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Human endogenous retroviruses (HERVs) are ‘fossil viruses’ that resulted from stable integrations of exogenous retroviruses throughout evolution. HERVs are defective and do not produce infectious viral particles. However, some HERVs retain a limited coding capacity and produce retroviral transcripts and proteins, which function in human developmental process and various pathologies, including many cancers and neurological diseases. Recently, it has been reported that HERVs are differently expressed in COVID-19 disease caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we discuss the molecular structure and function of HERV ENV proteins, particularly syncytins, and their conventional roles in human development and diseases, and potential involvement in COVID-19 regarding the newly reported mental symptoms. We also address COVID-19 vaccine-related infertility concerns arising from the similarity of syncytin with the spike protein of SARS-CoV-2, which have been proved invalid.

The vertebrate genome contains an endogenous retrovirus that has been inherited from the past millions of years. Although approximately 8% of human chromosomal DNA consists of sequences derived from human endogenous retrovirus (HERV) fragments, most of the HERVs are currently inactive and noninfectious due to recombination, deletions, and mutations after insertion into the host genome. Several studies suggested that Human endogenous retroviruses (HERVs) factors are significantly related to certain cancers. However, only limited studies have been conducted to analyze the expression of HERV derived elements at protein levels in certain cancers. Herein, we analyzed the expression profiles of HERV-K envelope (Env) and HERV-R Env proteins in eleven different kinds of cancer tissues. Furthermore, the expression patterns of both protein and correlation with various clinical data in each tissue were analyzed. The expressions of both HERV-K Env and HERV-R Env protein were identified to be significantly high in most of the tumors compared with normal surrounding tissues. Correlations between HERV Env expressions and clinical investigations varied depending on the HERV types and cancers. Overall expression patterns of HERV-K Env and HERV-R Env proteins were different in every individual but a similar pattern of expressions was observed in the same individual. These results demonstrate the expression profiles of HERV-K and HERV-R Env proteins in various cancer tissues and provide a good reference for the association of endogenous retroviral Env proteins in the progression of various cancers. Furthermore, the results elucidate the relationship between HERV-Env expression and the clinical significance of certain cancers. [BMB Reports 2021; 54(7): 368-373].

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral germline infections. Most HERV sequences are silenced in somatic cells, but interest is emerging on the involvement of HERV derived transcripts and proteins in human physiology and disease. A HERV-W encoded protein, syncytin-1, has been co-opted into fetal physiology, where it plays a role in trophoblast formation. Altered HERV transcription and expression of HERV derived proteins are associated with various cancer types and neurological diseases such as multiple sclerosis (MS). The implication of HERVs as potential mediators of both health and disease suggests important roles of regulatory mechanisms and alterations of these in physiological and pathological processes. The regulation of HERV sequences is mediated by a wide variety of mechanisms, and the focus of this review is on selected aspects of these, including epigenetic mechanisms such as CpG methylation and histone modifications of the HP1-H3K9me axis, viral transactivation events, and regulatory perspectives of transient stimuli in the microenvironment. Increasing knowledge of the regulation of HERV sequences will not only contribute to the understanding of complex pathogeneses, but also may pinpoint potential targets for better diagnosis and treatment in complex diseases as MS.

Endogenous retroviruses (ERVs) are retrotransposons present in various metazoan genomes and have been implicated in metazoan evolution as well as in nematodes and humans. The long terminal repeat (LTR) retrotransposons contain several regulatory sequences including promoters and enhancers that regulate endogenous gene expression and thereby control organismal development and response to environmental change. ERVs including the LTR retrotransposons constitute 8% of the human genome and less than 0.6% of the Caenorhabditis elegans (C. elegans) genome, a nematode genetic model system. To investigate the evolutionarily conserved mechanism behind the transcriptional activity of retrotransposons, we generated a transgenic worm model driving green fluorescent protein (GFP) expression using Human endogenous retroviruses (HERV)-K LTR as a promoter. The promoter activity of HERV-K LTR was robust and fluorescence was observed in various tissues throughout the developmental process. Interestingly, persistent GFP expression was specifically detected in the adult vulva muscle. Using deletion constructs, we found that the region from positions 675 to 868 containing the TATA box was necessary for promoter activity driving gene expression in the vulva. Interestingly, we found that the promoter activity of the LTR was dependent on che-1 transcription factor, a sensory neuron driver, and lin-15b, a negative regulator of RNAi and germline gene expression. These results suggest evolutionary conservation of the LTR retrotransposon activity in transcriptional regulation as well as the possibility of che-1 function in non-neuronal tissues. [BMB Reports 2020; 53(10): 521-526]

Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some of these patients do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the DNA of human cells in culture and that transcription of the integrated sequences might account for some of the positive PCR tests seen in patients. In support of this hypothesis, we found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected human cells. We found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites, consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition mechanism. We also found, in some patient-derived tissues, evidence suggesting that a large fraction of the viral sequences is transcribed from integrated DNA copies of viral sequences, generating viral-host chimeric transcripts. The integration and transcription of viral sequences may thus contribute to the detection of viral RNA by PCR in patients after infection and clinical recovery. Because we have detected only subgenomic sequences derived mainly from the 3' end of the viral genome integrated into the DNA of the host cell, infectious virus cannot be produced from the integrated subgenomic SARS-CoV-2 sequences.

Simple Summary Retroelements are endogenous DNA elements present in the human genome. They have a key role in tumorigenesis and cancer progression. Several studies have reported their expression as biomarkers and immunotherapeutic targets to cancer. Their expression can be induced by epigenetic alteration and virus infections. Retroelement overexpression has been shown in distinct types of cancer, such as breast cancer, melanoma, renal cell carcinoma and prostate cancer. However, studies on other specific types of cancer, such as in cervical cancer, are scarce. Here we explored the expression of retroelements in cervical cancer as well as their interplay with HPV infection and their association with expression of neighboring genes. We find expression of retroelements specific to cervical cancer, associated with tumor histological type and HPV infection, as a new target as biomarkers and for immune therapy approaches. Abstract Retroelements are expressed in diverse types of cancer and are related to tumorigenesis and to cancer progression. We characterized the expression of retroelements in cervical cancer and explored their interplay with HPV infection and their association with expression of neighboring genes. Forty biopsies of invasive cervical carcinoma (squamous cell carcinomas and adenocarcinomas) with genotyped HPV were selected and analyzed for human endogenous retrovirus (HERV) and long interspersed nuclear element 1 (L1) expression through RNA-seq data. We found 8060 retroelements expressed in the samples and a negative correlation of DNA methyltransferase 1 expression with the two most expressed L1 elements. A total of 103 retroelements were found differentially expressed between tumor histological types and between HPV types, including several HERV families (HERV-K, HERV-H, HERV-E, HERV-I and HERV-L). The comparison between HPV mono- and co-infections showed the highest proportion of differentially expressed L1 elements. The location of retroelements affected neighboring gene expression, such as shown for the interleukin-20 gene family. Three HERVs and seven L1 were located close to this gene family and two L1 showed a positive association with IL20RB expression. This study describes the expression of retroelements in cervical cancer and shows their association with HPV status and host gene expression.

