleagues reports a strong association between MSRV/HERV-W pol and env and MS [104].
Although it is not known whether HERV-W has a causal role in the development of MS, there is some evidence that it interacts with the immune system. Thus, MSRV/HERV-W env protein induces the release of inducible nitric oxide synthase and pro-inflammatory cytokines such as tumor necrosis factor alpha, IFNγ, interleukin (IL)-6, and IL-1β from PBMC of MS patients [16,113,114,115]. Moreover, IL-6 and the p40 subunit of IL-12 seem to correlate with disease severity [113]. In addition, the activation of certain cytokines by HERV-W env depends on the clinical course of the patient’s disease. For example, so-called type I cytokines (which favor cellular immune responses) predominate in stimulated PBMC of patients with acute MS, while in patients with stable MS, a type II cytokine profile (which favors humoral immune responses) dominates [116,117]. Interestingly, combined stimulation of PBMC from MS patients with antigens from Herpesviridae (herpes zoster virus, human herpesvirus 6A, herpes simplex virus 1) and antigens from HERV-H also leads to an altered Th1/Th2 response [114].
It has been shown for human brain endothelial cells, rat and human oligodendroglial precursor cells, and human PBMC that the HERV-W-induced release of proinflammatory cytokines is mediated by concentration-dependent activation of the pattern recognition receptors CD14 or TLR4 [16,113,115,118,119].
Increased cytokine release after MSRV/HERV-W env stimulation has also been recorded in human brain endothelial cells and rat oligodendrocyte precursor cells (OPCs) [118,119]. In addition to altered cytokine profiles, rat OPCs show a decrease in myelin proteins CNP and MBP as opposed to the unchanged expression of the precursor marker claudin 11 (CLDN11, also known as O4 antigen) following HERV-W env stimulation. This reflects the impairment of myelin sheath formation and cellular differentiation caused by HERV-W env [119]. These negative effects can be successfully neutralized by the anti-HERV-W env antibody GNbAC1 [120,121]. Cytotoxicity on OPCs might also be mediated via HERV-W expression in astrocytes as it induces endoplasmic reticulum stress and the release of redox reactants leading to OPC apoptosis [122]. In accordance, transgenic mice overexpressing HERV-W showed neuroinflammation, decreased levels of myelin proteins in the corpus callosum, and behavioral deficits compared to wild type littermates [123]. In addition, MSRV/HERV-W env causes axonal injury by altering microglial cells to form a degenerative phenotype and to associate with myelinated axons [91]. The immuno-stimulatory properties of HERV-W env protein were demonstrated using a myelin oligodendrocyte glycoprotein-induced mouse model of experimental autoimmune encephalomyelitis (EAE), in which mice injected with HERV-W instead of mycobacterial lysate developed a disease phenotype [124].
In summary, MSRV/HERV-W env is expressed in chronic active MS lesions. Preclinical models have shown that HERV-W env is a negative regulator of OPC maturation and a TLR4 agonist that activates innate immunity and might be involved in MS etiology.

3.2. Other HERV in MS

In addition to the HERV-W family, an association of other HERV with MS, such as HERV-H/F and HERV-K, has been suggested.
Concerning the HERV-H/F family, increased MS risk in Danish and Norwegian populations was related to the single nucleotide polymorphism (SNP) rs391745 in the vicinity of the HERVFC1 gene locus [125,126]. The same SNP showed significant association with MS in two Spanish cohorts [127]. Additionally, the amount of HERVFC1 gag RNA in plasma and of HERVFC1 gag protein in T cells and monocytes was increased in active MS patients compared with non-active MS and healthy controls [128]. Whereas HERV-H env and gag RNA was increased in the serum and PBMC of Danish MS patients [129,130], no difference in RNA expression (analyzed in CSF, PBMC, and brain) between MS and patients with other neurological diseases was observed in Spanish and Canadian studies [108,111,122,131]. Expression of HERV-H3 was shown to be significantly increased on the surface of non-classical monocytes in patients with CIS and RRMS compared to healthy controls [132]. However, expression of HERV-H3 seems to be inconsistent and probably depending on pre-treatment of patients [133] as immune-modulating therapy can lead to an increase of nonclassical monocyte populations [134].
Another HERV family implicated in MS is HERV-K (HML-2), which has many human-specific insertions as it contains many of the most recently integrated and “active” retroelements [135,136]. Studies analyzing HERV-K DNA, RNA, and protein levels in MS patients compared with healthy controls report different and sometimes inconsistent results depending on the member of the HERV-K family examined, the part of the virus analyzed (env, pol, or gag), and the investigated tissue. For example, expression of HERV-K pol [51], but not of HERV-K env [111,122], was elevated in the brain of MS patients compared to control groups. Moreover, an increase in the prevalence of HERV-K113, but not HERV-K115, was reported in patients with MS or Sjögren’s syndrome [7]. However, the same group failed to reproduce these findings in a larger cohort of MS patients [137]. The difference between these studies might be explained by the genetic variability between the populations studied [135,138]. From a genetic point of view, homozygous carriers of the HERV-K18.3 allele have a higher risk of developing MS compared with carriers of the other two alleles K18.1 or K18.2 [139,140]. Moreover, the SNP rs2435031 near the HERV-K113 locus has been shown to be associated with MS [125]. Based on published data, relevance for HERV-K in MS appears to be low. Instead, there is evidence of HERV-K involvement in amyotrophic lateral sclerosis (ALS).

4. HERV-K in Amyotrophic Lateral Sclerosis

ALS is a disease for which only symptomatic therapy is available. The etiology of ALS is unknown. Several mutations in seemingly unrelated genes, e.g., superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), or TAR DNA-binding protein 43 (TARDBP), have been described and it remains possible that ALS is not a single disease entity but a conglomerate of different diseases with a similar clinical endpoint. In most patients, however, no recurrent mutations can be found and for these “sporadic” ALS cases, non-genetic factors might play a role [141,142,143].
Epidemiological observations suggest that viruses might be involved in the disease. However, no exogenous virus has been found until now. Observations about ALS-like symptoms in patients with HTLV-1 infection remain anecdotal [144]. Reverse transcriptase (RT) activity is a hallmark of retrovirus infection. Early studies found elevated RT activity in the serum of patients with sporadic ALS [145]. Interestingly, the RT activity was not elevated in spouses of the ALS patients, but non-symptomatic blood relatives of ALS patients showed a similar elevation of RT activity to the ALS patients. This observation strongly suggests that the RT activity is not a consequence of infection with an exogenous virus but a consequence of genetic factors that influence the expression or activity of endogenous reverse transcriptase. Recently it has been shown that the human DNA polymerase eta has RT activity [146]. However, HERV are the best candidates for sources of the elevated RT activity in ALS patients. Indeed, high levels of HERV-K pol transcripts were found in the brain from ALS patients [147]. The expression correlated with the expression of the ALS-associated TARDBP and HERV-K pol protein co-localizes with TARDBP protein in neurons. HERV-K expression was not restricted to a single locus but, interestingly, a preference for pol loci with intact open reading frames was observed. Moreover, it was shown that HERV-K is expressed in the brain of ALS patients and that HERV-K can induce the apoptosis of neuronal cells in a mouse model [148]. In addition, antibodies with specificity for HERV-K have also been found to be elevated in patients with ALS [98].
TARDBP might play an important role in the activation of HERV-K. It was shown that the transgenic expression of mutated TARDBP leads to the accumulation of HERV-K proteins, especially reverse transcriptase [149]. Expression of TARDPB in Drosophila neuronal cells and glia cells induces the expression of diverse repetitive elements and leads to age-dependent neurodegeneration [150]. TARDPB inhibits the siRNA-mediated silencing of the Drosophila gypsy element (a Drosophila ERV) and in particular, gypsy seems to be responsible for the toxic effects on glia cells [150] and neuronal cells [151]. Interestingly, the toxicity of gypsy can spread to neighboring cells [151]. The activation of repetitive elements might be a common scheme of ALS-specific mutations. For instance, multiple repetitive elements are expressed in the brain of ALS patients with mutations in C9orf72 and the transgenic expression of C9orf72 in human embryonic kidney 293 cells leads to RNA polymerase II-dependent expression of repetitive elements [152]. Vice versa, it has been shown that knock-out of HERV-K env in prostate cancer cells results in the down-regulation of TARBP expression [153].
The reciprocal regulation of HERV and ALS-specific genes like TARBP requires further investigation. Stimulation with cytokines has also been shown to induce the expression of HERV-K in neuronal cells [154]. This poses the general question of whether HERV activation is an initializing step during disease development or whether HERV activation is a consequence of ongoing degeneration and inflammatory pathways. It should be noted that the involvement of HERV and especially HERV-K in ALS is discussed controversially. Some investigations failed to show increased HERV-K in ALS patients compared to controls [155,156]. Whether this can be explained by technical reasons solely remains an open question [157,158].

