scholarly journals CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2)

2005 ◽  
Vol 79 (2) ◽  
pp. 876-883 ◽  
Author(s):  
Laurence Lavie ◽  
Milena Kitova ◽  
Esther Maldener ◽  
Eckart Meese ◽  
Jens Mayer
Keyword(s):  
Cell Line ◽  
Transcriptional Activity ◽  
Significant Proportion ◽  
Endogenous Retrovirus ◽  
Cpg Methylation ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Long Terminal Repeats ◽  
Cpg Sites

ABSTRACT A significant proportion of the human genome consists of stably inherited retroviral sequences. Most human endogenous retroviruses (HERVs) became defective over time. The HERV-K(HML-2) family is exceptional because of its coding capacity and the possible involvement in germ cell tumor (GCT) development. HERV-K(HML-2) transcription is strongly upregulated in GCTs. However, regulation of HERV-K(HML-2) transcription remains poorly understood. We investigated in detail the role of CpG methylation on the transcriptional activity of HERV-K(HML-2) long terminal repeats (LTRs). We find that CpG sites in various HERV-K(HML-2) proviral 5′ LTRs are methylated at different levels in the cell line Tera-1. Methylation levels correlate with previously observed transcriptional activities of these proviruses. CpG-mediated silencing of HERV-K(HML-2) LTRs is further corroborated by transcriptional inactivity of in vitro-methylated 5′ LTR reporter plasmids. However, CpG methylation levels do not solely regulate HERV-K(HML-2) 5′ LTR activity, as evidenced by different LTR activities in the cell line T47D. A significant number of mutated CpG sites in evolutionary old HERV-K(HML-2) 5′ LTRs suggests that CpG methylation had already silenced HERV-K(HML-2) proviruses millions of years ago. Direct silencing of HERV-K(HML-2) expression by CpG methylation enlightens upregulated HERV-K(HML-2) expression in usually hypomethylated GCT tissue.

scholarly journals Human Endogenous Retrovirus HERV-K14 Families: Status, Variants, Evolution, and Mobilization of Other Cellular Sequences

2005 ◽  
Vol 79 (5) ◽  
pp. 2941-2949 ◽  
Author(s):  
Aline Flockerzi ◽  
Stefan Burkhardt ◽  
Werner Schempp ◽  
Eckart Meese ◽  
Jens Mayer
Keyword(s):  
Human Genome ◽  
Germ Line ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Long Terminal Repeats ◽  
Essential Information ◽  
Human Endogenous Retroviruses ◽  
Consensus Sequences

ABSTRACT The human genome harbors many distinct families of human endogenous retroviruses (HERVs) that stem from exogenous retroviruses that infected the germ line millions of years ago. Many HERV families remain to be investigated. We report in the present study the detailed characterization of the HERV-K14I and HERV-K14CI families as they are represented in the human genome. Most of the 68 HERV-K14I and 23 HERV-K14CI proviruses are severely mutated, frequently displaying uniform deletions of retroviral genes and long terminal repeats (LTRs). Both HERV families entered the germ line ∼39 million years ago, as evidenced by homologous sequences in hominoids and Old World primates and calculation of evolutionary ages based on a molecular clock. Proviruses of both families were formed during a brief period. A majority of HERV-K14CI proviruses on the Y chromosome mimic a higher evolutionary age, showing that LTR-LTR divergence data can indicate false ages. Fully translatable consensus sequences encoding major retroviral proteins were generated. Most HERV-K14I loci lack an env gene and are structurally reminiscent of LTR retrotransposons. A minority of HERV-K14I variants display an env gene. HERV-K14I proviruses are associated with three distinct LTR families, while HERV-K14CI is associated with a single LTR family. Hybrid proviruses consisting of HERV-K14I and HERV-W sequences that appear to have produced provirus progeny in the genome were detected. Several HERV-K14I proviruses harbor TRPC6 mRNA portions, exemplifying mobilization of cellular transcripts by HERVs. Our analysis contributes essential information on two more HERV families and on the biology of HERV sequences in general.