Simple Summary Human Endogenous retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) are remnants of ancient retroviral infections that make up about 8% of the human genome. HERV and MaLR expression is regulated in immunity, and, in particular, is known for their up-regulation after innate immune activation. In this work, we analyzed the differential expression of HERVs and MaLRs in different stages of immunity, triggered by the administration of an inactivated vaccine. Abstract Human Endogenous retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) are remnants of ancient retroviral infections that represent a large fraction of our genome. The HERV and MaLR transcriptional activity is regulated in developmental stages, adult tissues, and pathological conditions. In this work, we used a bioinformatics approach based on RNA-sequencing (RNA-seq) to study the expression and modulation of HERVs and MaLR in a scenario of activation of the immune response. We analyzed transcriptome data from subjects before and after the administration of an inactivated vaccine against the Hantaan orthohantavirus, the causative agent of Korean hemorrhagic fever, to investigate the HERV and MaLR expression and differential expression in response to the administration of the vaccine. Specifically, we described the HERV transcriptome in PBMCs and identified HERV and MaLR loci differentially expressed after the 2nd, 3rd, and 4th inactivated vaccine administrations. We found that the expression of 545 HERV and MaLR elements increased in response to the vaccine and that the activation of several individual HERV and MaLR loci is specific for each vaccine administration and correlated to different genes and immune-related pathways.

Many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K (HML6) and HERV-K (HML2). However, there is no report showing any relation between squamous cell carcinoma of head and neck (HNSCC) and HERVs in literature. Here we report the polymorphic changes of HERV-K6 and HERV-K11 in tumor tissue samples of HNSCC patients comparing with healthy individuals. For this purpose, genomic DNAs from tumor tissue samples of 2 healthy individuals and of 8 HNSCC patients were isolated and IRAP-PCR was performed. IRAP-PCR analyses demonstrated that there were 18–73% polymorphism rates for HERV-K6 and 38–100% polymorphism rates for HERV-K11 among all the samples. There were also polymorphic changes between two control materials. Therefore, HERV-K6 polymorphisms may arise on an individual-specific basis. In the previous studies, some associations have been reported between the expression of HERVs and some cancer types or other major diseases. However, few reports have analyzed HERV-K movements among HNSCC patients. This report is the first study investigating HERV-K6 and HERV-K11 retrotransposon polymorphic changes in HNSCC patients. WOS:000641584300007

The biological function and disease association of human endogenous retroviral (HERV) elements is largely elusive. HERV-K(HML-2) has been associated with neurotoxicity but there is no clear understanding of its role or mechanistic basis. We addressed the physiological functions of HERV-K(HML-2) in neuronal differentiation by using CRISPR engineering to activate or repress its expression levels in a human pluripotent stem cell-based system. We found that elevated HERV-K(HML-2) transcription is detrimental for the development and function of cortical neurons. These effects are cell type-specific, as dopaminergic neurons are unaffected. Moreover, high HERV-K(HML-2) transcription alters cortical layer formation in forebrain organoids. HERV-K(HML-2) transcriptional activation leads to hyperactivation of NTRK3 expression and other neurodegeneration-related genes. Direct activation of NTRK3 phenotypically resembles HERV-K(HML-2) induction, and reducing NTRK3 levels in context of HERV-K(HML-2) induction restores cortical neuron differentiation. Hence, these findings unravel a cell type-specific role for HERV-K(HML-2) in cortical neuron development.

In diseases where epigenetic mechanisms are changed, such as cancer, many genes show altered gene expression and inhibited genes become activated. Human endogenous retrovirus type K (HERV-K) expression is usually inhibited in normal cells from healthy adults. In tumor cells, however, HERV-K mRNA expression has been frequently documented to increase. Importantly, HERV-K-derived proteins can act as tumor-specific antigens, a class of neoantigens, and induce immune responses in different types of cancer. In this review, we describe the function of the HERV-K HML-2 subtype in carcinogenesis as biomarkers, and their potential as targets for cancer immunotherapy.

Human endogenous retrovirus (HERV) expression is currently studied for its possible activation by HIV infection. In this context, the HERV-K(HML2) group is the most investigated: it has been proposed that HIV-1 infection can prompt HML2 transcription, and that HML2 proteins can affect HIV-1 replication, either complementing HIV or possibly influencing antiretroviral therapy. However, little information is available on the expression of other HERV groups in HIV infection. In the present study, we used a bioinformatics pipeline to investigate the transcriptional modulation of approximately 3250 well-characterized HERV loci, comparing their expression in a public RNA-seq profile, including a HIV-1-infected and a control T cell culture. In our pilot study, we found approximately 200 HERV loci belonging to 35 HERV groups that were expressed in one or both conditions, with transcripts per million (TPM) values from 1 to &gt, 500. Intriguingly, HML2 elements constituted only the 3% of expressed HERV loci, and in most cases (160) HERV expression was downregulated in the HIV-infected culture, showing from a 1- to 14-fold decrease as compared to uninfected cells. HERV transcriptome has been inferred de novo and employed to predict a total of about 950 HERV open reading frames (ORFs). These have been validated according to the coding potential and estimated abundance of the corresponding transcripts, leading to a set of 57 putative proteins potentially encoded by 23 HERV loci. Analysis showed that some individual loci have a coding potential that deserves further investigation. Among them, a HML6 provirus at locus 19q13.43 was predicted to produce a transcript showing the highest TPM among HERV-derived transcripts, being upregulated in HIV+ cells and inferred to produce Gag and Env puteins with possible biological activity.