5. HERV in Other Nervous System Disorders

In addition to MS and ALS, other nervous system disorders have been associated with HERV activation. Elevated HERV transcripts have been found in the brains of patients with Alzheimer disease (AD) [159,160,161]. Interestingly, HERV-K RNA from the env region induces neurodegeneration in an TLR7- or TLR8-dependent manner [159]. TLR7 and TLR8 are two highly similar pattern recognition receptors that are activated by single-stranded RNA. The activation of these receptors by HERV-K RNA and subsequent neurodegeneration shows that HERV RNA can have profound biological effects without the necessity for HERV protein synthesis. Another interesting disease with possible involvement of non-coding RNAs from repetitive elements is Aicardi–Goutieres syndrome (AGS). AGS is caused by mutations in genes involved in the regulation of cytoplasmic nucleic acids and these mutations are considered to lead to the accumulation of double-stranded RNA, RNA/DNA hybrids, or single stranded DNA that activate innate immune response pathways (reviewed in [160]). The nucleic acids involved in the activation of innate immune responses in AGS are probably derived from repetitive elements of the L1 and Alu classes. However, HERV-derived sequences have also been found at least in animal models for AGS [161].
A hallmark of Alzheimer disease is the intraneuronal accumulation of pathogenic forms of the microtubule-associated protein tau. Interestingly, pathogenic tau can induce the expression of repetitive elements including HERV. In Drosophila, pathogenic tau induces the expression of gypsy and other transposable elements in an age-dependent manner [162,163]. One mechanism for this activation of ERV by tau seems to be the depletion of piwi-interacting RNAs (piRNAs). piRNAs are small non-coding RNAs that are known for their role in the repression of transposable elements, especially in the germline [164].
For other nervous system diseases, only a few studies have analyzed possible associations with HERV. Elevated expression of HERV has been found in progressive supranuclear palsy [163], chronic inflammatory demyelinating polyradiculoneuropathies [165], fibromyalgia [166], myalgic encephalomyelitis [167,168,169], prion disease [170,171,172], and spinal and bulbar muscular atrophy (SBMA) [173]. In the case of SBMA, HERV RNA was found unchanged but elevated levels of processed gag antigens have been found. This seems interesting as SBMA is caused by mutations in the androgen receptor (AR) gene. AR signaling has been shown to activate HERV LTRs and HERV-derived np9 protein has been shown to activate AR signaling [174]. Such reciprocal activation might be involved in the initiation of vicious cycles that freeze the activation status of signaling pathways. Interestingly, it has been reported that progerin, the protein constitutively expressed in patients with progeria but also increasingly expressed in aging normal individuals, inhibits the expression of transposable elements [175]. The author of this study speculates that progerin might serve as a safeguard which inhibits the aberrant activation of HERV and other transposable elements in aging cells [175]. With increasing age, the chance for stochastic activation of vicious cycles like the AR-np9 cycle increases, which might also explain the age-dependency of the aforementioned Drosophila models. The presence of safeguard mechanisms against such vicious cycles seem meaningful.
In addition to the mentioned neurological diseases, increased HERV expression has been described for some mental disorders, including autism spectrum disorders [176,177], attention deficit hyperactivity disorder [178,179,180], and schizophrenia. HERV-W and to a lower extent, HERV-K, have been found increased in the CSF and blood of patients with schizophrenia [181,182,183,184,185,186]. HERV-W env protein has been shown to alter glutamate synapse maturation in the developing brain, which might be an important factor for the development of neuropsychiatric disorders [187]. Moreover, polymorphisms in HERV loci or adjacent genes have been associated with schizophrenia [188,189,190,191,192,193]. One of these loci, proline dehydrogenase 1 (PRODH) from human chromosome 22, is an interesting example for the co-regulation of HERV and neighboring genes [193,194]. Here, the LTR form of an HERV (ERVK-24) drives the expression of HERV sequences as well as the expression of PRODH. Germ cell tumors with high expression of this HERV also show high expression of PRODH and forced differentiation of these tumor cells results in concomitant down-regulation of PRODH and ERVK-24 [194].

6. Possible Therapeutic Implications

With our current knowledge, HERV-W and HERV-K at least seem most likely to be involved in the pathogenesis of nervous system disorders, especially of MS and ALS. Therefore, new innovative therapeutic approaches are focusing on the reduction of HERV load in patients in order to achieve a positive effect on disease progression.
One approach assumes that highly active antiretroviral therapy (HAART), which is the standard treatment for HIV patients, blocks HERV expression. The experimental bases for this hypothesis are studies in HIV-positive patients, which showed a significant reduction in HERV-K RNA in plasma samples of successfully treated patients compared to patients who might have developed drug-resistance and/or received suboptimal therapeutic doses [195]. Other studies showed that the antibody titers against the transmembrane unit of HERV-K (HML-2) decreased with antiviral treatment [39].
Antiretroviral therapy has been applied both in ALS and MS. A pilot clinical trial of the protease inhibitor, indinavir, failed to show efficacy in ALS [196]. Interestingly, patients with HIV infection who subsequently developed motor neuron disease showed reduced HERV-K expression in blood following antiretroviral treatment. At the same time, the symptoms of three of these five patients regressed [197]. HIV-infected individuals with ALS might represent a unique sub-population of ALS patients that activate HERV under the influence of HIV. Therefore, anti-HIV drugs may turn off the activating effect of HIV on HERV. In ALS patients without HIV, alternative mechanisms might activate HERV. A phase 2a open label study with the antiretroviral drug Triumeq (which includes the two reverse transcriptase inhibitors abacavir and lamivudine, and the integrase inhibitor dolutegravir) has been conducted in 43 ALS patients (ClinicalTrials.gov Identifier: NCT02868580). Triumeq significantly decreased HERV-K env DNA in serum and showed a strong potential for biological activity as disease progression assessed on the ALS Functional Rating Scale was slowed down [198].
A case study on a patient with HIV infection and MS reported positive effects from antiretroviral treatment on MS symptoms [199]. In contrast, a phase 2a pilot study in 20 RRMS patients could not confirm this observation. In this study, patients showed no reduction in gadolinium-enhancing lesions on MRI after 3 months of treatment with raltegravir, an inhibitor of HIV integrase [200]. Since integrase-dependent chromosomal reintegration of viral DNA is not relevant for HERV transactivation, raltegravir may not have had an effect on HERV expression in MS, which may explain the negative results of the study. Furthermore, HERV might be transactivated by the HIV protein Tat [37]. Thus, it is possible that the effect of antiretroviral therapies on HERV is only indirectly based on the primary reduction of the HIV load and the concomitantly reduced transactivation of HERV. Thus, in patients without HIV, antiretroviral therapy would have no effect.
A completely different therapeutic approach assumes that harmful HERV proteins can be inactivated with specific antibodies. In this context, studies of the HERV-W-specific monoclonal antibody (mAb) GNbAC1, also called temelimab, are the most advanced. Temelimab is a recombinant, humanized IgG4κ mAb with high affinity (Kd = 2.2 nM) to the surface domain of a HERV-W envelope protein, for which a cDNA was cloned from virion-associated genomic RNA isolated from MS cell cultures [201]. In preclinical studies, temelimab could rescue myelin basic protein (MBP) expression in OPCs and improve the symptoms caused by HERV-W env in an EAE mouse model [120,121,202]. Three clinical phase 1 studies in a total of 78 healthy male volunteers showed good tolerability of intravenous-administered temelimab at doses up to 110 mg/kg without severe adverse drug reactions [203,204,205]. A rather small study on 10 MS patients confirmed the dose-linear pharmacokinetics and tolerability of previous studies [206,207]. The clinical phase 2b study CHANGE-MS (ClinicalTrials.gov Identifier: NCT02782858) and its extension ANGEL-MS (ClinicalTrials.gov Identifier: NCT03239860) were conducted in 270 and 219 RRMS patients, respectively [208]. According to publicly available information, the study did not show a significant reduction in the total number of gadolinium-enhancing lesions and clinically apparent relapses in temelimab-treated groups thereby failing to reach a primary study endpoint [209]. However, a benefit for brain atrophy and for the magnetization transfer ratio (MTR) signal of patients treated with the highest dose relative to the placebo group was claimed, suggesting a pharmacodynamic effect of temelimab in remyelination. These data await peer-reviewed publication.
In conclusion, numerous studies suggest the expression of HERV in different neurologic disorders. Whether it happens as bystanders of the disease or even in a causative fashion is currently unclear. Therefore, future studies are required to elucidate the nature of contribution of HERV to these disorders.

Author Contributions

Writing—original draft preparation, V.G., M.S.S., H.C.; writing—review and editing, M.S.S., V.G., A.E., H.C.; All authors have read and agreed to the published version of the manuscript.

Funding

The work was supported by grant ZS/2018/12/96228 (M.S.S. and A.E.) and ZS/2018/12/96169 (H.C.) from European Regional Development Fund within the local program “Sachsen-Anhalt WISSENSCHAFT Schwerpunkte”.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Acknowledgments

