Erratum: Genomic analysis of ERVWE2 locus in patients with Multiple sclerosis: absence of genetic association but potential role of Human Endogenous retrovirus type W elements in molecular mimicry with myelin antigen.
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ABSTRACT:
SUBMITTER: Romano CM
PROVIDER: S-EPMC3831600 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Erratum: Genomic analysis of ERVWE2 locus in patients with Multiple sclerosis: absence of genetic association but potential role of Human Endogenous retrovirus type W elements in molecular mimicry with myelin antigen.
Frontiers in microbiology 20131118
[This corrects the article on p. 172 in vol. 4, PMID: 23805135.]. ...[more]
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Project description:Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5' LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesis.
| S-EPMC3693062 | biostudies-literature
Project description:Genetic and environmental factors are believed to influence development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERV) correspond to the integrated proviral form of infectious retroviruses, which are trapped within the genome due to mutations. ERV represent a key molecular link between the host genome and infectious viral particles. ERV-encoded proteins are recognized by antiviral immune responses and become targets of autoreactivity. Alternatively, ERV protein may influence cellular processes and the life cycle of infectious viruses. As examples, the HRES-1 human ERV encodes a 28-kDa nuclear autoantigen and a 24-kDa small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a nuclear autoantigen recognized by cross-reactive antiviral antibodies, while HRES-1/Rab4 regulates surface expression of CD4 and the transferrin receptor (TFR) through endosome recycling. Expression of HRES-1/Rab4 is induced by the tat gene of HIV-1, which in turn down-regulates expression of CD4 and susceptibility to re-infection by HIV-1. CD4 and the TFR play essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. T-cell receptorzeta (TCRzeta) chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced lck and TCRzeta chain levels. HRES-1 is centrally located on chromosome 1 at q42 relative to lupus-linked microsatellite markers and polymorphic HRES-1 alleles have been linked to the development of SLE. 1q42 is one of the three most common fragile sites in the human genome, and is inducible by DNA demethylation, a known mechanism of retroviral gene activation. Molecular mimicry and immunomodulation by a ERV, such as HRES-1, may contribute to self-reactivity and abnormal T and B-cell functions in SLE.
| S-EPMC5294745 | biostudies-literature
Project description:Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.
| S-EPMC3250284 | biostudies-literature
Project description:BACKGROUND:It has been suggested that Human endogenous retroviruses (HERVs) are associated with multiple sclerosis (MS) pathogenesis. The objective of this study was to broadly evaluate the expression of HERV core (GAG) and envelope (ENV) genes in diseased brain white matter samples from MS patients compared to normal controls. METHODS:Twenty-eight HERV GAG and 88 ENV gene sequences were retrieved, classified by phylogeny, and grouped into clades. Consensus qPCR primers were designed for each clade, and quantitative PCR was performed on 33 MS and 9 normal control frozen brain samples. MS samples included chronic progressive (n=5), primary progressive (n=4), secondary progressive (n=14), relapsing remitting (n=3) and unclassified confirmed MS cases (n=7). The levels of GAG and ENV RNA within each of the samples were quantitated and normalized using the neuronal reference gene RPL19. Expression differences were analyzed for MS vs control. RESULTS:Expression of GAG clades 1A, 3B, and 3C mapping to HERV-E and HERV-K were significantly increased compared to controls, while GAG clade 3A expression was decreased. Expression of HERV ENV clades 2, 3A, 3B, mapping to RTVL, HERV-E and HERV-K and MSRV (HERV-W), were significantly increased in the MS group. However, the relative expression differences between the MS and control groups were small, differing less than 1.5-fold. CONCLUSION:Expression of GAG and ENV mapping to HERV-E, RTVL and HERV-K10 families were significantly increased in the MS group. However, the relative expression differences between the MS and control groups were small, differing less than 1.5-fold. These results indicate that the expression of HERV GAG and ENV regions do not differ greatly between MS and controls in these frozen brain samples.