Purpose of the Review The aim of this review is to discuss recent data pointing at an involvement of human endogenous retroviruses (HERVs) in type 1 diabetes (T1D) onset and progression. Recent Findings The envelope protein of HERV-W family, named HERV-W-Env, was detected in pancreata from T1D patients and was shown to display pro-inflammatory properties and direct toxicity toward pancreatic beta cells. Summary The etiopathogenesis of T1D remains elusive, even if conventional environmental viral infections have been recurrently involved. Nonetheless, a new category of pathogens may provide the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. A number of studies have now shown that HERV sequences, which are normally inactivated or repressed in the human genome, could be activated by environmental viruses. Thus, if similarly activated by viruses associated with T1D, disregarded HERV genes may underlie T1D genetic susceptibility. Moreover, once expressed, HERV elements may display broad pathogenic properties, which identify them as potential new therapeutic targets.

Endogenous Retroviruses (ERVs) are ancient relics of infections that affected the primate germ line and constitute about 8% of our genome. Growing evidence indicates that ERVs had a major role in vertebrate evolution, being occasionally domesticated by the host physiology. In addition, human ERV (HERV) expression is highly investigated for a possible pathological role, even if no clear associations have been reported yet. In fact, on the one side, the study of HERV expression in high-throughput data is a powerful and promising tool to assess their actual dysregulation in diseased conditions, but, on the other side, the poor knowledge about the various HERV group genomic diversity and individual members somehow prevented the association between specific HERV loci and a given molecular mechanism of pathogenesis. The present study is focused on the HERV-K(HML7) group that—differently from the other HERV-K members—still remains poorly characterized. Starting from an initial identification performed with the software RetroTector, we collected 23 HML7 proviral insertions and about 160 HML7 solitary LTRs that were analyzed in terms of genomic distribution, revealing a significant enrichment in chromosome X and the frequent localization within human gene introns as well as in pericentromeric and centromeric regions. Phylogenetic analyses showed that HML7 members form a monophyletic group, which based on age estimation and comparative localization in non-human primates had its major diffusion between 20 and 30 million years ago. Structural characterization revealed that besides 3 complete HML7 proviruses, the other group members shared a highly defective structure that, however, still presents recognizable functional domains, making it worth further investigation in the human population to assess the presence of residual coding potential.

Background Human endogenous retroviruses HERV-W encode a pro-inflammatory protein, named MSRV-Env from its original identification in Multiple Sclerosis. Though not detected in various neurological controls, MSRV-Env was found in patients with chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). This study investigated the expression of MSRV in CIDP and evaluated relevant MSRV-Env pathogenic effects. Methods 50 CIDP patients, 19 other neurological controls (ONDs) and 65 healthy blood donors (HBDs) were recruited from two different countries. MSRV-env and -pol transcripts, IL6 and CXCL10 levels were quantified from blood samples. MSRV-Env immunohistology was performed in distal sensory nerves from CIDP and neurological controls biopsies. MSRV-Env pathogenic effects and mode of action were assayed in cultured primary human Schwann cells (HSCs). Findings In both cohorts, MSRV-env and -pol transcripts, IL6 positivity prevalence and CXCL10 levels were significantly elevated in CIDP patients when compared to HBDs and ONDs (statistically significant in all comparisons). MSRV-Env protein was detected in Schwann cells in 5/7 CIDP biopsies. HSC exposed to or transfected with MSRV-env presented a strong increase of IL6 and CXCL10 transcripts and protein secretion. These pathogenic effects on HSC were inhibited by GNbAC1, a highly specific and neutralizing humanized monoclonal antibody targeting MSRV-Env. Interpretation The present study showed that MSRV-Env may trigger the release of critical immune mediators proposed as instrumental factors involved in the pathophysiology of CIDP. Significant MSRV-Env expression was detected in a significant proportion of patients with CIDP, in which it may play a role according to its presently observed effects on Schwann cells along with previously known effects on immune cells. Experimental results also suggest that a biomarker-driven therapeutic strategy targeting this protein with a neutralizing antibody such as GNbAC1 may offer new perspectives for treating CIDP patients with positive detection of MSRV-Env expression. Funding Geneuro-Innovation, France., Highlights • A protein from endogenous retroviruses (8% of human genome) is found in chronic inflammatory demyelinating polyradiculoneuropathies (CIDP). • Identified in multiple sclerosis, MSRV-Env induces inflammation and autoimmunity. • It is now shown in peripheral nerve lesions, serum and blood cells of CIDP patients. • In Schwann cells, it induces pro-inflammatory factors; the same is detected in serum. • Antibody neutralization of MSRV-Env effects raises therapeutic perspectives in CIDP. Since the 1980's, a new horizon in the search for pathogenic players in complex human disease arose from studies in which human endogenous retrovirus families (HERV) were identified. HERVs represent 8% of the human genome and may express pathogenic proteins as shown here in a chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). The present study shows that MSRV-Env, an HERV protein, is detected in CIDP lesions and blood. It triggers inflammation in immune and nervous cells. A specific antibody revealed efficient in experimental conditions. This offers new therapeutic and diagnostic perspectives for this disabling disease without curative treatment.

The aim of this bachelor thesis is to describe the effect of HIV-1 on the expression of HERV proviruses in infected cells, how the presence of HERV transcripts and proteins can affect the replication cycle of HIV-1, the composition, structure and infectivity. These interactions may have negative but also positive effects on HIV-1 infectivity. For example, the mutual presence of HIV-1 and HERV proteins encoded by the gag genes responsible for the capsid, nucleocapsid, and virion matrix, may mix together, and form aberrant capsids that will not play a correct role in the HIV-1 replication cycle. Further, due to the phenomenon called viral pseudotyping, HERV envelope glycoproteins could be incorporated into the HIV-1 membrane. This could be a pathway, how the HIV-1 could theoreticaly extend the tropism to other cells than only CD4 T-lymphocytes, macrophages and dedritic cells. Key Words: HERV, HIV-1, virus pseudotypes, retrovirus replication

Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called ‘viral mimicry’. By mimicking viral infections, HERVs could function as an ‘intrinsic adjuvant’, possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of ‘viral mimicry’ and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.