The authors thank Malte Kornhuber for helpful discussions and ongoing support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Mayer, J.; Meese, E. Human endogenous retroviruses in the primate lineage and their influence on host genomes. Cytogenet. Genome Res. 2005, 110, 448–456. [Google Scholar] [CrossRef] [PubMed]
  2. Belshaw, R.; Katzourakis, A.; Paces, J.; Burt, A.; Tristem, M. High copy number in human endogenous retrovirus families is associated with copying mechanisms in addition to reinfection. Mol. Biol. Evol. 2005, 814–817. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Belshaw, R.; Pereira, V.; Katzourakis, A.; Talbot, G.; Paces, J.; Burt, A.; Tristem, M. Long-term reinfection of the human genome by endogenous retroviruses. Proc. Natl. Acad. Sci. USA 2004, 101, 4894–4899. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Shin, W.; Lee, J.; Son, S.-Y.; Ahn, K.; Kim, H.-S.; Han, K. Human-specific HERV-K insertion causes genomic variations in the human genome. PLoS ONE 2013, 8, e60605. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Marchi, E.; Kanapin, A.; Magiorkinis, G.; Belshaw, R. Unfixed endogenous retroviral insertions in the human population. J. Virol. 2014, 9529–9537. [Google Scholar] [CrossRef] [Green Version]
  6. Wildschutte, J.H.; Williams, Z.H.; Montesion, M.; Subramanian, R.P.; Kidd, J.M.; Coffin, J.M. Discovery of unfixed endogenous retrovirus insertions in diverse human populations. Proc. Natl. Acad. Sci. USA 2016, E2326–E2334. [Google Scholar] [CrossRef] [Green Version]
  7. Moyes, D.L.; Martin, A.; Sawcer, S.; Temperton, N.; Worthington, J.; Griffiths, D.J.; Venables, P.J. The distribution of the endogenous retroviruses HERV-K113 and HERV-K115 in health and disease. Genomics 2005, 86, 337–341. [Google Scholar] [CrossRef]
  8. Turner, G.; Barbulescu, M.; Su, M.; Jensen-Seaman, M.I.; Kidd, K.K.; Lenz, J. Insertional polymorphisms of full-length endogenous retroviruses in humans. Curr. Biol. 2001, 11, 1531–1535. [Google Scholar] [CrossRef] [Green Version]
  9. Hughes, J.F.; Coffin, J.M. Evidence for genomic rearrangements mediated by human endogenous retroviruses during primate evolution. Nat. Genet. 2001, 29, 487–489. [Google Scholar] [CrossRef]
  10. Villesen, P.; Aagaard, L.; Wiuf, C.; Pedersen, F.S. Identification of endogenous retroviral reading frames in the human genome. Retrovirology 2004, 1, 32. [Google Scholar] [CrossRef] [Green Version]
  11. Bonnaud, B.; Bouton, O.; Oriol, G.; Cheynet, V.; Duret, L.; Mallet, F. Evidence of selection on the domesticated ERVWE1 env retroviral element involved in placentation. Mol. Biol. Evol. 2004, 21, 1895–1901. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Chuong, E.B.; Elde, N.C.; Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 2016, 351, 1083–1087. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Faulkner, G.J.; Kimura, Y.; Daub, C.O.; Wani, S.; Plessy, C.; Irvine, K.M.; Schroder, K.; Cloonan, N.; Steptoe, A.L.; Lassmann, T.; et al. The regulated retrotransposon transcriptome of mammalian cells. Nat. Genet. 2009, 41, 563–571. [Google Scholar] [CrossRef] [PubMed]
  14. Brattås, P.L.; Jönsson, M.E.; Fasching, L.; Nelander Wahlestedt, J.; Shahsavani, M.; Falk, R.; Falk, A.; Jern, P.; Parmar, M.; Jakobsson, J. TRIM28 controls a gene regulatory network based on endogenous retroviruses in human neural progenitor cells. Cell Rep. 2017, 18, 1–11. [Google Scholar] [CrossRef]
  15. Fasching, L.; Kapopoulou, A.; Sachdeva, R.; Petri, R.; Jonsson, M.E.; Manne, C.; Turelli, P.; Jern, P.; Cammas, F.; Trono, D.; et al. TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells. Cell Rep. 2015, 10, 20–28. [Google Scholar] [CrossRef]
  16. Rolland, A.; Jouvin-Marche, E.; Viret, C.; Faure, M.; Perron, H.; Marche, P.N. The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J. Immunol. 2006, 176, 7636–7644. [Google Scholar] [CrossRef]
  17. Mangeney, M.; de Parseval, N.; Thomas, G.; Heidmann, T. The full-length envelope of an HERV-H human endogenous retrovirus has immunosuppressive properties. J. Gen. Virol. 2001, 82, 2515–2518. [Google Scholar] [CrossRef] [Green Version]
  18. Sutkowski, N.; Conrad, B.; Thorley-Lawson, D.A.; Huber, B.T. Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen. Immunity 2001, 15, 579–589. [Google Scholar] [CrossRef] [Green Version]
  19. Morozov, V.A.; Thi, V.L.D.; Denner, J. The transmembrane protein of the human endogenous retrovirus-K (HERV-K) modulates cytokine release and gene expression. PLoS ONE 2013, 8, e70399. [Google Scholar] [CrossRef] [Green Version]
  20. Lavie, L.; Kitova, M.; Maldener, E.; Meese, E.; Mayer, J. CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J. Virol. 2005, 79, 876–883. [Google Scholar] [CrossRef] [Green Version]
  21. Groh, S.; Schotta, G. Silencing of endogenous retroviruses by heterochromatin. Cell Mol. Life Sci. 2017, 74, 2055–2065. [Google Scholar] [CrossRef] [PubMed]
  22. Schulz, W.A.; Steinhoff, C.; Florl, A.R. Methylation of endogenous human retroelements in health and disease. Curr. Top. Microbiol. Immunol. 2006, 310, 211–250. [Google Scholar] [CrossRef] [PubMed]
  23. Turelli, P.; Castro-Diaz, N.; Marzetta, F.; Kapopoulou, A.; Raclot, C.; Duc, J.; Tieng, V.; Quenneville, S.; Trono, D. Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements. Genome Res. 2014, 24, 1260–1270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Grow, E.J.; Flynn, R.A.; Chavez, S.L.; Bayless, N.L.; Wossidlo, M.; Wesche, D.J.; Martin, L.; Ware, C.B.; Blish, C.A.; Chang, H.Y.; et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 2015, 522, 221–225. [Google Scholar] [CrossRef] [Green Version]
  25. Takahashi, K.; Jeong, D.; Wang, S.; Narita, M.; Jin, X.; Iwasaki, M.; Perli, S.D.; Conklin, B.R.; Yamanaka, S. Critical roles of translation initiation and RNA uridylation in endogenous retroviral expression and neural differentiation in pluripotent stem cells. Cell Rep. 2020, 31, 107715. [Google Scholar] [CrossRef]
  26. Wang, T.; Medynets, M.; Johnson, K.R.; Doucet-O’Hare, T.T.; DiSanza, B.; Li, W.; Xu, Y.; Bagnell, A.; Tyagi, R.; Sampson, K.; et al. Regulation of stem cell function and neuronal differentiation by HERV-K via mTOR pathway. Proc. Natl. Acad. Sci. USA 2020, 117, 17842–17853. [Google Scholar] [CrossRef]
  27. Ohtani, H.; Liu, M.; Zhou, W.; Liang, G.; Jones, P.A. Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses. Genome Res. 2018, 28, 1147–1157. [Google Scholar] [CrossRef] [Green Version]
  28. Brocks, D.; Schmidt, C.R.; Daskalakis, M.; Jang, H.S.; Shah, N.M.; Li, D.; Li, J.; Zhang, B.; Hou, Y.; Laudato, S.; et al. DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nat. Genet. 2017, 49, 1052–1060. [Google Scholar] [CrossRef]
  29. Downey, R.F.; Sullivan, F.J.; Wang-Johanning, F.; Ambs, S.; Giles, F.J.; Glynn, S.A. Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice? Int. J. Cancer 2014. [Google Scholar] [CrossRef] [Green Version]
  30. Dupressoir, A.; Lavialle, C.; Heidmann, T. From ancestral infectious retroviruses to bona fide cellular genes: Role of the captured syncytins in placentation. Placenta 2012, 33, 663–671. [Google Scholar] [CrossRef]
  31. Mangeney, M.; Renard, M.; Schlecht-Louf, G.; Bouallaga, I.; Heidmann, O.; Letzelter, C.; Richaud, A.; Ducos, B.; Heidmann, T. Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc. Natl. Acad. Sci. USA 2007, 104, 20534–20539. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Liu, C.; Chen, Y.; Li, S.; Yu, H.; Zeng, J.; Wang, X.; Zhu, F. Activation of elements in HERV-W family by caffeine and aspirin. Virus Genes 2013, 47, 219–227. [Google Scholar] [CrossRef] [PubMed]
  33. Li, F.; Nellåker, C.; Sabunciyan, S.; Yolken, R.H.; Jones-Brando, L.; Johansson, A.-S.; Owe-Larsson, B.; Karlsson, H. Transcriptional derepression of the ERVWE1 locus following influenza A virus infection. J. Virol. 2014, 88, 4328–4337. [Google Scholar] [CrossRef] [Green Version]
  34. Nellaker, C.; Yao, Y.; Jones-Brando, L.; Mallet, F.; Yolken, R.H.; Karlsson, H. Transactivation of elements in the human endogenous retrovirus W family by viral infection. Retrovirology 2006, 3, 44. [Google Scholar] [CrossRef] [PubMed]
  35. Toufaily, C.; Landry, S.; Leib-Mosch, C.; Rassart, E.; Barbeau, B. Activation of LTRs from different human endogenous retrovirus (HERV) families by the HTLV-1 tax protein and T-cell activators. Viruses 2011, 3, 2146–2159. [Google Scholar] [CrossRef]
  36. Liu, C.; Liu, L.; Wang, X.; Liu, Y.; Wang, M.; Zhu, F. HBV X Protein induces overexpression of HERV-W env through NF-κB in HepG2 cells. Virus Genes 2017, 53, 797–806. [Google Scholar] [CrossRef]
  37. Gonzalez-Hernandez, M.J.; Swanson, M.D.; Contreras-Galindo, R.; Cookinham, S.; King, S.R.; Noel, R.J.; Kaplan, M.H.; Markovitz, D.M. Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1. J. Virol. 2012, 86, 7790–7805. [Google Scholar] [CrossRef] [Green Version]
  38. Gonzalez-Hernandez, M.J.; Cavalcoli, J.D.; Sartor, M.A.; Contreras-Galindo, R.; Meng, F.; Dai, M.; Dube, D.; Saha, A.K.; Gitlin, S.D.; Omenn, G.S.; et al. Regulation of the human endogenous retrovirus K (HML-2) transcriptome by the HIV-1 Tat protein. J. Virol. 2014, 88, 8924–8935. [Google Scholar] [CrossRef] [Green Version]