| S-EPMC5580941 | biostudies-literature
Project description:Background: Endogenous retrovirus-K is a group of related genomic elements descending from retroviral infections in human ancestors. HML2 is the clade of these viruses which contains the most intact provirus copies. These elements can be transcribed and translated in healthy and diseased tissues, and some of them produce active retroviral enzymes, such as protease. Retroviral gene products, including protease, contribute to illness in exogenous retroviral infections. There are ongoing efforts to test anti-retroviral regimens against endogenous retroviruses. Herein, we examine the potential activity and diversity of human endogenous retrovirus-K proteases, and their potential for impact on immunity and human disease. Results: Sequences similar to the endogenous retrovirus-K HML2 protease and reverse transcriptase were identified in the human genome, classified by phylogenetic inference and compared to Repbase reference sequences. The topologies of trees inferred from protease and reverse transcriptase sequences were similar and agreed with the classification using reference sequences. Surprisingly, only 62/480 protease sequences identified by BLAST were classified as HML2; the remainder were classified as other HML groups, with the majority (216) classified as HML3. Variation in functionally significant protease motifs was explored, and two major active site variants were identified - the DTGAD variant is common in all groups, but the DTGVD motif appears limited to HML3, HML5, and HML6. Furthermore, distinct RNA expression patterns of protease variants are seen in disease states, such as amyotrophic lateral sclerosis, breast cancer, and prostate cancer. Conclusion: Transcribed ERVK proteases exhibit a diversity which could impact immunity and inhibitor-based treatments, and these facets should be considered when designing therapeutic regimens.
| S-EPMC6058741 | biostudies-literature
Project description:Human endogenous retroviruses (HERVs) of the HERV-W group comprise hundreds of loci in the human genome. Deregulated HERV-W expression and HERV-W locus ERVWE1-encoded Syncytin-1 protein have been implicated in the pathogenesis of multiple sclerosis (MS). However, the actual transcription of HERV-W loci in the MS context has not been comprehensively analyzed. We investigated transcription of HERV-W in MS brain lesions and white matter brain tissue from healthy controls by employing next-generation amplicon sequencing of HERV-W env-specific reverse transcriptase (RT) PCR products, thus revealing transcribed HERV-W loci and the relative transcript levels of those loci. We identified more than 100 HERV-W loci that were transcribed in the human brain, with a limited number of loci being predominantly transcribed. Importantly, relative transcript levels of HERV-W loci were very similar between MS and healthy brain tissue samples, refuting deregulated transcription of HERV-W env in MS brain lesions, including the high-level-transcribed ERVWE1 locus encoding Syncytin-1. Quantitative RT-PCR likewise did not reveal differences in MS regarding HERV-W env general transcript or ERVWE1- and ERVWE2-specific transcript levels. However, we obtained evidence for interindividual differences in HERV-W transcript levels. Reporter gene assays indicated promoter activity of many HERV-W long terminal repeats (LTRs), including structurally incomplete LTRs. Our comprehensive analysis of HERV-W transcription in the human brain thus provides important information on the biology of HERV-W in MS lesions and normal human brain, implications for study design, and mechanisms by which HERV-W may (or may not) be involved in MS.
| S-EPMC3838257 | biostudies-literature
Project description:We have previously identified in the human genome a family of 200 endogenous retrovirus-like elements, the HERV-L elements, disclosing similarities with the foamy retroviruses and which might be the evolutionary intermediate between classical intracellular retrotransposons and infectious retroviruses. Southern blot analysis of a large series of mammalian genomic DNAs shows that HERV-L-related elements-so-called ERV-L-are present among all placental mammals, suggesting that ERV-L elements were already present at least 70 million years ago. Most species exhibit a low copy number of ERV-L elements (from 10 to 30), while simians (not prosimians) and mice (not rats) have been subjected to bursts resulting in increases in the number of copies up to 200. The burst of copy number in primates can be dated to shortly after the prosimian and simian branchpoint, 45 to 65 million years ago, whereas murine species have been subjected to two much more recent bursts (less than 10 million years ago), occurring after the Mus/Rattus split. We have amplified and sequenced 360-bp ERV-L internal fragments of the highly conserved pol gene from a series of 22 mammalian species. These sequences exhibit high percentages of identity (57 to 99%) with the murine fully coding MuERV-L element. Phylogenetic analyses allowed the establishment of a plausible evolutionary scheme for ERV-L elements, which accounts for the high level of sequence conservation and the widespread dispersion among mammals.