About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome. Recent studies have considered HERVs as potential pathogenic factors. The majority of HERV genes are mutated and not capable of encoding functional proteins; regardless, some HERV genes, such as HERV-W envelope (env) glycoprotein, are known to have intact open reading frames. The HERV-W element on 7q21.2, which encodes a protein referred to as Syncytin-1, participates in human placental morphogenesis and can activate a pro-inflammatory and autoimmune cascade. Neuropsychological disorders are typically linked to inflammatory abnormalities. In this study, we review that Syncytin-1 has been increasingly involved in the development of neuropsychological disorders, such as schizophrenia and multiple sclerosis (MS). This study also presents inflammation imbalances in schizophrenia and MS. More importantly, we discuss the potential role and molecular mechanisms by which Syncytin-1 regulates inflammatory abnormalities in neuropsychological diseases. In summary, Syncytin-1 activity may represent a novel molecular pathogenic mechanism in neuropyschological diseases, such as schizophrenia and MS.

How do some methods of evolution, used in the emergence of multicellular organisms may result in failure of the immune system? What kind of diseases can this lead to? Virus of an immune upgrade HIV++ and its estimated functions. Hypothesis of extraterrestrial origin of the virus of immune upgrade. Interpretation of Chilbolton field drawings of 2000-2002, as a presentation of the HIV++ virus, its purpose and basic properties. Whether it is possible to find and sequence the HIV++ virus?

Background Human endogenous retrovirus (HERVs) constitute approximately 8% of the human genome. Induction of HERV transcription is possible under certain circumstances, and may have a possible role in some pathological conditions. Objectives The aim of this study was to evaluate HERV-K and –W pol gene expression in kidney transplant recipients and to investigate the possible relationship between HERVs gene expression and CMV infection in these patients. Study design Thirty-three samples of kidney transplant patients and twenty healthy blood donors were used to analyze, HERV-K and –W pol gene RNA expression by relative quantitative relative Real-Time PCR. Result We demonstrated that HERVs pol gene expression levels were higher in kidney transplant recipients than in healthy subjects. Moreover, HERV-K and –W pol gene expression was significantly higher in the group of kidney transplant recipients with high CMV viral load than in the groups with no or moderate CMV viral load. Conclusion Our data suggest that CMV may facilitate in vivo HERV activation.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers such as Kaposi's sarcoma (KS), which represents the most common AIDS-associated malignancy that lacks effective treatment options. Despite its clear role in AIDS malignancies, the fact that only a small set of KSHV-infected patients will eventually develop these tumors implies that additional co-factors are required for the development of KSHV-related cancers. In the current study, we demonstrate for the first time that KSHV de novo infection or viral latent proteins are able to transactivate human endogenous retrovirus K (HERV-K) through a variety of cellular signaling pathways and transcriptional factors. Moreover, we found that HERV-K transactivation, particularly activation of its encoded oncogenic NP9 protein, plays an important role in KSHV pathogenesis and tumorigenesis in vitro and in vivo. Our data provide innovative insights into the mechanisms of HERV-K transactivation contributing to viral oncogenesis, which may represent a promising target for KS treatment.

Background: An estimated 8% of the human genome consists of integrated virus genomes that have been left over from past retroviral infections. These human endogenous retroviruses (HERV) have been ravaged by mutational decay, often over millions of years, and most have been rendered inactive. However, some still contain open reading frames and may even code for functional protein products. Upregulation of these retroelements has been observed in certain disease states and in aging mice. Materials and Methods: PBMC and plasma samples were previously obtained from nonagenarians (n=7, age 90) and young controls (n=7, age 26-32, median age 28). RNA-sequencing of the samples was performed and the expression of endogenous human genes and HERV proviruses of the families HERV-K (HML-2) and HERV-W was quantified. This thesis work focused on the characterization and comparison of proviral expression values between the biological sources and across age groups. Results: Proviral expression differed greatly between PBMCs and plasma. Age-associated significant differential expression of three HERV-K (HML-2) and one HERV-W provirus was found in PBMCs. Furthermore, hierarchical clustering of samples indicated aging-associated differences in proviral expression patterns. No age-associated differences in proviral expression could be found in plasma samples. Conclusion: There are age-associated differences in the expression of HERV-K (HML-2) and HERV-W in PBMCs. Between sample differences in proviral expressions in plasma were too great to determine differences between age groups. The differing proviral expression between PBMC and plasma supports the hypothesis of enriched proviral cargo of extracellular vesicles (EV). It was not possible to determine with confidence the origin of the EVs in the plasma samples. Investigation of proviral expression using the same approach with larger datasets of RNA-sequencing data, potentially from external databases, could offer further insights.

How do some methods of evolution, used in the emergence of multicellular organisms may result in failure of the immune system? What kind of diseases can this lead to? Virus of an immune upgrade HIV++ and its estimated functions. Hypothesis of extraterrestrial origin of the virus of immune upgrade. Interpretation of Chilbolton field drawings of 2000-2002, as a presentation of the HIV++ virus, its purpose and basic properties. Whether it is possible to find and sequence the HIV++ virus?

Human endogenous retroviruses (HERVs) are remnants of retroviral germ line infections of human ancestors and make up ~8% of the human genome. Under physiological conditions, these elements are frequently inactive or non-functional due to deactivating mutations and epigenetic control. However, they can be reactivated under certain pathological conditions and produce viral transcripts and proteins. Several disorders, like multiple sclerosis or amyotrophic lateral sclerosis are associated with increased HERV expression. Although their detailed contribution to individual diseases has yet to be elucidated, an increasing number of studies in vitro and in vivo suggest HERVs as potent modulators of the immune system. They are able to affect the transcription of other immune-related genes, interact with pattern recognition receptors, and influence the positive and negative selection of developing thymocytes. Interestingly, HERV envelope proteins can both stimulate and suppress immune responses based on different mechanisms. In the light of HERV proteins becoming an emerging drug target for autoimmune-related disorders and cancer, we will provide an overview on recent findings of the complex interactions between HERVs and the human immune system with a focus on autoimmunity.

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.

Human endogenous retroviruses (HERV) env proteins have been recently reported to be significantly up-regulated in certain cancers. Specifically, mRNA and protein levels of HERV-K (HML-2) are up-regulated in the blood plasma or serum of breast cancer patients. Here, we collected blood samples of 49 breast cancer patients and analyzed mRNA expressions of various HERVs env genes including HERV-R, HERV-H, HERV-K, and HERV-P by real-time PCR. The expression of env genes were significantly increased in the blood of primary breast cancer patients but were decreased in patients undergoing chemotherapy to a similar level with benign patients. When we compared the group currently undergoing chemotherapy and those patients undergoing chemotherapy simultaneously with radiotherapy, HERVs env genes were reduced more in the chemotherapy only group, suggesting that chemotherapy is more effective in reducing HERV env gene expression than is radiotherapy. Among chemotherapy groups, HERV env gene expression was the lowest in the taxotere- or taxol-treated group, suggesting that taxotere and taxol can reduce HERVs env expression. These data suggest the potential to use HERVs env genes as a diagnosis marker for primary breast cancer, and further studies are needed to identify the mechanism and physiological significance of the reduction of HERV env gene expression during chemotherapy.