  39. Michaud, H.-A.; de Mulder, M.; SenGupta, D.; Deeks, S.G.; Martin, J.N.; Pilcher, C.D.; Hecht, F.M.; Sacha, J.B.; Nixon, D.F. Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection. Retrovirology 2014, 11, 10. [Google Scholar] [CrossRef] [Green Version]
  40. Sutkowski, N.; Chen, G.; Calderon, G.; Huber, B.T. Epstein-Barr virus latent membrane protein LMP-2A is sufficient for transactivation of the human endogenous retrovirus HERV-K18 superantigen. J. Virol. 2004, 78, 7852–7860. [Google Scholar] [CrossRef] [Green Version]
  41. Hsiao, F.C.; Lin, M.; Tai, A.; Chen, G.; Huber, B.T. Cutting edge: Epstein-Barr virus transactivates the HERV-K18 superantigen by docking to the human complement receptor 2 (CD21) on primary B cells. J. Immunol. 2006, 177, 2056–2060. [Google Scholar] [CrossRef] [Green Version]
  42. Ruprecht, K.; Obojes, K.; Wengel, V.; Gronen, F.; Kim, K.S.; Perron, H.; Schneider-Schaulies, J.; Rieckmann, P. Regulation of human endogenous retrovirus W protein expression by herpes simplex virus type 1: Implications for multiple sclerosis. J. Neurovirol. 2006, 12, 65–71. [Google Scholar] [CrossRef] [PubMed]
  43. Lee, W.J.; Kwun, H.J.; Kim, H.S.; Jang, K.L. Activation of the human endogenous retrovirus W long terminal repeat by herpes simplex virus type 1 immediate early protein 1. Mol. Cells 2003, 15, 75–80. [Google Scholar] [PubMed]
  44. Kwun, H.J.; Han, H.J.; Lee, W.J.; Kim, H.S.; Jang, K.L. Transactivation of the human endogenous retrovirus K long terminal repeat by herpes simplex virus type 1 immediate early protein 0. Virus Res. 2002, 86, 93–100. [Google Scholar] [CrossRef]
  45. Assinger, A.; Yaiw, K.-C.; Göttesdorfer, I.; Leib-Mösch, C.; Söderberg-Nauclér, C. Human cytomegalovirus (HCMV) induces human endogenous retrovirus (HERV) transcription. Retrovirology 2013, 10, 132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Mameli, G.; Poddighe, L.; Mei, A.; Uleri, E.; Sotgiu, S.; Serra, C.; Manetti, R.; Dolei, A. Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: Inference for multiple sclerosis. PLoS ONE 2012, 7, e44991. [Google Scholar] [CrossRef] [PubMed]
  47. Mameli, G.; Madeddu, G.; Mei, A.; Uleri, E.; Poddighe, L.; Delogu, L.G.; Maida, I.; Babudieri, S.; Serra, C.; Manetti, R.; et al. Activation of MSRV-type endogenous retroviruses during infectious mononucleosis and Epstein-Barr virus latency: The missing link with multiple sclerosis? PLoS ONE 2013, 8, e78474. [Google Scholar] [CrossRef]
  48. Chen, J.; Foroozesh, M.; Qin, Z. Transactivation of human endogenous retroviruses by tumor viruses and their functions in virus-associated malignancies. Oncogenesis 2019, 8, 6. [Google Scholar] [CrossRef] [Green Version]
  49. Frank, O.; Jones-Brando, L.; Leib-Mosch, C.; Yolken, R.; Seifarth, W. Altered transcriptional activity of human endogenous retroviruses in neuroepithelial cells after infection with Toxoplasma gondii. J. Infect. Dis. 2006, 194, 1447–1449. [Google Scholar] [CrossRef] [Green Version]
  50. Manghera, M.; Ferguson, J.; Douville, R. ERVK polyprotein processing and reverse transcriptase expression in human cell line models of neurological disease. Viruses 2015, 7, 320–332. [Google Scholar] [CrossRef] [Green Version]
  51. Serra, C.; Mameli, G.; Arru, G.; Sotgiu, S.; Rosati, G.; Dolei, A. In Vitro Modulation of the Multiple Sclerosis (MS)-Associated Retrovirus by Cytokines: Implications for MS Pathogenesis. J. Neurovirol. 2003, 9, 637–643. [Google Scholar] [CrossRef] [PubMed]
  52. Miller, D.H.; Chard, D.T.; Ciccarelli, O. Clinically isolated syndromes. Lancet Neurol. 2012, 11, 157–169. [Google Scholar] [CrossRef]
  53. Okuda, D.T.; Mowry, E.M.; Beheshtian, A.; Waubant, E.; Baranzini, S.E.; Goodin, D.S.; Hauser, S.L.; Pelletier, D. Incidental MRI anomalies suggestive of multiple sclerosis: The radiologically isolated syndrome. Neurology 2009, 72, 800–805. [Google Scholar] [CrossRef] [PubMed]
  54. Hosseiny, M.; Newsome, S.D.; Yousem, D.M. Radiologically isolated syndrome: A review for neuroradiologists. AJNR Am. J. Neuroradiol. 2020, 41, 1542–1549. [Google Scholar] [CrossRef] [PubMed]
  55. Minagar, A.; Alexander, J.S. Blood-brain barrier disruption in multiple sclerosis. Mult. Scler. 2003, 9, 540–549. [Google Scholar] [CrossRef]
  56. Dobson, R.; Giovannoni, G. Multiple sclerosis—A review. Eur. J. Neurol. 2019, 26, 27–40. [Google Scholar] [CrossRef] [Green Version]
  57. Ponath, G.; Park, C.; Pitt, D. The role of astrocytes in multiple sclerosis. Front. Immunol. 2018, 9, 217. [Google Scholar] [CrossRef]
  58. Kuhlmann, T.; Lingfeld, G.; Bitsch, A.; Schuchardt, J.; Brück, W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002, 125, 2202–2212. [Google Scholar] [CrossRef] [Green Version]
  59. Haines, J.D.; Inglese, M.; Casaccia, P. Axonal damage in multiple sclerosis. Mt. Sinai J. Med. 2011, 78, 231–243. [Google Scholar] [CrossRef] [Green Version]
  60. Lassmann, H.; Brück, W.; Lucchinetti, C.; Rodriguez, M. Remyelination in multiple sclerosis. Mult. Scler. 1997, 3, 133–136. [Google Scholar] [CrossRef]
  61. Willer, C.J.; Dyment, D.A.; Risch, N.J.; Sadovnick, A.D.; Ebers, G.C. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc. Natl. Acad. Sci. USA 2003, 100, 12877–12882. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Sadovnick, A.D.; Baird, P.A. The familial nature of multiple sclerosis: Age-corrected empiric recurrence risks for children and siblings of patients. Neurology 1988, 38, 990–991. [Google Scholar] [CrossRef] [PubMed]
  63. Olerup, O.; Hillert, J. HLA class II-associated genetic susceptibility in multiple sclerosis: A critical evaluation. Tissue Antigens 1991, 38, 1–15. [Google Scholar] [CrossRef] [PubMed]
  64. Link, J.; Kockum, I.; Lorentzen, A.R.; Lie, B.A.; Celius, E.G.; Westerlind, H.; Schaffer, M.; Alfredsson, L.; Olsson, T.; Brynedal, B.; et al. Importance of human leukocyte antigen (HLA) class I and II alleles on the risk of multiple sclerosis. PLoS ONE 2012, 7, e36779. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Didonna, A.; Oksenberg, J.R. The Genetics of multiple sclerosis. In Multiple Sclerosis: Perspectives in Treatment and Pathogenesis; Zagon, I.S., McLaughlin, P.J., Eds.; Codon Publications: Brisbane, Australia, 2017; Chapter 1. Available online: https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/books/NBK470155/ (accessed on 15 January 2021). [CrossRef] [Green Version]
  66. Patsopoulos, N.A. Genetics of multiple sclerosis: An overview and new directions. Cold Spring Harb. Perspect. Med. 2018, 8. [Google Scholar] [CrossRef] [PubMed]
  67. Patsopoulos, N.A.; Barcellos, L.F.; Hintzen, R.Q.; Schaefer, C.; van Duijn, C.M.; Noble, J.A.; Raj, T.; Gourraud, P.-A.; Stranger, B.E.; Oksenberg, J.; et al. Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet. 2013, 9, e1003926. [Google Scholar] [CrossRef]
  68. Jia, X.; Madireddy, L.; Caillier, S.; Santaniello, A.; Esposito, F.; Comi, G.; Stuve, O.; Zhou, Y.; Taylor, B.; Kilpatrick, T.; et al. Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. Ann. Neurol. 2018, 84, 51–63. [Google Scholar] [CrossRef]
  69. Olsson, T.; Barcellos, L.F.; Alfredsson, L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat. Rev. Neurol. 2017, 13, 25–36. [Google Scholar] [CrossRef]
  70. Sundqvist, E.; Sundström, P.; Lindén, M.; Hedström, A.K.; Aloisi, F.; Hillert, J.; Kockum, I.; Alfredsson, L.; Olsson, T. Epstein-Barr virus and multiple sclerosis: Interaction with HLA. Genes Immun. 2012, 13, 14–20. [Google Scholar] [CrossRef] [Green Version]
  71. Nielsen, T.R.; Pedersen, M.; Rostgaard, K.; Frisch, M.; Hjalgrim, H. Correlations between Epstein-Barr virus antibody levels and risk factors for multiple sclerosis in healthy individuals. Mult. Scler. 2007, 13, 420–423. [Google Scholar] [CrossRef]
  72. Hedström, A.K.; Sundqvist, E.; Bäärnhielm, M.; Nordin, N.; Hillert, J.; Kockum, I.; Olsson, T.; Alfredsson, L. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 2011, 134, 653–664. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Ascherio, A. Environmental factors in multiple sclerosis. Expert Rev. Neurother. 2013, 13, 3–9. [Google Scholar] [CrossRef] [PubMed]
  74. Jilek, S.; Schluep, M.; Meylan, P.; Vingerhoets, F.; Guignard, L.; Monney, A.; Kleeberg, J.; Le Goff, G.; Pantaleo, G.; Du Pasquier, R.A. Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 2008, 131, 1712–1721. [Google Scholar] [CrossRef] [PubMed]
  75. Pender, M.P.; Csurhes, P.A.; Smith, C.; Douglas, N.L.; Neller, M.A.; Matthews, K.K.; Beagley, L.; Rehan, S.; Crooks, P.; Hopkins, T.J.; et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight 2018, 3. [Google Scholar] [CrossRef] [PubMed]
  76. Bar-Or, A.; Pender, M.P.; Khanna, R.; Steinman, L.; Hartung, H.-P.; Maniar, T.; Croze, E.; Aftab, B.T.; Giovannoni, G.; Joshi, M.A. Epstein-Barr virus in multiple sclerosis: Theory and emerging immunotherapies. Trends Mol. Med. 2020, 26, 296–310. [Google Scholar] [CrossRef] [Green Version]
  77. Perron, H.; Lalande, B.; Gratacap, B.; Laurent, A.; Genoulaz, O.; Geny, C.; Mallaret, M.; Schuller, E.; Stoebner, P.; Seigneurin, J.M. Isolation of retrovirus from patients with multiple sclerosis. Lancet 1991, 337, 862–863. [Google Scholar] [CrossRef]