scholarly journals Human endogenous retrovirus transcription profiles of the kidney and kidney-derived cell lines

2011 ◽  
Vol 92 (10) ◽  
pp. 2356-2366 ◽  
Author(s):  
Sonja Haupt ◽  
Michele Tisdale ◽  
Michelle Vincendeau ◽  
Mary Anne Clements ◽  
David T. Gauthier ◽  
...  
Keyword(s):  
Cell Culture ◽  
Cell Line ◽  
Cell Lines ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Tissue Samples ◽  
Transcription Pattern

The human genome comprises approximately 8–9 % of human endogenous retroviruses (HERVs) that are transcribed with tissue specificity. However, relatively few organs have been examined in detail for individual differences in HERV transcription pattern, nor have tissue-to-cell culture comparisons been frequently performed. Using an HERV-specific DNA microarray, a core HERV transcription profile was established for the human kidney comparing 10 tissue samples. This core represents HERV groups expressed uniformly or nearly so in non-tumour kidney tissue. The profiles obtained from non-tumour tissues were compared to 10 renal tumour tissues (renal cell carcinoma, RCC) derived from the same individuals and additionally, to 22 RCC cell lines. No RCC cell line or tumour-specific differences were observed, suggesting that HERV transcription is not altered in RCC. However, when comparing tissue transcription to cell line transcription, there were consistent differences. The differences were irrespective of cancer state and included cell lines derived from non-tumour kidney tissue, suggesting that a specific alteration of HERV transcription occurs when establishing cell lines. In contrast to previous publications, all known HERV-derived tumour antigens, including those identified in RCC, were expressed both in multiple RCC cell lines and several non-tumour tissue-derived cell lines, a result that contrasts with findings from patient samples. The results establish the core kidney transcription pattern of HERVs and reveal differences between cell culture lines and tissue samples.

scholarly journals Comprehensive Analysis of Human Endogenous Retrovirus Transcriptional Activity in Human Tissues with a Retrovirus-Specific Microarray

2005 ◽  
Vol 79 (1) ◽  
pp. 341-352 ◽  
Author(s):  
Wolfgang Seifarth ◽  
Oliver Frank ◽  
Udo Zeilfelder ◽  
Birgit Spiess ◽  
Alex D. Greenwood ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Activity Patterns ◽  
Qualitative Evaluation ◽  
Reproductive Organs ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Human Tissues ◽  
Human Endogenous Retroviruses ◽  
Transcriptional Regulatory

ABSTRACT Retrovirus-like sequences account for 8 to 9% of the human genome. Among these sequences, about 8,000 pol-containing proviral elements have been identified to date. As part of our ongoing search for active and possibly disease-relevant human endogenous retroviruses (HERVs), we have recently developed an oligonucleotide-based microarray. The assay allows for both the detection and the identification of most known retroviral reverse transcriptase (RT)-related nucleic acids in biological samples. In the present study, we have investigated the transcriptional activity of representative members of 20 HERV families in 19 different normal human tissues. Qualitative evaluation of chip hybridization signals and quantitative analysis by real-time RT-PCR revealed distinct HERV activity in the human tissues under investigation, suggesting that HERV elements are active in human cells in a tissue-specific manner. Most active members of HERV families were found in mRNA prepared from skin, thyroid gland, placenta, and tissues of reproductive organs. In contrast, only few active HERVs were detectable in muscle cells. Human tissues that lack HERV transcription could not be found, confirming that human endogenous retroviruses are permanent components of the human transcriptome. Distinct activity patterns may reflect the characteristics of the regulatory machinery in these cells, e.g., cell type-dependent occurrence of transcriptional regulatory factors.

scholarly journals Conserved Footprints of APOBEC3G on Hypermutated Human Immunodeficiency Virus Type 1 and Human Endogenous Retrovirus HERV-K(HML2) Sequences