Autoimmune rheumatic diseases, such as RA and SLE, are caused by genetic, hormonal and environmental factors. Human Endogenous Retroviruses (HERVs) may be triggers of autoimmune rheumatic disease. HERVs are fossil viruses that began to be integrated into the human genome some 30-40 million years ago and now make up 8% of the genome. Evidence suggests HERVs may cause RA and SLE, among other rheumatic diseases. The key mechanisms by which HERVS are postulated to cause disease include molecular mimicry and immune dysregulation. Identification of HERVs in RA and SLE could lead to novel treatments for these chronic conditions. This review summarises the evidence for HERVs as contributors to autoimmune rheumatic disease and the clinical implications and mechanisms of pathogenesis are discussed.

Multiple sclerosis is a neuroimmunological disease in which etiologic agents have not been identified yet. The etiology of MS is complex in its nature and may involve many different agents acting simultaneously or in a cascade manner leading to the development of the disease. The causes of MS development were sought among the factors associated with HLA and TCR genes and human endogenous retroviruses (HERV). Environmental factors such as bacterial, fungal and viral infections as well as potential participation of vitamin D in the pathogenesis of the disease have also been examined. The current state of knowledge concerning potential factors participating in the etiopathogenesis of multiple sclerosis has been reviewed in this paper.

Introduction A diverse range of human diseases, including allergy, asthma, autoimmune disease, cancer and chronic neurologic diseases, notably multiple sclerosis and endogenous depression, is becoming more prevalent in industrialized countries. It has been postulated that environmental factors associated with improved standards of hygiene play a leading role in this process since the immune system seems to need extrinsic challenges for its proper maturation. The inner world An added dimension has now emerged—the impact on disease of the inner world, principally the numerous endogenous retroviruses (HERVs) within the human genome. Taking melanoma as an example, we propose a framework for understanding how a complex infectious and immunological background can induce or inhibit expression of a HERV-related disease process. The central role of a failure to induce or to maintain certain populations of self-specific CD8+ T-cells mediating immune surveillance, the expression of HERV-encoded peptides on affected cells and pathological mechanisms directly attributable to HERV proteins are discussed. Conclusions The presented concepts explain events preceding the clinical manifestation of diseases by several years and provide a rationale for the use of currently available vaccines to protect against certain HERV-induced diseases, especially melanoma. Criteria for establishing the causal role of HERVs in a given disease are proposed.

Background Human endogenous retroviruses (HERVs) are ancient sequences integrated in the germ line cells and vertically transmitted through the offspring constituting about 8 % of our genome. In time, HERVs accumulated mutations that compromised their coding capacity. A prominent exception is HERV-W locus 7q21.2, producing a functional Env protein (Syncytin-1) coopted for placental syncytiotrophoblast formation. While expression of HERV-W sequences has been investigated for their correlation to disease, an exhaustive description of the group composition and characteristics is still not available and current HERV-W group information derive from studies published a few years ago that, of course, used the rough assemblies of the human genome available at that time. This hampers the comparison and correlation with current human genome assemblies. Results In the present work we identified and described in detail the distribution and genetic composition of 213 HERV-W elements. The bioinformatics analysis led to the characterization of several previously unreported features and provided a phylogenetic classification of two main subgroups with different age and structural characteristics. New facts on HERV-W genomic context of insertion and co-localization with sequences putatively involved in disease development are also reported. Conclusions The present work is a detailed overview of the HERV-W contribution to the human genome and provides a robust genetic background useful to clarify HERV-W role in pathologies with poorly understood etiology, representing, to our knowledge, the most complete and exhaustive HERV-W dataset up to date. Electronic supplementary material The online version of this article (doi:10.1186/s12977-016-0301-x) contains supplementary material, which is available to authorized users.

Human endogenous retrovirus-H (HERV-H) is implicated in leukaemias and lymphomas, but the precise molecular mechanism underlying HERV-mediated carcinogenesis remains unknown. We determined the prevalence of HERV-H in a cross-section of the Singapore population and explored the relationship between HERV-H positivity and incidence rates for Hodgkin's lymphoma in three major ethnic groups of Singapore. We observed that Malays were 1.11 times likely (95% CI=1.05–1.17; P

The chronic shortage of human donor organs and tissues for allotransplantation could be relieved if clinical xenotransplantation were to become a viable clinical therapy. Balanced against the benefits of xenotransplantation are the possible consequences of zoonotic infections, and in particular, infection by porcine endogenous retrovirus (PERV). An often-proclaimed risk of PERV infection is the possible recombination of PERV with human endogenous retroviruses (HERV) (Lee et al., 2002) . To address this issue, we examined the potential for HERV sequences to be cross-packaged into PERV particles produced from infected human 293 cells. Although HERV-K, W, E, R, and ERV-9 RNA transcripts are expressed in 293 cells, we did not detect cross-packaging of any of these HERV groups. Quantitative analysis indicated that less than approximately 1 in 104–107 PERV particles might contain HERV sequences. In comparison, we found that murine leukemia virus (MLV)-based vector transcripts were cross-packaged at a rate of approximately one copy in 104 PERV particles. Our results indicate that the potential for recombination of PERV and HERV sequences is low and that novel viruses generated by this mechanism are unlikely to represent a significant risk for xenotransplantation.

In a previous search based on the envelope gene, we had identified two related proviral elements that could not be included in identified ERV families. An in silico database screening associated with an in vivo polymerase chain reaction search using primers in the reverse transcriptase domain, now allowed identification of a series of related elements, found at a limited number in simians. A phylogenetic analysis led to their inclusion in a new family of endogenous retroviruses with limited expansion, which we named ERV-Fc, and which is part of the enlarged ERV-F/H family. The human genome comprises only six HERV-Fc, among which two possess full-length coding envelope genes. A complete provirus was identified in the baboon, also disclosing a fully open envelope gene. Cloning of the sites orthologous to the envelope-coding human proviruses demonstrated presence of the integrated proviruses in chimpanzee and gorilla, but not in orangutan. For the baboon element, the orthologous locus was found empty even in the phylogenetically most closely related macaque, again suggesting, together with the complete identity of its LTRs, “recent” integration. The data presented are compatible with an evolutionary scheme in which the ERV-Fc proviruses would be the endogenous traces of an active retroviral element, possibly acting as an infectious retrovirus with low endogeneization potency, with evidence for integrations at two distinct periods of primate evolution.