  78. Blond, J.L.; Besème, F.; Duret, L.; Bouton, O.; Bedin, F.; Perron, H.; Mandrand, B.; Mallet, F. Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J. Virol. 1999, 73, 1175–1185. [Google Scholar] [CrossRef] [Green Version]
  79. Schmitt, K.; Richter, C.; Backes, C.; Meese, E.; Ruprecht, K.; Mayer, J. Comprehensive analysis of human endogenous retrovirus group HERV-W locus transcription in multiple sclerosis brain lesions by high-throughput amplicon sequencing. J. Virol. 2013, 87, 13837–13852. [Google Scholar] [CrossRef] [Green Version]
  80. Voisset, C.; Blancher, A.; Perron, H.; Mandrand, B.; Mallet, F.; Paranhos-Baccalà, G. Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in humans and other primates. AIDS Res. Hum. Retroviruses 1999, 15, 1529–1533. [Google Scholar] [CrossRef]
  81. Flockerzi, A.; Maydt, J.; Frank, O.; Ruggieri, A.; Maldener, E.; Seifarth, W.; Medstrand, P.; Lengauer, T.; Meyerhans, A.; Leib-Mosch, C.; et al. Expression pattern analysis of transcribed HERV sequences is complicated by ex vivo recombination. Retrovirology 2007, 4, 39. [Google Scholar] [CrossRef] [Green Version]
  82. Laufer, G.; Mayer, J.; Mueller, B.F.; Mueller-Lantzsch, N.; Ruprecht, K. Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus env sequences. Retrovirology 2009, 6, 37. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Roebke, C.; Wahl, S.; Laufer, G.; Stadelmann, C.; Sauter, M.; Mueller-Lantzsch, N.; Mayer, J.; Ruprecht, K. An N-terminally truncated envelope protein encoded by a human endogenous retrovirus W locus on chromosome Xq22.3. Retrovirology 2010, 7, 69. [Google Scholar] [CrossRef] [Green Version]
  84. Grandi, N.; Cadeddu, M.; Blomberg, J.; Tramontano, E. Contribution of type W human endogenous retroviruses to the human genome: Characterization of HERV-W proviral insertions and processed pseudogenes. Retrovirology 2016, 13, 67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Ruprecht, K.; Mayer, J. On the origin of a pathogenic HERV-W envelope protein present in multiple sclerosis lesions. Proc. Natl. Acad. Sci. USA 2019, 19791–19792. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Kremer, D.; Perron, H.; Küry, P. Reply to Ruprecht and Mayer: Unearthing genomic fossils in the pathogenesis of multiple sclerosis. Proc. Natl. Acad. Sci. USA 2019, 19793–19794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Perron, H.; Lazarini, F.; Ruprecht, K.; Pechoux-Longin, C.; Seilhean, D.; Sazdovitch, V.; Creange, A.; Battail-Poirot, N.; Sibai, G.; Santoro, L.; et al. Human endogenous retrovirus (HERV)-W ENV and GAG proteins: Physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions. J. Neurovirol. 2005, 11, 23–33. [Google Scholar] [CrossRef] [PubMed]
  88. Weis, S.; Llenos, I.C.; Sabunciyan, S.; Dulay, J.R.; Isler, L.; Yolken, R.; Perron, H. Reduced expression of human endogenous retrovirus (HERV)-W GAG protein in the cingulate gyrus and hippocampus in schizophrenia, bipolar disorder, and depression. J. Neural Transm. 2007, 114, 645–655. [Google Scholar] [CrossRef] [PubMed]
  89. Van Horssen, J.; van der Pol, S.; Nijland, P.; Amor, S.; Perron, H. Human endogenous retrovirus W in brain lesions: Rationale for targeted therapy in multiple sclerosis. Mult. Scler. Relat. Disord. 2016, 8, 11–18. [Google Scholar] [CrossRef] [Green Version]
  90. Perron, H.; Germi, R.; Bernard, C.; Garcia-Montojo, M.; Deluen, C.; Farinelli, L.; Faucard, R.; Veas, F.; Stefas, I.; Fabriek, B.O.; et al. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult. Scler. 2012, 18, 1721–1736. [Google Scholar] [CrossRef]
  91. Kremer, D.; Gruchot, J.; Weyers, V.; Oldemeier, L.; Göttle, P.; Healy, L.; Ho Jang, J.; Kang, T.; Xu, Y.; Volsko, C.; et al. PHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis. Proc. Natl. Acad. Sci. USA 2019, 116, 15216–15225. [Google Scholar] [CrossRef] [Green Version]
  92. Brudek, T.; Christensen, T.; Aagaard, L.; Petersen, T.; Hansen, H.J.; Møller-Larsen, A. B cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity. Retrovirology 2009, 6, 104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Morandi, E.; Tanasescu, R.; Tarlinton, R.E.; Constantin-Teodosiu, D.; Gran, B. Do Antiretroviral Drugs Protect from Multiple Sclerosis by Inhibiting Expression of MS-Associated Retrovirus? Front. Immunol. 2018, 9, 3092. [Google Scholar] [CrossRef] [PubMed]
  94. Garcia-Montojo, M.; Rodriguez-Martin, E.; Ramos-Mozo, P.; Ortega-Madueño, I.; Dominguez-Mozo, M.I.; Arias-Leal, A.; García-Martínez, M.Á.; Casanova, I.; Galan, V.; Arroyo, R.; et al. Syncytin-1/HERV-W envelope is an early activation marker of leukocytes and is upregulated in multiple sclerosis patients. Eur. J. Immunol. 2020, 50, 685–694. [Google Scholar] [CrossRef] [PubMed]
  95. Arru, G.; Sechi, E.; Mariotto, S.; Zarbo, I.R.; Ferrari, S.; Gajofatto, A.; Monaco, S.; Deiana, G.A.; Bo, M.; Sechi, L.A.; et al. Antibody response against HERV-W in patients with MOG-IgG associated disorders, multiple sclerosis and NMOSD. J. Neuroimmunol. 2020, 338, 577110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Arru, G.; Sechi, E.; Mariotto, S.; Farinazzo, A.; Mancinelli, C.; Alberti, D.; Ferrari, S.; Gajofatto, A.; Capra, R.; Monaco, S.; et al. Antibody response against HERV-W env surface peptides differentiates multiple sclerosis and neuromyelitis optica spectrum disorder. Mult. Scler. J. Exp. Transl. Clin. 2017, 2055217317742425. [Google Scholar] [CrossRef]
  97. Mameli, G.; Cossu, D.; Cocco, E.; Frau, J.; Marrosu, M.G.; Niegowska, M.; Sechi, L.A. Epitopes of HERV-Wenv induce antigen-specific humoral immunity in multiple sclerosis patients. J. Neuroimmunol. 2015, 280, 66–68. [Google Scholar] [CrossRef]
  98. Arru, G.; Mameli, G.; Deiana, G.A.; Rassu, A.L.; Piredda, R.; Sechi, E.; Caggiu, E.; Bo, M.; Nako, E.; Urso, D.; et al. Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases. Eur. J. Neurol. 2018, 1076-e84. [Google Scholar] [CrossRef]
  99. Mameli, G.; Astone, V.; Arru, G.; Marconi, S.; Lovato, L.; Serra, C.; Sotgiu, S.; Bonetti, B.; Dolei, A. Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not Human herpesvirus 6. J. Gen. Virol. 2007, 88, 264–274. [Google Scholar] [CrossRef]
  100. Arru, G.; Mameli, G.; Astone, V.; Serra, C.; Huang, Y.-M.; Link, H.; Fainardi, E.; Castellazzi, M.; Granieri, E.; Fernandez, M.; et al. Multiple Sclerosis and HERV-W/MSRV: A Multicentric Study. Int. J. Biomed. Sci. 2007, 3, 292–297. [Google Scholar]
  101. Garson, J.A.; Tuke, P.W.; Giraud, P.; Paranhos-Baccala, G.; Perron, H. Detection of virion-associated MSRV-RNA in serum of patients with multiple sclerosis. Lancet 1998, 351, 33. [Google Scholar] [CrossRef]
  102. Sotgiu, S.; Arru, G.; Mameli, G.; Serra, C.; Pugliatti, M.; Rosati, G.; Dolei, A. Multiple sclerosis-associated retrovirus in early multiple sclerosis: A six-year follow-up of a Sardinian cohort. Mult. Scler. 2006, 12, 698–703. [Google Scholar] [CrossRef] [PubMed]
  103. Garcia-Montojo, M.; Dominguez-Mozo, M.; Arias-Leal, A.; Garcia-Martinez, Á.; de las Heras, V.; Casanova, I.; Faucard, R.; Gehin, N.; Madeira, A.; Arroyo, R.; et al. The DNA copy number of human endogenous retrovirus-W (MSRV-type) is increased in multiple sclerosis patients and is influenced by gender and disease severity. PLoS ONE 2013, 8, e53623. [Google Scholar] [CrossRef] [PubMed]
  104. Morandi, E.; Tanasescu, R.; Tarlinton, R.E.; Constantinescu, C.S.; Zhang, W.; Tench, C.; Gran, B. The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis. PLoS ONE 2017, 12, e0172415. [Google Scholar] [CrossRef] [PubMed]
  105. Sotgiu, S.; Mameli, G.; Serra, C.; Zarbo, I.R.; Arru, G.; Dolei, A. Multiple sclerosis-associated retrovirus and progressive disability of multiple sclerosis. Mult. Scler. 2010, 16, 1248–1251. [Google Scholar] [CrossRef]
  106. Mostafa, A.; Jalilvand, S.; Shoja, Z.; Nejati, A.; Shahmahmoodi, S.; Sahraian, M.A.; Marashi, S.M. Multiple sclerosis-associated retrovirus, Epstein-Barr virus, and vitamin D status in patients with relapsing remitting multiple sclerosis. J. Med. Virol. 2017, 89, 1309–1313. [Google Scholar] [CrossRef]
  107. Nowak, J.; Januszkiewicz, D.; Pernak, M.; Liweń, I.; Zawada, M.; Rembowska, J.; Nowicka, K.; Lewandowski, K.; Hertmanowska, H.; Wender, M. Multiple sclerosis-associated virus-related pol sequences found both in multiple sclerosis and healthy donors are more frequently expressed in multiple sclerosis patients. J. Neurovirol. 2003, 9, 112–117. [Google Scholar] [CrossRef]
  108. Alvarez-Lafuente, R.; García-Montojo, M.; de las Heras, V.; Domínguez-Mozo, M.I.; Bartolome, M.; Benito-Martin, M.S.; Arroyo, R. Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients. Mult. Scler. 2008, 14, 595–601. [Google Scholar] [CrossRef]
  109. Ruprecht, K.; Gronen, F.; Sauter, M.; Best, B.; Rieckmann, P.; Mueller-Lantzsch, N. Lack of immune responses against multiple sclerosis-associated retrovirus/human endogenous retrovirus W in patients with multiple sclerosis. J. Neurovirol. 2008, 14, 143–151. [Google Scholar] [CrossRef]
  110. Avrameas, S.; Alexopoulos, H.; Moutsopoulos, H.M. Natural Autoantibodies: An Undersugn Hero of the Immune System and Autoimmune Disorders-A Point of View. Front. Immunol. 2018, 1320. [Google Scholar] [CrossRef] [Green Version]