2008 ◽  
Vol 82 (17) ◽  
pp. 8743-8761 ◽  
Author(s):  
Andrew E. Armitage ◽  
Aris Katzourakis ◽  
Tulio de Oliveira ◽  
John J. Welch ◽  
Robert Belshaw ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human polynucleotide cytidine deaminases APOBEC3G (hA3G) and APOBEC3F (hA3F) are antiviral restriction factors capable of inducing extensive plus-strand guanine-to-adenine (G-to-A) hypermutation in a variety of retroviruses and retroelements, including human immunodeficiency virus type 1 (HIV-1). They differ in target specificity, favoring plus-strand 5′GG and 5′GA dinucleotide motifs, respectively. To characterize their mutational preferences in detail, we analyzed single-copy, near-full-length HIV-1 proviruses which had been hypermutated in vitro by hA3G or hA3F. hA3-induced G-to-A mutation rates were significantly influenced by the wider sequence context of the target G. Moreover, hA3G, and to a lesser extent hA3F, displayed clear tetranucleotide preference hierarchies, irrespective of the genomic region examined and overall hypermutation rate. We similarly analyzed patient-derived hypermutated HIV-1 genomes using a new method for estimating reference sequences. The majority of these, regardless of subtype, carried signatures of hypermutation that strongly correlated with those induced in vitro by hA3G. Analysis of genome-wide hA3-induced mutational profiles confirmed that hypermutation levels were reduced downstream of the polypurine tracts. Additionally, while hA3G mutations were found throughout the genome, hA3F often intensely mutated shorter regions, the locations of which varied between proviruses. We extended our analysis to human endogenous retroviruses (HERVs) from the HERV-K(HML2) family, finding two elements that carried clear footprints of hA3G activity. This constitutes the most direct evidence to date for hA3G activity in the context of natural HERV infections, demonstrating the involvement of this restriction factor in defense against retroviral attacks over millions of years of human evolution.

scholarly journals Structural basis for Fullerene geometry in a human endogenous retrovirus capsid

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Oliver Acton ◽  
Tim Grant ◽  
Giuseppe Nicastro ◽  
Neil J. Ball ◽  
David C. Goldstone ◽  
...  
Keyword(s):  
Early Stage ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
Structural Basis ◽  
Human Endogenous Retrovirus ◽  
Structural Protein ◽  
Human Endogenous Retroviruses ◽  
Reading Frames

AbstractThe HML2 (HERV-K) group constitutes the most recently acquired family of human endogenous retroviruses, with many proviruses less than one million years old. Many maintain intact open reading frames and provirus expression together with HML2 particle formation are observed in early stage human embryo development and are associated with pluripotency as well as inflammatory disease, cancers and HIV-1 infection. Here, we reconstruct the core structural protein (CA) of an HML2 retrovirus, assemble particles in vitro and employ single particle cryogenic electron microscopy (cryo-EM) to determine structures of four classes of CA Fullerene shell assemblies. These icosahedral and capsular assemblies reveal at high-resolution the molecular interactions that allow CA to form both pentamers and hexamers and show how invariant pentamers and structurally plastic hexamers associate to form the unique polyhedral structures found in retroviral cores.

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

2017 ◽  
Vol 23 (8) ◽  
pp. 1050-1055 ◽  
Author(s):  
Elena Morandi ◽  
Rachael E. Tarlinton ◽  
Radu Tanasescu ◽  
Bruno Gran
Keyword(s):  
Experimental Studies ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Human Endogenous Retroviruses ◽  
Immune Mediated ◽  
After Effect ◽  
Possible Cause

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

scholarly journals The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy

2018 ◽  
Vol 19 (11) ◽  
pp. 3286 ◽  
Author(s):  
Cipriani Chiara ◽  
Pitzianti Bernanda ◽  
Matteucci Claudia ◽  
D’Agati Elisa ◽  
Miele Tony ◽  
...  
Keyword(s):  
Time Course ◽  
Mononuclear Cells ◽  
Clinical Symptoms ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Peripheral Blood Mononuclear ◽  
Dynamic Regulation ◽  
Expression Levels

Increasing scientific evidence demonstrated the deregulation of human endogenous retroviruses (HERVs) expression in complex diseases, such as cancer, autoimmune, psychiatric, and neurological disorders. The dynamic regulation of HERV activity and their responsiveness to a variety of environmental stimuli designate HERVs as genetic elements that could be modulated by drugs. Methylphenidate (MPH) is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). The aim of this study was to evaluate the time course of human endogenous retrovirus H (HERV-H) expression in peripheral blood mononuclear cells (PBMCs) with respect to clinical response in ADHD patients undergoing MPH therapy. A fast reduction in HERV-H activity in ADHD patients undergoing MPH therapy was observed in parallel with an improvement in clinical symptoms. Moreover, when PBMCs from drug-naïve patients were cultured in vitro, HERV-H expression increased, while no changes in the expression levels were found in ADHD patients undergoing therapy. This suggests that MPH could affect the HERV-H activity and supports the hypothesis that high expression levels of HERV-H could be considered a distinctive trait of ADHD patients.

scholarly journals Unusually long target site duplications flanking some of the long terminal repeats of human endogenous retrovirus K in the human genome

2004 ◽  
Vol 85 (6) ◽  
pp. 1485-1488 ◽  
Author(s):  
Ilgar Z. Mamedov ◽  
Yuri B. Lebedev ◽  
Eugene D. Sverdlov
Keyword(s):  
Human Genome ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Substantial Part ◽  
Direct Repeats ◽  
Long Terminal Repeats ◽  
Solo Ltrs ◽  
Insertion Mechanism ◽  
Terminal Repeats

Human endogenous retroviruses (HERVs) make up a substantial part of the human genome. HERVs and solitary long terminal repeats (solo LTRs) are usually flanked by 4–6 nt short direct repeats through the well-known mechanism of their integration. A number of solo LTRs flanked by unusually long direct repeats were detected in the human genome. These unusual structures might be a product of an alternative virus insertion mechanism.

scholarly journals Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1999
Author(s):  
Annacarmen Petrizzo ◽  
Concetta Ragone ◽  
Beatrice Cavalluzzo ◽  
Angela Mauriello ◽  
Carmen Manolio ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Genetic Material ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Danger Signal ◽  
Human Endogenous Retroviruses ◽  
Double Stranded Rna ◽  
Specific Antigens ◽  
Viral Mimicry

Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes occurring in tumor cells. Indeed, several studies indicate that HERV proviral DNA can be transcribed either to double-stranded RNA (dsRNA) that is sensed as a “danger signal” by pattern recognition receptors (PRRs), leading to a viral mimicry state, or to mRNA that is translated into proteins that may contribute to the landscape of tumor-specific antigens (TSAs). Alternatively, HERV reactivation is associated with the expression of long noncoding RNAs (lncRNAs). In this review, we will highlight recent findings on HERV reactivation in cancer and its implications for cancer immunotherapy.

scholarly journals Identification and Characterization of Novel Human Endogenous Retrovirus Families by Phylogenetic Screening of the Human Genome Mapping Project Database

2000 ◽  
Vol 74 (8) ◽  
pp. 3715-3730 ◽  
Author(s):  
Michael Tristem
Keyword(s):  
Human Genome ◽  
Genome Mapping ◽  
Sequence Data ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Sequence Information ◽  
Class Iii ◽  
Genome Mapping Project ◽  
Human Genome Mapping Project

ABSTRACT Human endogenous retroviruses (HERVs) were first identified almost 20 years ago, and since then numerous families have been described. It has, however, been difficult to obtain a good estimate of both the total number of independently derived families and their relationship to each other as well as to other members of the familyRetroviridae. In this study, I used sequence data derived from over 150 novel HERVs, obtained from the Human Genome Mapping Project database, and a variety of recently identified nonhuman retroviruses to classify the HERVs into 22 independently acquired families. Of these, 17 families were loosely assigned to the class I HERVs, 3 to the class II HERVs and 2 to the class III HERVs. Many of these families have been identified previously, but six are described here for the first time and another four, for which only partial sequence information was previously available, were further characterized. Members of each of the 10 families are defective, and calculation of their integration dates suggested that most of them are likely to have been present within the human lineage since it diverged from the Old World monkeys more than 25 million years ago.

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