We have identified and characterized a human endogenous retrovirus (HERV) gag transcript in the human pre-B cell leukemia line Reh. The transcript was found to be a splice product of a structurally intact HERV element located on chromosome 6q13. Its primer binding site is complementary to phenylalanine (F) tRNA, common for the HERV-F family, but the overall genome sequence is closely related to the HERV-H family. The retroviral sequence was therefore designated HERV-H/F The HERV element shows a distinct mRNA expression pattern among hematopoietic cancer cell lines with expression in some leukemia-derived cell lines of B-lymphoid and myeloid origin. No expression was observed in normal human tissues, indicating a cancer-specific expression pattern. The 5' long terminal repeat (LTR) was tested for promoter activity in HERV-H/F expressing and nonexpressing cell lines. The cell specificity of the LTR-mediated reporter gene expression did not conclusively correlate with endogenous virus expression, indicating that the transcription regulation of this gene is not alone dependent on cell-specific activity of transcription factors. (C) 2002 Elsevier Science (USA). (Less)

Background Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats. However, other genomic structures, including AT-rich palindromes and retroviruses, have also been reported to underlie recurrent structural rearrangements. Notably, recurrent deletions of Yq12 conveying azoospermia, as well as non-pathogenic reciprocal duplications, are mediated by human endogenous retroviral elements (HERVs). We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV). Results We developed parameters to identify HERV elements similar to those that mediate Yq12 rearrangements as well as recurrent deletions of 3q13.2q13.31. We used these parameters to identify HERV pairs genome-wide that may cause instability. Our analysis highlighted 170 pairs, flanking 12.1% of the genome. We cross-referenced these predicted susceptibility regions with CNVs from our clinical databases for potentially HERV-mediated rearrangements and identified 78 CNVs. We subsequently molecularly confirmed recurrent deletion and duplication rearrangements at four loci in ten individuals, including reciprocal rearrangements at two loci. Breakpoint sequencing revealed clustering in regions of high sequence identity enriched in PRDM9-mediated recombination hotspot motifs. Conclusions The presence of deletions and reciprocal duplications suggests NAHR as the causative mechanism of HERV-mediated CNV, even though the length and the sequence homology of the HERV elements are less than currently thought to be required for NAHR. We propose that in addition to HERVs, other repetitive elements, such as long interspersed elements, may also be responsible for the formation of recurrent CNVs via NAHR. Electronic supplementary material The online version of this article (doi:10.1186/s12915-014-0074-4) contains supplementary material, which is available to authorized users.

In addition to the coding sequences, the human genome contains a so noncoding DNA, among which we count transposable elements capable of transposition in the genome. The remnants of the past retrovirus infections - endogenous retroviruses (human endogenous retroviruses - HERVs) belong to the transposable elements, which contain the LTR sequences. Human endogenous retroviruses make up to 8% of the size of the human genome. The retroviruses are not only passive relicts, but they have gained some key functions - too. They increase the plasticity of the human genome and some HERV LTRs can serve as binding sites for transcription factors like. Env protein from the families HERV-W and HERV- FRD were coopted by the human genome and are nowadays expressed as proteins Syncitin-1 and Syncitin-2, which are necessary by the forming of human placenta. Unfortunately, the HERV elements can have a negative health impacts. In the last decades they are subject of a debate in connection with various diseases, such as multiple sclerosis, schizophrenia, HIV proliferation and some types of tumorigenesis. The role of HERVs in the human genome is not completely known yet and it is important to continue with their research. Powered by TCPDF (www.tcpdf.org)

Recent studies suggested a role for the human endogenous retrovirus (HERV) group HERV-K(HML-2) in melanoma because of upregulated transcription and expression of HERV-K(HML-2)-encoded proteins. Very little is known about which HML-2 loci are transcribed in melanoma. We assigned >1,400 HML-2 cDNA sequences generated from various melanoma and related samples to genomic HML-2 loci, identifying a total of 23 loci as transcribed. Transcription profiles of loci differed significantly between samples. One locus was found transcribed only in melanoma-derived samples but not in melanocytes and might represent a marker for melanoma. Several of the transcribed loci harbor ORFs for retroviral Gag and/or Env proteins. Env-encoding loci were transcribed only in melanoma. Specific investigation of rec and np9 transcripts indicated transcription of protein encoding loci in melanoma and melanocytes hinting at the relevance of Rec and Np9 in melanoma. UVB irradiation changed transcription profiles of loci and overall transcript levels decreased in melanoma and melanocytes. We further identified transcribed HML-2 loci formed by reverse transcription of spliced HML-2 transcripts by L1 machinery or in a retroviral fashion, with loci potentially encoding HML-2-like proteins. We reveal complex, sample-specific transcription of HML-2 loci in melanoma and related samples. Identified HML-2 loci and proteins encoded by those loci are particularly relevant for further studying the role of HML-2 in melanoma. Transcription of HERVs appears as a complex mechanism requiring specific studies to elucidate which HERV loci are transcribed and how transcribed HERVs may be involved in disease.

Myalgic encephalomyelitis (ME) is a debilitating illness of unknown etiology characterized by neurocognitive dysfunction, inflammation, immune abnormalities and gastrointestinal distress. An increasing body of evidence suggests that disruptions in the gut may contribute to the induction of neuroinflammation. Therefore, reports of human endogenous retroviral (HERV) expression in association with neuroinflammatory diseases prompted us to investigate the gut of individuals with ME for the presence of HERV proteins. In eight out of 12 individuals with ME, immunoreactivity to HERV proteins was observed in duodenal biopsies. In contrast, no immunoreactivity was detected in any of the eight controls. Immunoreactivity to HERV Gag and Env proteins was uniquely co-localized in hematopoietic cells expressing the C-type lectin receptor CLEC4C (CD303/BDCA2), the costimulatory marker CD86 and the class II major histocompatibility complex HLA-DR, consistent with plasmacytoid dendritic cells (pDCs). Although the significance of HERVs present in the pDCs of individuals with ME has yet to be determined, these data raise the possibility of an involvment of pDCs and HERVs in ME pathology. To our knowledge, this report describes the first direct association between pDCs and HERVs in human disease.