  111. Antony, J.M.; Izad, M.; Bar-Or, A.; Warren, K.G.; Vodjgani, M.; Mallet, F.; Power, C. Quantitative analysis of human endogenous retrovirus-W env in neuroinflammatory diseases. AIDS Res. Hum. Retroviruses 2006, 22, 1253–1259. [Google Scholar] [CrossRef]
  112. Mameli, G.; Serra, C.; Astone, V.; Castellazzi, M.; Poddighe, L.; Fainardi, E.; Neri, W.; Granieri, E.; Dolei, A. Inhibition of multiple-sclerosis-associated retrovirus as biomarker of interferon therapy. J. Neurovirol. 2008, 14, 73–77. [Google Scholar] [CrossRef] [PubMed]
  113. Rolland, A.; Jouvin-Marche, E.; Saresella, M.; Ferrante, P.; Cavaretta, R.; Creange, A.; Marche, P.; Perron, H. Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis. J. Neuroimmunol. 2005, 160, 195–203. [Google Scholar] [CrossRef] [PubMed]
  114. Brudek, T.; Christensen, T.; Hansen, H.J.; Petersen, T.; Møller-Larsen, A. Synergistic immune responses induced by endogenous retrovirus and herpesvirus antigens result in increased production of inflammatory cytokines in multiple sclerosis patients. Scand. J. Immunol. 2008, 67, 295–303. [Google Scholar] [CrossRef] [PubMed]
  115. Madeira, A.; Burgelin, I.; Perron, H.; Curtin, F.; Lang, A.B.; Faucard, R. MSRV envelope protein is a potent, endogenous and pathogenic agonist of human toll-like receptor 4: Relevance of GNbAC1 in multiple sclerosis treatment. J. Neuroimmunol. 2016, 291, 29–38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Trabattoni, D.; Ferrante, P.; Fusi, M.L.; Saresella, M.; Caputo, D.; Urnovitz, H.; Cazzullo, C.L.; Clerici, M. Augmented type I cytokines and human endogenous retroviruses specific immune responses in patients with acute multiple sclerosis. J. Neurovirol. 2000, 6, S38–S41. [Google Scholar]
  117. Clerici, M.; Fusi, M.L.; Caputo, D.; Guerini, F.R.; Trabattoni, D.; Salvaggio, A.; Cazzullo, C.L.; Arienti, D.; Villa, M.L.; Urnovitz, H.B.; et al. Immune responses to antigens of human endogenous retroviruses in patients with acute or stable multiple sclerosis. J. Neuroimmunol. 1999, 99, 173–182. [Google Scholar] [CrossRef]
  118. Duperray, A.; Barbe, D.; Raguenez, G.; Weksler, B.B.; Romero, I.A.; Couraud, P.-O.; Perron, H.; Marche, P.N. Inflammatory response of endothelial cells to a human endogenous retrovirus associated with multiple sclerosis is mediated by TLR4. Int. Immunol. 2015, 27, 545–553. [Google Scholar] [CrossRef] [Green Version]
  119. Kremer, D.; Schichel, T.; Förster, M.; Tzekova, N.; Bernard, C.; van der Valk, P.; van Horssen, J.; Hartung, H.-P.; Perron, H.; Küry, P. Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann. Neurol. 2013, 74, 721–732. [Google Scholar] [CrossRef]
  120. Kremer, D.; Förster, M.; Schichel, T.; Göttle, P.; Hartung, H.-P.; Perron, H.; Küry, P. The neutralizing antibody GNbAC1 abrogates HERV-W envelope protein-mediated oligodendroglial maturation blockade. Mult. Scler. 2015, 21, 1200–1203. [Google Scholar] [CrossRef]
  121. Göttle, P.; Förster, M.; Gruchot, J.; Kremer, D.; Hartung, H.P.; Perron, H.; Küry, P. Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination. Glia 2019, 67, 160–170. [Google Scholar] [CrossRef] [Green Version]
  122. Antony, J.M.; van Marle, G.; Opii, W.; Butterfield, D.A.; Mallet, F.; Yong, V.W.; Wallace, J.L.; Deacon, R.M.; Warren, K.; Power, C. Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat. Neurosci. 2004, 7, 1088–1095. [Google Scholar] [CrossRef] [PubMed]
  123. Antony, J.M.; Ellestad, K.K.; Hammond, R.; Imaizumi, K.; Mallet, F.; Warren, K.G.; Power, C. The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinflammation and its receptor expression in multiple sclerosis: A role for endoplasmic reticulum chaperones in astrocytes. J. Immunol. 2007, 179, 1210–1224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Perron, H.; Dougier-Reynaud, H.-L.; Lomparski, C.; Popa, I.; Firouzi, R.; Bertrand, J.-B.; Marusic, S.; Portoukalian, J.; Jouvin-Marche, E.; Villiers, C.L.; et al. Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice. PLoS ONE 2013, 8, e80128. [Google Scholar] [CrossRef] [PubMed]
  125. Nexo, B.A.; Villesen, P.; Nissen, K.K.; Lindegaard, H.M.; Rossing, P.; Petersen, T.; Tarnow, L.; Hansen, B.; Lorenzen, T.; Horslev-Petersen, K.; et al. Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci. Immunol. Res. 2015, 55–63. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Nexø, B.A.; Christensen, T.; Frederiksen, J.; Møller-Larsen, A.; Oturai, A.B.; Villesen, P.; Hansen, B.; Nissen, K.K.; Laska, M.J.; Petersen, T.S.; et al. The etiology of multiple sclerosis: Genetic evidence for the involvement of the human endogenous retrovirus HERV-Fc1. PLoS ONE 2011, 6, e16652. [Google Scholar] [CrossRef] [PubMed]
  127. De la Hera, B.; Varade, J.; Garcia-Montojo, M.; Alcina, A.; Fedetz, M.; Alloza, I.; Astobiza, I.; Leyva, L.; Fernandez, O.; Izquierdo, G.; et al. Human endogenous retrovirus HERV-Fc1 association with multiple sclerosis susceptibility: A Meta-Analysis. PLoS ONE 2014, 9, e90182. [Google Scholar] [CrossRef] [PubMed]
  128. Laska, M.J.; Brudek, T.; Nissen, K.K.; Christensen, T.; Møller-Larsen, A.; Petersen, T.; Nexø, B.A. Expression of HERV-Fc1, a human endogenous retrovirus, is increased in patients with active multiple sclerosis. J. Virol. 2012, 86, 3713–3722. [Google Scholar] [CrossRef] [Green Version]
  129. Christensen, T.; Dissing Sørensen, P.; Riemann, H.; Hansen, H.J.; Munch, M.; Haahr, S.; Møller-Larsen, A. Molecular characterization of HERV-H variants associated with multiple sclerosis. Acta Neurol. Scand. 2000, 101, 229–238. [Google Scholar] [CrossRef]
  130. Christensen, T.; Sørensen, P.D.; Hansen, H.J.; Møller-Larsen, A. Antibodies against a human endogenous retrovirus and the preponderance of env splice variants in multiple sclerosis patients. Mult. Scler. 2003, 9, 6–15. [Google Scholar] [CrossRef]
  131. Johnston, J.B.; Silva, C.; Holden, J.; Warren, K.G.; Clark, A.W.; Power, C. Monocyte activation and differentiation augment human endogenous retrovirus expression: Implications for inflammatory brain diseases. Ann. Neurol. 2001, 50, 434–442. [Google Scholar] [CrossRef]
  132. Gjelstrup, M.C.; Stilund, M.; Petersen, T.; Møller, H.J.; Petersen, E.L.; Christensen, T. Subsets of activated monocytes and markers of inflammation in incipient and progressed multiple sclerosis. Immunol. Cell Biol. 2018, 96, 160–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Carstensen, M.; Christensen, T.; Stilund, M.; Møller, H.J.; Petersen, E.L.; Petersen, T. Activated monocytes and markers of inflammation in newly diagnosed multiple sclerosis. Immunol. Cell Biol. 2020, 98, 549–562. [Google Scholar] [CrossRef]
  134. Waschbisch, A.; Schröder, S.; Schraudner, D.; Sammet, L.; Weksler, B.; Melms, A.; Pfeifenbring, S.; Stadelmann, C.; Schwab, S.; Linker, R.A. Pivotal Role for CD16+ Monocytes in Immune Surveillance of the Central Nervous System. J. Immunol. 2016, 196, 1558–1567. [Google Scholar] [CrossRef] [PubMed]
  135. Belshaw, R.; Dawson, A.L.A.; Woolven-Allen, J.; Redding, J.; Burt, A.; Tristem, M. Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): Implications for present-day activity. J Virol 2005, 79, 12507–12514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Barbulescu, M.; Turner, G.; Seaman, M.I.; Deinard, A.S.; Kidd, K.K.; Lenz, J. Many human endogenous retrovirus K (HERV-K) proviruses are unique to humans. Curr. Biol. 1999, 9, 861-S1. [Google Scholar] [CrossRef] [Green Version]
  137. Moyes, D.L.; Goris, A.; Ban, M.; Compston, A.; Griffiths, D.J.; Sawcer, S.; Venables, P.J. HERV-K113 is not associated with multiple sclerosis in a large family-based study. AIDS Res. Hum. Retroviruses 2008, 24, 363–365. [Google Scholar] [CrossRef]
  138. Kahyo, T.; Yamada, H.; Tao, H.; Kurabe, N.; Sugimura, H. Insertionally polymorphic sites of human endogenous retrovirus-K (HML-2) with long target site duplications. BMC Genomics 2017, 18, 487. [Google Scholar] [CrossRef] [Green Version]
  139. Tai, A.K.; O’Reilly, E.J.; Alroy, K.A.; Simon, K.C.; Munger, K.L.; Huber, B.T.; Ascherio, A. Human endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis. Mult. Scler. 2008, 14, 1175–1180. [Google Scholar] [CrossRef] [Green Version]
  140. De la Hera, B.; Varadé, J.; García-Montojo, M.; Lamas, J.R.; de la Encarnación, A.; Arroyo, R.; Fernández-Gutiérrez, B.; Alvarez-Lafuente, R.; Urcelay, E. Role of the human endogenous retrovirus HERV-K18 in autoimmune disease susceptibility: Study in the Spanish population and meta-analysis. PLoS ONE 2013, 8, e62090. [Google Scholar] [CrossRef]
  141. Kim, G.; Gautier, O.; Tassoni-Tsuchida, E.; Ma, X.R.; Gitler, A.D. ALS genetics: Gains, losses, andi for future therapies. Neuron 2020, 108, 822–842. [Google Scholar] [CrossRef]
  142. Norris, S.P.; Likanje, M.N.; Andrews, J.A. Amyotrophic lateral sclerosis: Update on clinical management. Curr. Opin. Neurol. 2020, 33, 641–648. [Google Scholar] [CrossRef] [PubMed]
  143. Le Gall, L.; Anakor, E.; Connolly, O.; Vijayakumar, U.G.; Duddy, W.J.; Duguez, S. Molecular and cellular mechanisms affected in ALS. J. Pers. Med. 2020, 10, 101. [Google Scholar] [CrossRef] [PubMed]
