Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family

Unité Mixte 103 CNRS-bioMérieux, Ecole Normale Supérieure de Lyon, 69364 Lyon, Cédex 07, France.
Journal of Virology (Impact Factor: 4.44). 03/1999; 73(2):1175-85.
Source: PubMed

ABSTRACT The multiple sclerosis-associated retrovirus (MSRV) isolated from plasma of MS patients was found to be phylogenetically and experimentally related to human endogenous retroviruses (HERVs). To characterize the MSRV-related HERV family and to test the hypothesis of a replication-competent HERV, we have investigated the expression of MSRV-related sequences in healthy tissues. The expression of MSRV-related transcripts restricted to the placenta led to the isolation of overlapping cDNA clones from a cDNA library. These cDNAs spanned a 7.6-kb region containing gag, pol, and env genes; RU5 and U3R flanking sequences; a polypurine tract; and a primer binding site (PBS). As this PBS showed similarity to avian retrovirus PBSs used by tRNATrp, this new HERV family was named HERV-W. Several genomic elements were identified, one of them containing a complete HERV-W unit, spanning all cDNA clones. Elements of this multicopy family were not replication competent, as gag and pol open reading frames (ORFs) were interrupted by frameshifts and stop codons. A complete ORF putatively coding for an envelope protein was found both on the HERV-W DNA prototype and within an RU5-env-U3R polyadenylated cDNA clone. Placental expression of 8-, 3.1-, and 1.3-kb transcripts was observed, and a putative splicing strategy was described. The apparently tissue-restricted HERV-W long terminal repeat expression is discussed with respect to physiological and pathological contexts.

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Available from: Perron Hervé, Jun 18, 2014
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    • "Most ERV genes are non-functional due to DNA recombination, mutations, and deletions, but some produce functional proteins including group-specific antigen (gag), polymerase (pol) with reverse transcriptase (RT), and the envelope (env) surface unit (SU) with a transmembrane immunosuppressive-like peptide (Mi et al., 2000; Blaise et al., 2005; de Parseval et al., 2003; Villesen et al., 2004). The env gene of ERVW-1 (chromosome 7q21.2) called Syncytin-1 has an essential role in placentogenesis (Blond et al., 1999; Mi et al., 2000). Importantly, and key to our findings, a major function of DNA methylation in humans is silencing of ERVs and other viral sequences in the human genome; up to 90% of methylated CpGs are located in 45% of the human genome harboring repetitive elements like ERVs (Walsh et al., 1998; Bestor and Tycko, 1996). "
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    ABSTRACT: We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 08/2015; 162(5):974-986. DOI:10.1016/j.cell.2015.07.011 · 32.24 Impact Factor
    • "In multiple sclerosis (MS) patients, the Multiple Sclerosis Associated Retrovirus element (MSRV), member of type-W endogenous retrovirus family (HERV-W), shows an increased expression, with the accumulation of its RNA transcripts especially in the brain [93]. In addition, retrovirus-like particles are found in different cell types [94] [95] and MSRV-Env protein is reproducibly detected in MS brain lesions within microglia and perivascular macrophages [96]. This protein can be used to induce autoimmunity and EAE (Experimental Allergic Encephalomyelitis, an animal model for MS) in mice, and has been suggested as a possible therapeutic target [96]. "
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    ABSTRACT: Endogenous retroelements (ERs) represent nearly half of the human genome. Considered up to recent years as "functionless" DNA sequences, they are now known to be involved in important cellular functions such as stress response and generation of non coding regulatory RNAs. Moreover, an increasing amount of data supports the idea of ERs as key players in cellular senescence and in different senescence-related pathogenic cellular processes, including those leading to inflammation, cancer and major age-related multifactorial diseases. The involvement of ERs in these biological mechanisms can suggest new therapeutic strategies in neoplasms, inflammatory/autoimmune diseases and in different age-related pathologies, such as macular degeneration, diabetes, cardiovascular diseases and major age-related neurodegenerative disorders. The therapeutic approaches which can be suggested range from a set of well-known, common drugs that have been shown to modulate ERs activity, to immune therapy against ER-derived tumor antigens, to more challenging strategies such as those based on anti-ERs RNA interference.
    Current drug targets 05/2015; · 3.02 Impact Factor
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    • "HERV-W is a multicopy human endogenous retrovirus group [65] that consists of about 1300 loci (including solo LTR, complete and partial loci [66]). In our study, HERV-W loci on chromosomes 6q21 and 7q21.2 were identified as being transcribed at higher levels in MF lesions (Table S2, Figure 3). "
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    ABSTRACT: The pathomechanism of mycosis fungoides (MF), the most common type of primary cutaneous T-cell lymphomas (CTCLs) and a malignancy of non-recirculating, skin-resident T-cells, is unknown albeit underlying viral infections have been sought for. Human endogenous retroviruses (HERVs) are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancers. We explored the transcriptional activity of HERV sequences in a total of 34 samples comprising MF and psoriasis skin lesions, as well as corresponding non-malignant skin using a retrovirus-specific microarray and quantitative RT-PCR. To identify active HERV-W loci, we cloned the HERV-W specific RT-PCR products, sequenced the cDNA clones and assigned the sequences to HERV-W loci. Finally, we used immunohistochemistry on MF patient and non-malignant inflammatory skin samples to confirm specific HERV-encoded protein expression. Firstly, a distinct, skin-specific transcription profile consisting of five constitutively active HERV groups was established. Although individual variability was common, HERV-W showed significantly increased transcription in MF lesions compared to clinically intact skin from the same patient. Predominantly transcribed HERV-W loci were found to be located in chromosomes 6q21 and 7q21.2, chromosomal regions typically altered in CTCL. Surprisingly, we also found the expression of 7q21.2/ERVWE1-encoded Syncytin-1 (Env) protein in MF biopsies and expression of Syncytin-1 was seen in malignant lymphocytes, especially in the epidermotropic ones, in 15 of 30 cases studied. Most importantly, no Syncytin-1 expression was detected in inflammatory dermatosis (Lichen ruber planus) with skin-homing, non-malignant T lymphocytes. The expression of ERVWE1 mRNA was further confirmed in 3/7 MF lesions analyzed. Our observations strengthen the association between activated HERVs and cancer. The study offers a new perspective into the pathogenesis of CTCL since we demonstrate that differences in HERV-W transcription levels between lesional MF and non-malignant skin are significant, and that ERVWE1-encoded Syncytin-1 is expressed in MF lymphoma cells.
    PLoS ONE 10/2013; 8(10):e76281. DOI:10.1371/journal.pone.0076281 · 3.23 Impact Factor
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