Background Emerging evidence suggests that human cytomegalovirus (HCMV) is highly prevalent in tumours of different origin. This virus is implied to have oncogenic and oncomodulatory functions, through its ability to control host gene expression. Human endogenous retroviruses (HERV) are also frequently active in tumours of different origin, and are supposed to contribute as cofactors to cancer development. Due to the high prevalence of HCMV in several different tumours, and its ability to control host cell gene expression, we sought to define whether HCMV may affect HERV transcription. Findings Infection of 3 established cancer cell lines, 2 primary glioblastoma cells, endothelial cells from 3 donors and monocytes from 4 donors with HCMV (strains VR 1814 or TB40/F) induced reverse transcriptase (RT) activity in all cells tested, but the response varied between donors. Both, gammaretrovirus-related class I elements HERV-T, HERV-W, HERV-F and ERV-9, and betaretrovirus-related class II elements HML-2 - 4 and HML-7 - 8, as well as spuma-virus related class III elements of the HERV-L group were up-regulated in response to HCMV infection in GliNS1 cells. Up-regulation of HERV activity was more pronounced in cells harbouring active HCMV infection, but was also induced by UV-inactivated virus. The effect was only slightly affected by ganciclovir treatment and was not controlled by the IE72 or IE86 HCMV genes. Conclusions Within this brief report we show that HCMV infection induces HERV transcriptional activity in different cell types.

Humane Endogene Retroviren (HERVs) sind Sequenzen ehemals exogener Retroviren, die vor Millionen von Jahren Keimbahnzellen menschlicher Vorfahren infizierten und ein Bestandteil des Genoms wurden. Nach ihrer Integration entstanden bei allen heute bekannten Elementen inaktivierende Mutationen. Die am besten erhaltenen und exprimierten Proviren mit zum Teil noch vollständig offenen Leserahmen für alle viralen Proteine gehören zur Familie HERV-K(HML-2). Die postinsertionalen Mutationen verhindern oder erschweren generelle Aussagen zu funktionellen Eigenschaften dieser Proteine. Aus diesem Grund wurde für die Untersuchungen ein Hüllprotein des Elements HERV-K113 verwendet, dessen postinsertionale Mutationen identifiziert und revertiert wurden. Die Sequenz des so rekonstituierten Hüllproteins eines prototypischen HERV-K(HML-2) Provirus vom Zeitpunkt der Integration und die Sequenz des heutigen Hüllproteins wurden zudem codonoptimiert. Dadurch wurde die Expression um den Faktor 50 gesteigert. Dies ermöglichte die in dieser Arbeit erfolgte weitreichende Charakterisierung des Proteins. Das rekonstituierte Hüllprotein ist im Vergleich zu dem heutigen stark glykosyliert und wird in virale Partikel eingebaut. Es ist in der Lage Infektionen zu vermitteln. Sowohl die Glykosylierung des Hüllproteins als auch das C-terminale Ende sind kritisch für den Partikeleinbau und deren Infektiosität. Beides kann durch Deletion des nahezu kompletten zytoplasmatischen Endes signifikant gesteigert werden. Mit dem rekonstituierten funktionellen Hüllprotein und pseudotypisierten Viren wurde eine umfangreiche Tropismusstudie durchgeführt. Dabei wurde deutlich, dass HERV-K(HML-2) eine sehr breite Wirtsspezifität aufweist und Zellen der meisten Spezies infiziert. Die Ergebnisse deuten darauf hin, dass die Verbreitung des noch unbekannten Rezeptors für HERV-K(HML-2) nicht gewebespezifisch ist, denn sowohl Leber-, Prostata-, Muskel-, Nieren-, Lungen-, Dickdarm-, Thymus-, Embryo-, Ovariums-, Bindegewebs-, Gehirn-, Harnblasen-, Keim- oder Hautzellen werden infiziert. HERV-K(HML-2) besitzt somit einen amphotropen Zelltropismus, wobei feline und canine Zelllinien besonders permissiv für Infektionen sind. Mit Hilfe von HERV-K113 Env-IgG- Immunoadhäsinen wurde der Tropismus für einige der Zellen bestätigt. In ersten Rezeptorstudien konnte gezeigt werden, dass der Transferrin Rezeptor 1 und die Hyaluronidase 2, die spezifischen Rezeptormoleküle der nahe verwandten Betaretroviren Mouse Mammary Tumor Virus und Jaagsiekte Sheep Retrovirus, den Eintritt von HERV-K113 in die Wirtzelle nicht vermitteln., Human endogenous retroviruses (HERVs) are sequences of ancient exogenous retroviruses that millions of years ago infected the germ cell line of human ancestors, becoming thereby part of the genome. Subsequent to integration, all HERVs known today suffered inactivating mutations. The best preserved and expressed proviruses, some of which have maintained open reading frames for all viral proteins, belong to the HERV-K(HML-2) family. However, postinsertional mutations make it difficult to draw general conclusions concerning the functional characteristics of these proteins and for this reason we used in these studies a HERV-K113 envelope protein (Env) for which postinsertional mutations had been identified and reversed. Furthermore this sequence, representing the reconstituted prototypical HERV-K(HML-2) provirus existing at the time of integration, together with the sequence of the present-day Env, was codon optimized. This resulted in a 50-fold or more increase in expression, allowing the protein to be characterized in detail. Compared to the modern envelope protein, the reconstituted ancient Env is heavily glycosylated, moderately incorporated into retroviral particles and able to mediate entry. The carbohydrates of the envelope protein as well as the cytoplasmic tail are critical for particle incorporation and infectivity, functions that can both be dramatically enhanced by deletion of virtually the complete cytoplasmic tail. Protein tropism was extensively studied using the reconstituted functional Env and pseudotyped viral particles. HERV-K(HML-2) was shown to have a broad host range and to be able to infect cell lines of most species studied. The results suggest that the distribution of the still unknown receptor is not tissue specific as many tissues including liver, prostate, muscle, kidney, lung, colon, thymus, embryo, ovary, fibroblast, brain, urinary bladder, germ cell and skin are permissive to HERV-K(HML-2) infection. HERV-K(HML-2) therefore has an amphotropic cell tropism, with feline and canine cell lines being particularly susceptible. The tropism of some of these cell lines was confirmed using HERV-K113 Env immunoadhesins. Initial receptor studies demonstrated that Transferrin Receptor 1 and Hyaluronidase 2, the specific receptor proteins used by the closely related βretroviruses, Mouse Mammary Tumor Virus and Jaagsiekte Sheep Retrovirus, do not facilitate the entry of HERV-K113 into host cells.