  144. Gonzalez Trujillo, F.; Parra Cortes, K.; Álvarez Pareja, Y.; Onate, J. Human T-cell lymphotropic virus type 1 associated with amyotrophic lateral sclerosis syndrome: Immunopathological aspects and treatment options. Cureus 2020, 12, e7531. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Steele, A.J.; Al-Chalabi, A.; Ferrante, K.; Cudkowicz, M.E.; Brown, R.H.J.; Garson, J.A. Detection of serum reverse transcriptase activity in patients with ALS and unaffected blood relatives. Neurology 2005, 64, 454–458. [Google Scholar] [CrossRef] [PubMed]
  146. Su, Y.; Ghodke, P.P.; Egli, M.; Li, L.; Wang, Y.; Guengerich, F.P. Human DNA polymerase eta has reverse transcriptase activity in cellular environments. J. Biol. Chem. 2019, 294, 6073–6081. [Google Scholar] [CrossRef] [Green Version]
  147. Douville, R.; Liu, J.; Rothstein, J.; Nath, A. Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann. Neurol. 2011, 69, 141–151. [Google Scholar] [CrossRef]
  148. Li, W.; Lee, M.H.; Henderson, L.; Tyagi, R.; Bachani, M.; Steiner, J.; Campanac, E.; Hoffman, D.A.; von Geldern, G.; Johnson, K.; et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl. Med. 2015, 7, 307ra153. [Google Scholar] [CrossRef]
  149. Manghera, M.; Ferguson-Parry, J.; Douville, R.N. TDP-43 regulates endogenous retrovirus-K viral protein accumulation. Neurobiol. Dis. 2016, 94, 226–236. [Google Scholar] [CrossRef]
  150. Krug, L.; Chatterjee, N.; Borges-Monroy, R.; Hearn, S.; Liao, W.W.; Morrill, K.; Prazak, L.; Rozhkov, N.; Theodorou, D.; Hammell, M.; et al. Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet. 2017, 13, e1006635. [Google Scholar] [CrossRef] [Green Version]
  151. Chang, Y.H.; Dubnau, J. The gypsy endogenous retrovirus drives non-cell-autonomous propagation in a Drosophila TDP-43 model of neurodegeneration. Curr. Biol. 2019, 29, 3135–3152.e4. [Google Scholar] [CrossRef]
  152. Prudencio, M.; Gonzales, P.K.; Cook, C.N.; Gendron, T.F.; Daughrity, L.M.; Song, Y.; Ebbert, M.T.W.; van Blitterswijk, M.; Zhang, Y.J.; Jansen-West, K.; et al. Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Hum. Mol. Genet. 2017, 26, 3421–3431. [Google Scholar] [CrossRef]
  153. Ibba, G.; Piu, C.; Uleri, E.; Serra, C.; Dolei, A. Disruption by SaCas9 Endonuclease of HERV-Kenv, a retroviral gene with oncogenic and neuropathogenic potential, inhibits molecules involved in cancer and amyotrophic lateral sclerosis. Viruses 2018, 10, 412. [Google Scholar] [CrossRef] [Green Version]
  154. Manghera, M.; Ferguson-Parry, J.; Lin, R.; Douville, R.N. NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5’ Long Terminal Repeat. J. Virol. 2016, 90, 9338–9349. [Google Scholar] [CrossRef] [Green Version]
  155. Mayer, J.; Harz, C.; Sanchez, L.; Pereira, G.C.; Maldener, E.; Heras, S.R.; Ostrow, L.W.; Ravits, J.; Batra, R.; Meese, E.; et al. Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins. Mol. Neurodegener. 2018, 13, 39. [Google Scholar] [CrossRef]
  156. Garson, J.A.; Usher, L.; Al-Chalabi, A.; Huggett, J.; Day, E.F.; McCormick, A.L. Quantitative analysis of human endogenous retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 2019, 7, 45. [Google Scholar] [CrossRef] [Green Version]
  157. Garcia-Montojo, M.; Li, W.; Nath, A. Technical considerations in detection of HERV-K in amyotrophic lateral sclerosis: Selection of controls and the perils of qPCR. Acta Neuropathol. Commun. 2019, 7, 101. [Google Scholar] [CrossRef] [Green Version]
  158. Garson, J.A.; Usher, L.; Al-Chalabi, A.; Huggett, J.; Day, E.F.; McCormick, A.L. Response to the letter from Garcia-Montojo and colleagues concerning our paper entitled, quantitative analysis of human endogenous retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 2019, 7, 102. [Google Scholar] [CrossRef] [Green Version]
  159. Dembny, P.; Newman, A.G.; Singh, M.; Hinz, M.; Szczepek, M.; Krüger, C.; Adalbert, R.; Dzaye, O.; Trimbuch, T.; Wallach, T.; et al. Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. JCI Insight 2020, 5, e131093. [Google Scholar] [CrossRef] [Green Version]
  160. Tam, O.H.; Ostrow, L.W.; Hammell, M.G. Diseases of the nERVous system: Retrotransposon activity in neurodegenerative disease. Mob. DNA 2019, 10, 32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  161. Stetson, D.B.; Ko, J.S.; Heidmann, T.; Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 2008, 134, 587–598. [Google Scholar] [CrossRef] [Green Version]
  162. Guo, C.; Jeong, H.H.; Hsieh, Y.C.; Klein, H.U.; Bennett, D.A.; De Jager, P.L.; Liu, Z.; Shulman, J.M. Tau activates transposable elements in Alzheimer’s disease. Cell Rep. 2018, 23, 2874–2880. [Google Scholar] [CrossRef]
  163. Sun, W.; Samimi, H.; Gamez, M.; Zare, H.; Frost, B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat. Neurosci. 2018, 21, 1038–1048. [Google Scholar] [CrossRef]
  164. Weick, E.M.; Miska, E.A. piRNAs: From biogenesis to function. Development 2014, 141, 3458–3471. [Google Scholar] [CrossRef] [Green Version]
  165. Faucard, R.; Madeira, A.; Gehin, N.; Authier, F.J.; Panaite, P.A.; Lesage, C.; Burgelin, I.; Bertel, M.; Bernard, C.; Curtin, F.; et al. Human endogenous retrovirus and neuroinflammation in chronic inflammatory demyelinating polyradiculoneuropathy. EBioMedicine 2016, 6, 190–198. [Google Scholar] [CrossRef] [Green Version]
  166. Ovejero, T.; Sadones, O.; Sánchez-Fito, T.; Almenar-Pérez, E.; Espejo, J.A.; Martín-Martínez, E.; Nathanson, L.; Oltra, E. Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients. Int. J. Mol. Sci. 2020, 21, 1366. [Google Scholar] [CrossRef] [Green Version]
  167. Singh, S.; Stafford, P.; Schlauch, K.A.; Tillett, R.R.; Gollery, M.; Johnston, S.A.; Khaiboullina, S.F.; De Meirleir, K.L.; Rawat, S.; Mijatovic, T.; et al. Humoral immunity profiling of subjects with myalgic encephalomyelitisu a random peptide microarray differentiates cases from controls with high specificity and sensitivity. Mol. Neurobiol. 2018, 55, 633–6641. [Google Scholar] [CrossRef] [Green Version]
  168. Rodrigues, L.S.; da Silva Nali, L.H.; Leal, C.O.D.; Sabino, E.C.; Lacerda, E.M.; Kingdon, C.C.; Nacul, L.; Romano, C.M. HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome. Auto Immun. Highlights 2019, 10, 12. [Google Scholar] [CrossRef] [Green Version]
  169. De Meirleir, K.L.; Khaiboullina, S.F.; Frémont, M.; Hulstaert, J.; Rizvanov, A.A.; Palotás, A.; Lombardi, V.C. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins. In Vivo 2013, 27, 177–187. [Google Scholar]
  170. Greenwood, A.D.; Vincendeau, M.; Schmädicke, A.C.; Montag, J.; Seifarth, W.; Motzkus, D. Bovine spongiform encephalopathy infection alters endogenous retrovirus expression in distinct brain regions of cynomolgus macaques (Macaca fascicularis). Mol. Neurodegener. 2011, 6, 44. [Google Scholar] [CrossRef] [Green Version]
  171. Jeong, B.H.; Lee, Y.J.; Carp, R.I.; Kim, Y.S. The prevalence of human endogenous retroviruses in cerebrospinal fluids from patients with sporadic Creutzfeldt-Jakob disease. J. Clin. Virol. 2010, 47, 136–142. [Google Scholar] [CrossRef]
  172. Stengel, A.; Bach, C.; Vorberg, I.; Frank, O.; Gilch, S.; Lutzny, G.; Seifarth, W.; Erfle, V.; Maas, E.; Schätzl, H.; et al. Prion infection influences murine endogenous retrovirus expression in neuronal cells. Biochem. Biophys. Res. Commun. 2006, 343, 825–831. [Google Scholar] [CrossRef]
  173. Rex, C.; Nadeau, M.J.; Douville, R.; Schellenberg, K. Expression of human endogenous retrovirus-K in spinal and bulbar muscular atrophy. Front. Neurol. 2019, 10, 968. [Google Scholar] [CrossRef]
  174. Hanke, K.; Chudak, C.; Kurth, R.; Bannert, N. The Rec protein of HERV-K(HML-2) upregulates androgen receptor activity by binding to the human small glutamine-rich tetratricopeptide repeat protein (hSGT). Int. J. Cancer 2013, 132, 556–567. [Google Scholar] [CrossRef]
  175. Arancio, W. Progerin expression induces a significant downregulation of transcription from human repetitive sequences in iPSC-derived dopaminergic neurons. Geroscience 2019, 41, 39–49. [Google Scholar] [CrossRef]
  176. Balestrieri, E.; Cipriani, C.; Matteucci, C.; Benvenuto, A.; Coniglio, A.; Argaw-Denboba, A.; Toschi, N.; Bucci, I.; Miele, M.T.; Grelli, S.; et al. Children with autism spectrum disorder and their mothers share abnormal expression of selected endogenous retroviruses families and cytokines. Front. Immunol. 2019, 10, 2244. [Google Scholar] [CrossRef] [Green Version]
  177. Balestrieri, E.; Arpino, C.; Matteucci, C.; Sorrentino, R.; Pica, F.; Alessandrelli, R.; Coniglio, A.; Curatolo, P.; Rezza, G.; Macciardi, F.; et al. HERVs expression in autism spectrum disorders. PLoS ONE 2012, 7, e48831. [Google Scholar] [CrossRef] [Green Version]
  178. Balestrieri, E.; Pitzianti, M.; Matteucci, C.; D’Agati, E.; Sorrentino, R.; Baratta, A.; Caterina, R.; Zenobi, R.; Curatolo, P.; Garaci, E.; et al. Human endogenous retroviruses and ADHD. World J. Biol. Psychiatry 2014, 15, 499–504. [Google Scholar] [CrossRef]
  179. D’Agati, E.; Pitzianti, M.; Balestrieri, E.; Matteucci, C.; Sinibaldi Vallebona, P.; Pasini, A. First evidence of HERV-H transcriptional activity reduction after methylphenidate treatment in a young boy with ADHD. New Microbiol. 2016, 39, 237–239. [Google Scholar]