| S-EPMC104094 | biostudies-literature
Project description:BackgroundThe human endogenous retrovirus (HERV)-K18 Env is an Epstein-Barr virus (EBV)-associated superantigen. Given the evidence for a role of EBV in the etiology of multiple sclerosis (MS), HERV-K18 Env is a plausible candidate for association with MS.ObjectiveTo assess whether variation in HERV-K18 Env is a risk factor for MS.MethodsWe developed a single nucleotide polymorphism-based genotyping method to determine the distribution of the three alleles of HERV-K18 env. We then conducted a nested case-control study including 207 MS cases and 403 matched controls. Analyses were replicated in an independent series of 909 MS cases and 339 controls.ResultsOverall, there was a significant association between HERV-K18 env genotype and MS risk (chi2 P = 0.03). As compared with K18.2/K18.2 individuals, risk of MS was three fold higher among K18.3/K18.3 individuals (P = 0.03). An increase in MS risk among carriers of the K18.3 allele was also observed in the replication study, but did not reach statistical significance. In pooled analyses, K18.3/K18.3 individuals had a significantly increased risk of MS (relative risks [RR] comparing K18.3/K18.3 vs K18.2/K18.2 = 2.7; 95% confidence interval: 1.1-6.4).ConclusionVariation in EBV-associated superantigen HERV-K18 Env could influence the genetic susceptibility to MS.
| S-EPMC2754175 | biostudies-literature
Project description:BACKGROUND: Aberrant expression of human endogenous retrovirus (HERV) elements in the W family has previously been associated with schizophrenia, multiple sclerosis and preeclampsia. Little is know regarding the basal expression, transcriptional regulation and functional significance of individual HERV-elements. Since viral infections have previously been reported to transactivate retroviral long terminal repeat regions we examined the basal expression of HERV-W elements and following infections by influenza A/WSN/33 and Herpes simplex 1 viruses in human cell-lines. METHODS: Relative levels of transcripts encoding HERV-W elements and cellular genes were analyzed by qPCR methods. An analysis of amplicon melting temperatures was used to detect variations in the frequencies of amplicons in discrete ranges of such melting temperatures. These frequency-distributions were taken as proxy markers for the repertoires of transcribed HERV-W elements in the cells. RESULTS: We report cell-specific expression patterns of HERV-W elements during base-line conditions. Expressed elements include those with intact regulatory long terminal repeat regions (LTRs) as well as elements flanked by truncated LTRs. Subsets of HERV-W elements were transactivated by viral infection in the different cell-lines. Transcriptional activation of these elements, including that encoding syncytin, was dependent on viral replication and was not induced by antiviral responses. Serum deprivation of cells induced similar changes in the expression of HERV-W elements suggesting that the observed phenomena are, in part, an effect of cellular stress. CONCLUSION: We found that HERV-W elements, including elements lacking regulatory LTRs, are expressed in cell-specific patterns which can be modulated by environmental influences. This brings into light that mechanisms behind the regulation of expression of HERV-W elements are more complex than previously assumed and suggests biological functions of these transcripts.
| S-EPMC1539011 | biostudies-literature
Project description:Elevated endogenous retrovirus (ERV) transcription and anti-ERV antibody reactivity are implicated in lupus pathogenesis. Overproduction of non-ecotropic ERV (NEERV) envelope glycoprotein gp70 and resultant nephritis occur in lupus-prone mice, but whether NEERV mis-expression contributes to lupus etiology is unclear. Here we identified suppressor of NEERV (Snerv) 1 and 2, Krüppel-associated box zinc-finger proteins (KRAB-ZFPs) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1. Germline Snerv1/Snerv2 deletion increased activating chromatin modifications, transcription, and gp70 expression from NEERV loci. F1 crosses of lupus-prone New Zealand Black (NZB) and 129 mice to Snerv1/Snerv2-/- mice failed to restore NEERV repression, demonstrating that loss of SNERV underlies the lupus autoantigen gp70 overproduction that promotes nephritis in susceptible mice and that SNERV encodes for Sgp3 (in NZB mice) and Gv-1 loci (in 129 mice). Increased ERV expression in lupus patients inversely correlated with three putative ERV-suppressing KRAB-ZFPs, suggesting that loss of KRAB-ZFP-mediated ERV control may contribute to human lupus pathogenesis.
| S-EPMC6382577 | biostudies-literature