Human endogenous retroviruses (HERVs) are globally silent in somatic cells. However, some HERVs display high transcription in physiological conditions. In particular, ERVWE1, ERVFRDE1 and ERV3, three proviruses of distinct families, are highly transcribed in placenta and produce envelope proteins associated with placenta development. As silencing of repeated elements is thought to occur mainly by DNA methylation, we compared the methylation of ERVWE1 and related HERVs to appreciate whether HERV methylation relies upon the family, the integration site, the tissue, the long terminal repeat (LTR) function or the associated gene function. CpG methylation of HERV-W LTRs in placenta-associated tissues was heterogeneous but a joint epigenetic control was found for ERVWE1 5'LTR and its juxtaposed enhancer, a mammalian apparent LTR retrotransposon. Additionally, ERVWE1, ERVFRDE1 and ERV3 5'LTRs were all essentially hypomethylated in cytotrophoblasts during pregnancy, but showed distinct and stage-dependent methylation profiles. In non-cytotrophoblastic cells, they also exhibited different methylation profiles, compatible with their respective transcriptional activities. Comparative analyses of transcriptional activity and LTR methylation in cell lines further sustained a role for methylation in the control of functional LTRs. These results suggest that HERV methylation might not be family related but copy-specific, and related to the LTR function and the tissue. In particular, ERVWE1 and ERV3 could be developmentally epigenetically regulated HERVs.

Few human endogenous retroviruses (HERVs) have been extensively studied in non-human primates. Such investigations have demonstrated that several element classes are primate unique, contain members with important biological function, are conserved in specific primate lineages, and have in some cases expanded in copy number. We have examined multiple sub-families of all major groups of HERVs using a DNA microarray based on the reverse transcriptase (RT) domain of the viral polymerase gene (pol). The microarray was used to investigate the distribution of HERVs in non-human primates with particular focus on the differences between New World monkeys (NWMs) and other anthropoids. This is the first study examining most HERV families in multiple non-human primate DNAs using a uniform and sensitive method and suggests that major differences exist between primate groups. The results indicate that a major invasion and expansion of pol containing HERVs occurred after the platyrrhine (NWM) lineage separated from the catarrhines (Old World Monkeys and apes).

Human endogenous retroviruses (HERVs) represent approximately 7% of the human genome. This investigation was focused on one particular HERV, ERV3, with the main purpose of characterising its gene expression patterns and genomic distribution of ERV3-like sequences. Furthermore, this careful expression study should provide insights into the biological role of HERVs. The impact of HERVs in health and disease is not yet clarified. ERV3 is expressed as three envelope (env) transcripts, of which two also contain a cellular gene, H-plk (human proviral linked Krüppel). ERV3 env expression was mainly investigated at the RNA level. The gene expression of two other HERVs, HERV-K and HERV-E was analysed and compared with ERV3 activity. Real-time PCRs were developed and in combination with in situ hybridisation, it was found that ERV3 is expressed in a tissue- and cell-specific way. High levels of ERV3 mRNA (up to six times over Histone3.3) were demonstrated in placenta, sebaceous glands, foetal and adult adrenal glands, brown adipose tissue, corpus luteum, pituitary gland, thymus and testis. In monocytic cells including both normal monocytes and malignant U-937 cells, elevated mRNA levels were observed after retinoic acid (RA)-induced differentiation. ERV3-encoded Env protein was detected in selected cases, one following RA-treatment. In addition, several new ERV3-like sequences were discovered in the human genome. ERV3 was found to have conserved open reading frames in contrast to other ERV3-like sequences in the human genome. This suggests that ERV3 may be involved in important cellular processes such as differentiation, cell fusion, immunomodulation and protection against infectious retroviruses. The developed techniques and obtained results will allow further studies of HERV expression to better correlate HERV activity to both normal development and disease.

Background Human Endogenous Retroviruses (HERVs) comprise about 8% of the human genome and have lost their ability to replicate or to produce infectious particles after having accumulated mutations over time. We assessed the kinetics of expression of HERV-K (HML-2) Envelope mRNA transcript and surface unit (SU) and transmembrane (TM) subunit proteins during HIV-1 infection. We also mapped the specificity of the humoral response to HERV-K (HML-2) Envelope protein in HIV-1 infected subjects at different stages of disease, and correlated the response with plasma viral load. Results We found that HIV-1 modified HERV-K (HML-2) Env mRNA expression, resulting in the expression of a fully N-glycosylated HERV-K (HML-2) envelope protein on the cell surface. Serological mapping of HERV-K (HML-2) envelope protein linear epitopes revealed two major immunogenic domains, one on SU and another on the ectodomain of TM. The titers of HERV-K (HML-2) TM antibodies were dramatically increased in HIV-1 infected subjects (p Conclusions These data collectively suggest that HIV-1 infection induces fully glycosylated HERV-K (HML-2) envelope TM protein to which antibodies are induced. These anti-HERV-K (HML-2) TM antibodies are a potential marker of HIV-1 infection, and are at higher titer in elite controllers. HERV-K (HML-2) envelope TM protein may be a new therapeutic target in HIV-1 infection.

Background Chromosome rearrangements are caused by many mutational mechanisms; of these, recurrent rearrangements can be particularly informative for teasing apart DNA sequence-specific factors. Some recurrent translocations are mediated by homologous recombination between large blocks of segmental duplications on different chromosomes. Here we describe a recurrent unbalanced translocation casued by recombination between shorter homologous regions on chromosomes 4 and 18 in two unrelated children with intellectual disability. Results Array CGH resolved the breakpoints of the 6.97-Megabase (Mb) loss of 18q and the 7.30-Mb gain of 4q. Sequencing across the translocation breakpoints revealed that both translocations occurred between 92%-identical human endogenous retrovirus (HERV) elements in the same orientation on chromosomes 4 and 18. In addition, we find sequence variation in the chromosome 4 HERV that makes one allele more like the chromosome 18 HERV. Conclusions Homologous recombination between HERVs on the same chromosome is known to cause chromosome deletions, but this is the first report of interchromosomal HERV-HERV recombination leading to a translocation. It is possible that normal sequence variation in substrates of non-allelic homologous recombination (NAHR) affects the alignment of recombining segments and influences the propensity to chromosome rearrangement.