  180. Cipriani, C.; Pitzianti, M.B.; Matteucci, C.; D’Agati, E.; Miele, M.T.; Rapaccini, V.; Grelli, S.; Curatolo, P.; Sinibaldi-Vallebona, P.; Pasini, A.; et al. The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy. Int. J. Mol. Sci. 2018, 19, 3286. [Google Scholar] [CrossRef] [Green Version]
  181. Frank, O.; Giehl, M.; Zheng, C.; Hehlmann, R.; Leib-Mösch, C.; Seifarth, W. Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders. J. Virol. 2005, 79, 10890–108901. [Google Scholar] [CrossRef] [Green Version]
  182. Perron, H.; Hamdani, N.; Faucard, R.; Lajnef, M.; Jamain, S.; Daban-Huard, C.; Sarrazin, S.; LeGuen, E.; Houenou, J.; Delavest, M.; et al. Molecular characteristics of human endogenous retrovirus type-W in schizophrenia and bipolar disorder. Transl. Psychiatry 2012, 2, e201. [Google Scholar] [CrossRef] [PubMed]
  183. Karlsson, H.; Bachmann, S.; Schröder, J.; McArthur, J.; Torrey, E.F.; Yolken, R.H. Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Proc. Natl. Acad. Sci. USA 2001, 98, 4634–4639. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Yao, Y.; Schröder, J.; Nellåker, C.; Bottmer, C.; Bachmann, S.; Yolken, R.H.; Karlsson, H. Elevated levels of human endogenous retrovirus-W transcripts in blood cells from patients with first episode schizophrenia. Genes Brain Behav. 2008, 7, 103–112. [Google Scholar] [CrossRef]
  185. Perron, H.; Mekaoui, L.; Bernard, C.; Veas, F.; Stefas, I.; Leboyer, M. Endogenous retrovirus type W GAG and envelope protein antigenemia in serum of schizophrenic patients. Biol. Psychiatry 2008, 64, 1019–1023. [Google Scholar] [CrossRef]
  186. Li, F.; Sabunciyan, S.; Yolken, R.H.; Lee, D.; Kim, S.; Karlsson, H. Transcription of human endogenous retroviruses in human brain by RNA-seq analysis. PLoS ONE 2019, 14, e0207353. [Google Scholar] [CrossRef] [Green Version]
  187. Johansson, E.M.; Bouchet, D.; Tamouza, R.; Ellul, P.; Morr, A.S.; Avignone, E.; Germi, R.; Leboyer, M.; Perron, H.; Groc, L. Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis. Sci. Adv. 2020, 6, eabc0708. [Google Scholar] [CrossRef]
  188. Dickerson, F.; Rubalcaba, E.; Viscidi, R.; Yang, S.; Stallings, C.; Sullens, A.; Origoni, A.; Leister, F.; Yolken, R. Polymorphisms in human endogenous retrovirus K-18 and risk of type 2 diabetes in individuals with schizophrenia. Schizophr. Res. 2008, 104, 121–126. [Google Scholar] [CrossRef]
  189. Deb-Rinker, P.; O’Reilly, R.L.; Torrey, E.F.; Singh, S.M. Molecular characterization of a 2.7-kb, 12q13-specific, retroviral-related sequence isolated by RDA from monozygotic twin pairs discordant for schizophrenia. Genome 2002, 45, 381–390. [Google Scholar] [CrossRef]
  190. Deb-Rinker, P.; Klempan, T.A.; O’Reilly, R.L.; Torrey, E.F.; Singh, S.M. Molecular characterization of a MSRV-like sequence identified by RDA from monozygotic twin pairs discordant for schizophrenia. Genomics 1999, 61, 133–144. [Google Scholar] [CrossRef]
  191. Nakamura, A.; Okazaki, Y.; Sugimoto, J.; Oda, T.; Jinno, Y. Human endogenous retroviruses with transcriptional potential in the brain. J. Hum. Genet. 2003, 48, 575–581. [Google Scholar] [CrossRef] [Green Version]
  192. Kim, H.S.; Wadekar, R.V.; Takenaka, O.; Winstanley, C.; Mitsunaga, F.; Kageyama, T.; Hyun, B.H.; Crow, T.J. SINE-R.C2 (a Homo sapiens specific retroposon) is homologous to CDNA from postmortem brain in schizophrenia and to two loci in the Xq21.3/Yp block linked to handedness and psychosis. Am. J. Med. Genet. 1999, 88, 560–566. [Google Scholar] [CrossRef]
  193. Suntsova, M.; Gogvadze, E.V.; Salozhin, S.; Gaifullin, N.; Eroshkin, F.; Dmitriev, S.E.; Martynova, N.; Kulikov, K.; Malakhova, G.; Tukhbatova, G.; et al. Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH. Proc. Natl. Acad. Sci. USA 2013, 110, 19472–19477. [Google Scholar] [CrossRef] [Green Version]
  194. Mueller, T.; Hantsch, C.; Volkmer, I.; Staege, M.S. Differentiation-dependent regulation of human endogenous retrovirus K sequences and neighboring genes in germ cell tumor cells. Front. Microbiol. 2018, 9, 1253. [Google Scholar] [CrossRef] [Green Version]
  195. Contreras-Galindo, R.; González, M.; Almodovar-Camacho, S.; González-Ramírez, S.; Lorenzo, E.; Yamamura, Y. A new Real-Time-RT-PCR for quantitation of human endogenous retroviruses type K (HERV-K) RNA load in plasma samples: Increased HERV-K RNA titers in HIV-1 patients with HAART non-suppressive regimens. J. Virol. Methods 2006, 136, 51–57. [Google Scholar] [CrossRef]
  196. Scelsa, S.N.; MacGowan, D.J.L.; Mitsumoto, H.; Imperato, T.; LeValley, A.J.; Liu, M.H.; DelBene, M.; Kim, M.Y. A pilot, double-blind, placebo-controlled trial of indinavir in patients with ALS. Neurology 2005, 64, 1298–1300. [Google Scholar] [CrossRef]
  197. Bowen, L.N.; Tyagi, R.; Li, W.; Alfahad, T.; Smith, B.; Wright, M.; Singer, E.J.; Nath, A. HIV-associated motor neuron disease: HERV-K activation and response to antiretroviral therapy. Neurology 2016, 87, 1756–1762. [Google Scholar] [CrossRef] [Green Version]
  198. Gold, J.; Rowe, D.B.; Kiernan, M.C.; Vucic, S.; Mathers, S.; van Eijk, R.P.A.; Nath, A.; Garcia Montojo, M.; Norato, G.; Santamaria, U.A.; et al. Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: The Lighthouse trial. Amyotroph. Lateral Scler. Frontotemporal Degener. 2019, 20, 595–604. [Google Scholar] [CrossRef] [Green Version]
  199. Maruszak, H.; Brew, B.J.; Giovannoni, G.; Gold, J. Could antiretroviral drugs be effective in multiple sclerosis? A case report. Eur. J. Neurol. 2011, 9, e110–e111. [Google Scholar] [CrossRef]
  200. Gold, J.; Marta, M.; Meier, U.C.; Christensen, T.; Miller, D.; Altmann, D.; Holden, D.; Bianchi, L.; Adiutori, R.; MacManus, D.; et al. A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study. Mult. Scler. Relat. Disord. 2018, 24, 123–128. [Google Scholar] [CrossRef]
  201. Perron, H.; Jouvin-Marche, E.; Michel, M.; Ounanian-Paraz, A.; Camelo, S.; Dumon, A.; Jolivet-Reynaud, C.; Marcel, F.; Souillet, Y.; Borel, E.; et al. Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation. Virology 2001, 287, 321–332. [Google Scholar] [CrossRef] [Green Version]
  202. Curtin, F.; Perron, H.; Kromminga, A.; Porchet, H.; Lang, A.B. Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein. MAbs 2015, 7, 265–275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  203. Porchet, H.; Vidal, V.; Kornmann, G.; Malpass, S.; Curtin, F. A High-dose pharmacokinetic study of a new IgG4 monoclonal antibody temelimab/GNbAC1 antagonist of an endogenous retroviral protein pHERV-W Env. Clin. Ther. 2019, 41, 1737–1746. [Google Scholar] [CrossRef] [PubMed]
  204. Curtin, F.; Lang, A.B.; Perron, H.; Laumonier, M.; Vidal, V.; Porchet, H.C.; Hartung, H.-P. GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: A first-in-humans randomized clinical study. Clin. Ther. 2012, 34, 2268–2278. [Google Scholar] [CrossRef] [PubMed]
  205. Curtin, F.; Vidal, V.; Bernard, C.; Kromminga, A.; Lang, A.B.; Porchet, H. Serum pharmacokinetics and cerebrospinal fluid concentration analysis of the new IgG4 monoclonal antibody GNbAC1 to treat multiple sclerosis: A Phase 1 study. MAbs 2016, 8, 854–860. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Derfuss, T.; Curtin, F.; Guebelin, C.; Bridel, C.; Rasenack, M.; Matthey, A.; Du Pasquier, R.; Schluep, M.; Desmeules, J.; Lang, A.B.; et al. A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients—A twelve month follow-up. J. Neuroimmunol. 2015, 285, 68–70. [Google Scholar] [CrossRef] [Green Version]
  207. Derfuss, T.; Curtin, F.; Guebelin, C.; Bridel, C.; Rasenack, M.; Matthey, A.; Du Pasquier, R.; Schluep, M.; Desmeules, J.; Lang, A.B.; et al. A phase II a randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients. Mult. Scler. 2015, 21, 885–893. [Google Scholar] [CrossRef] [Green Version]
  208. Curtin, F.; Porchet, H.; Glanzman, R.; Schneble, H.M.; Vidal, V.; Audoli-Inthavong, M.-L.; Lambert, E.; Hartung, H.P. A placebo randomized controlled study to test the efficacy and safety of GNbAC1, a monoclonal antibody for the treatment of multiple sclerosis—Rationale and design. Mult. Scler. Relat. Disord. 2016, 9, 95–100. [Google Scholar] [CrossRef]
  209. Hartung, H.P. Week 48 results from a phase IIb trial of GNbAC1 in patients with relapsing remitting multiple sclerosis (CHANGE-MS; clinical trial assessing the HERV-W Env antagonist GNbAC1 for Efficacy in MS). ECTRIMS Online Libr. 2018, 24, 51–52. [Google Scholar]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Gröger, V.; Emmer, A.; Staege, M.S.; Cynis, H. Endogenous Retroviruses in Nervous System Disorders. Pharmaceuticals 2021, 14, 70. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010070

AMA Style

Gröger V, Emmer A, Staege MS, Cynis H. Endogenous Retroviruses in Nervous System Disorders. Pharmaceuticals. 2021; 14(1):70. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010070

Chicago/Turabian Style

Gröger, Victoria, Alexander Emmer, Martin S. Staege, and Holger Cynis. 2021. "Endogenous Retroviruses in Nervous System Disorders" Pharmaceuticals 14, no. 1: 70. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010070

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop