The Association between Plasma ERVWE1 Concentrations and Affective Symptoms during Pregnancy: Is This a Friendly Alien?

Human endogenous retroviruses (HERVs) comprise 8% of the human genome, and HERV DNA was reported to be essential in human embryonic development. Specifically, HERV-W encodes a protein, syncytin-1, alternatively known as ERVWE1 (Human Endogenous Retrovirus W EnvC7-1 Envelope Protein), participating in human placental morphogenesis and having a role in immune system regulation. Syncytin-1 activity is increased in neuropsychiatric disorders, autoimmune diseases, and cancer. In our study, forty-four women in the third trimester of pregnancy were tested for ERVWE1 plasma levels. In concomitance with blood samples the following rating scales were administered to women: the Edinburgh Postnatal Depression Scale (EPDS), State Anxiety Inventory (STAI-S), Trait Anxiety Inventory (STAI-T), and Prenatal Attachment Inventory (PAI). We found that higher ERVWE1 protein plasma levels were significantly associated with higher PAI scores (p = 0.02), an earlier gestational age at the time of blood collection (p = 0.01), a longer duration of symptoms (p = 0.03), and fewer lifetime attempted suicides (p = 0.02). Our results seem to support the role of ERVWE1 in maintaining clinical psychiatric symptoms as a result of potential prolonged inflammation. At the same time, this protein may have a protective role in pregnant women by a reduction of suicidal behavior and a better mother–fetus relationship.

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The Methylation of Clock Genes in Perinatal Depression: Which Role for Oxytocin?

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.734825 ◽

2021 ◽

Vol 12 ◽

Author(s):

Simona Iodice ◽

Martina Di Paolo ◽

Jennifer Lynn Barkin ◽

Letizia Tarantini ◽

Silvia Grassi ◽

...

Keyword(s):

Plasma Levels ◽

Rating Scales ◽

Edinburgh Postnatal Depression Scale ◽

Perinatal Depression ◽

Clock Genes ◽

Depression Scale ◽

Protective Role ◽

Prenatal Attachment ◽

Gene Methylation ◽

Neuropeptide Release

Background: Perinatal Depression (PD) is a widespread disabling condition that is hypothesized to be associated with abnormalities in circadian rhythms and neuropeptide release including oxytocin (OXT).Methods: Fourty-four pregnant women (28 with PD, and 16 controls) were evaluated through the Edinburgh Postnatal Depression Scale (EPDS), the State/Trait Anxiety Inventory Form Y (STAI-Y), and the Prenatal Attachment Inventory (PAI). A blood sample was collected from all participants, and OXT plasma levels, DNA methylation of clock genes, as well as of FOXp3 and HERV-W were measured. Linear regression analyses were performed to assess the effect of oxytocin on the methylation of selected genes. Continuous ordinal regression models was further applied to see if the score of rating scales was associated to gene methylation, adjusting for oxytocin-methylation interaction.Results: OXT plasma levels were positively associated with CRY1 methylation. Women with higher OXT plasma levels showed an association between higher degree of CRY2 methylation (thus, reduced expression) and lower EPDS (OR = 0.21; P = 0.043) and STAI-S scores (OR = 6.96; P = 0.019). Finally, with high OXT levels, hypermethylation of CRY1 was associated to higher scores on the PAI (OR = 2.74; P = 0.029) while higher methylation of HERV-W related to lower PAI scores (OR = 0.273; P = 0.019).Conclusion: Our results suggest a possible protective role played by oxytocin in the development of PD by promoting a favorable methylation profile characterized by reduced expression of CRY1 and CRY2. Moreover, oxytocin strengthens the association between maternal prenatal attachment with a favorable pattern of methylation of clock genes and HERV-W, which is essential for pregnancy outcomes.

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Human Endogenous Retrovirus Reactivation: Implications for Cancer Immunotherapy

Cancers ◽

10.3390/cancers13091999 ◽

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.

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

Journal of Virology ◽

10.1128/jvi.74.8.3715-3730.2000 ◽

2000 ◽

Vol 74 (8) ◽

pp. 3715-3730 ◽

Cited By ~ 202

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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Human Endogenous Retrovirus Family HERV-K(HML-5): Status, Evolution, and Reconstruction of an Ancient Betaretrovirus in the Human Genome

Journal of Virology ◽

10.1128/jvi.78.16.8788-8798.2004 ◽

2004 ◽

Vol 78 (16) ◽

pp. 8788-8798 ◽

Cited By ~ 32

Author(s):

Laurence Lavie ◽

Patrik Medstrand ◽

Werner Schempp ◽

Eckart Meese ◽

Jens Mayer

Keyword(s):

Human Genome ◽

Germ Line ◽

Consensus Sequence ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Open Reading Frames ◽

Primer Binding Site ◽

Human Endogenous Retrovirus ◽

New World Primates ◽

Human Endogenous Retroviruses

ABSTRACT The human genome harbors numerous distinct families of so-called human endogenous retroviruses (HERV) which are remnants of exogenous retroviruses that entered the germ line millions of years ago. We describe here the hitherto little-characterized betaretrovirus HERV-K(HML-5) family (named HERVK22 in Repbase) in greater detail. Out of 139 proviruses, only a few loci represent full-length proviruses, and many lack gag protease and/or env gene regions. We generated a consensus sequence from multiple alignment of 62 HML-5 loci that displays open reading frames for the four major retroviral proteins. Four HML-5 long terminal repeat (LTR) subfamilies were identified that are associated with monophyletic proviral bodies, implying different evolution of HML-5 LTRs and genes. Sequence analysis indicated that the proviruses formed approximately 55 million years ago. Accordingly, HML-5 proviral sequences were detected in Old World and New World primates but not in prosimians. No recent activity is associated with this HERV family. We also conclude that the HML-5 consensus sequence primer binding site is identical to methionine tRNA. Therefore, the family should be designated HERV-M. Our study provides important insights into the structure and evolution of the oldest betaretrovirus in the primate genome known to date.

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Human endogenous retrovirus-W envelope (syncytin) is expressed in both villous and extravillous trophoblast populations

Journal of General Virology ◽

10.1099/vir.0.81412-0 ◽

2006 ◽

Vol 87 (7) ◽

pp. 2067-2071 ◽

Cited By ~ 26

Author(s):

A. Muir ◽

A. M. L. Lever ◽

A. Moffett

Keyword(s):

Cell Lines ◽

First Trimester ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Extravillous Trophoblast ◽

Human Endogenous Retrovirus ◽

Human Trophoblast ◽

Human Endogenous Retroviruses ◽

Normal Tissues ◽

Villous Trophoblast

The placenta is unique amongst normal tissues in transcribing numerous different human endogenous retroviruses at high levels. In this study, RT-PCR and immunohistochemistry were used to investigate the expression of syncytin in human trophoblast. Syncytin transcripts were found in first-trimester trophoblast cells with both villous and extravillous phenotypes and also in the JAR and JEG-3 choriocarcinoma cell lines. Syncytin protein was detected in villous trophoblast and in all extravillous trophoblast subpopulations of first- and second-trimester placental tissues. It was also present in ectopic trophoblast from tubal implantations. This study confirms that syncytin is expressed widely by a variety of normal human trophoblast populations, as well as choriocarcinoma cell lines.

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

Journal of Virology ◽

10.1128/jvi.79.5.2941-2949.2005 ◽

2005 ◽

Vol 79 (5) ◽

pp. 2941-2949 ◽

Cited By ~ 20

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.

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

Journal of General Virology ◽

10.1099/vir.0.031518-0 ◽

2011 ◽

Vol 92 (10) ◽

pp. 2356-2366 ◽

Cited By ~ 9

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.

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Effects of Recombination Rate on Human Endogenous Retrovirus Fixation and Persistence

Journal of Virology ◽

10.1128/jvi.00410-07 ◽

2007 ◽

Vol 81 (19) ◽

pp. 10712-10717 ◽

Cited By ~ 29

Author(s):

Aris Katzourakis ◽

Vini Pereira ◽

Michael Tristem

Keyword(s):

Meiotic Recombination ◽

Segmental Duplication ◽

Recombination Rate ◽

Germ Line ◽

Endogenous Retrovirus ◽

Gene Density ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Diverse Group ◽

Genomic Distribution

ABSTRACT Endogenous retroviruses (ERVs) result from germ line infections by exogenous retroviruses. They can proliferate within the genome of their host species until they are either inactivated by mutation or removed by recombinational deletion. ERVs belong to a diverse group of mobile genetic elements collectively termed transposable elements (TEs). Numerous studies have attempted to elucidate the factors determining the genomic distribution and persistence of TEs. Here we show that, within humans, gene density and not recombination rate correlates with fixation of endogenous retroviruses, whereas the local recombination rate determines their persistence in a full-length state. Recombination does not appear to influence fixation either via the ectopic exchange model or by indirect models based on the efficacy of selection. We propose a model linking rates of meiotic recombination to the probability of recombinational deletion to explain the effect of recombination rate on persistence. Chromosomes 19 and Y are exceptions, possessing more elements than other regions, and we suggest this is due to low gene density and elevated rates of human ERV integration in males for chromosome Y and segmental duplication for chromosome 19.

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Human Endogenous Retrovirus Expression Profiles in Samples from Brains of Patients with Schizophrenia and Bipolar Disorders

Journal of Virology ◽

10.1128/jvi.79.17.10890-10901.2005 ◽

2005 ◽

Vol 79 (17) ◽

pp. 10890-10901 ◽

Cited By ~ 103

Author(s):

Oliver Frank ◽

Michelle Giehl ◽

Chun Zheng ◽

Rüdiger Hehlmann ◽

Christine Leib-Mösch ◽

...

Keyword(s):

Genetic Background ◽

Expression Profiles ◽

Bipolar Disorders ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Pcr Analysis ◽

Recent Onset ◽

Detection And Identification ◽

Neuropsychiatric Diseases

ABSTRACT The detection and identification of retroviral transcripts in brain samples, cerebrospinal fluid, and plasma of individuals with recent-onset schizophrenia and schizoaffective disorders suggest that activation or upregulation of distinct human endogenous retroviruses (HERVs) may play a role in the etiopathogenesis of neuropsychiatric diseases. To test this hypothesis, we performed a comprehensive microarray-based analysis of HERV transcriptional activity in human brains. We investigated 50 representative members of 20 HERV families in a total of 215 brain samples derived from individuals with schizophrenia or bipolar disorders and matched controls. A characteristic brain-specific retroviral activity profile was found that consists of members of the class I families HERV-E, HERV-F, and ERV9 and members of HERV-K taxa. In addition to these constitutively expressed HERVs, a number of differentially active HERV elements were identified in all brain samples independent of the disease pattern that may reflect differences in the genetic background of the tested individuals. Only a subgroup of the HML-2 family (HERV-K10) was significantly overrepresented in both bipolar-disorder- and schizophrenia-associated samples compared to healthy brains, suggesting a potential association with disease. Real-time PCR analysis of HERV env transcripts with coding capacity potentially involved in neuroinflammatory conditions revealed that env expression of HERV-W, HERV-FRD, and HML-2 remains unaffected regardless of the clinical picture. Our data suggest that HERV transcription in brains is weakly correlated with schizophrenia and related diseases but may be influenced by the individual genetic background, brain-infiltrating immune cells, or medical treatment.

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Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

10.1101/721241 ◽

2019 ◽

Author(s):

Paul Dembny ◽

Andrew G. Newman ◽

Manvendra Singh ◽

Michael Hinz ◽

Michal Szczepek ◽

...

Keyword(s):

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Toll Like Receptor ◽

Wild Type ◽

Endogenous Ligand ◽

Human Endogenous Retroviruses ◽

Retroviral Transcripts ◽

The Brain ◽

Deficient Mice

AbstractAlthough human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer’s disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

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