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Human endogenous retroviruses (HERVs) are emerging as critical elements in host genomic regulation. Aberrant HERV transcription has been implicated in developmental and tissue-specific aging and pathological processes. In this study, we presented a comprehensive locus-specific characterization of the HERV expression landscape in esophageal squamous cell carcinoma (ESCC). We demonstrated the transcriptional diversity among patients and identified 12 clinically relevant HERVs in the SCH cohort, which were experimentally validated by Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) in the CAMS cohort. ESCC patients were stratified into three HERV-based subtypes (HERVhigh, HERVmedian and HERVlow) with distinct clinical and biological characteristics. The HERVhigh subtype was associated with worse survival, increased CD4+ T cells infiltration and decreased metabolic activity, whereas the HERVlow subtype was characterized by abundant CD8+ T cells, increased metabolic activity, and better survival. The HERV-based tumor subtyping was further robustly validated by RNA sequencing and RT-qPCR in two additional external cohorts. Our findings demonstrate the clinical significance of HERVs for tumor subtyping and prognosis, provide insights into the functional role of HERVs and a valuable resource for developing novel biomarkers and therapeutic targets in ESCC.

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BACKGROUND: Human endogenous retroviruses (HERVs), integrated into the human genome during primate evolution, constitute approximately 8% of the human genome. Although most HERVs are non-protein-coding owing to mutations, insertions, deletions, and truncations, recent research has revealed their diverse roles in biological processes, including disease pathogenesis. OBJECTIVE: Although many HERVs remain inactive, they have been implicated in various diseases, particularly cancer, prompting an increased interest in harnessing HERVs for therapeutic purposes. This review explores the recent advancements in our understanding of the biological roles of HERVs, emphasizing their clinical relevance in cancer treatment. METHODS: Here, we discuss how the detection of transposable elements (TEs), including HERVs, by the immune system triggers innate immune responses in human cancers. CONCLUSION: Additionally, we outline recent progress in elucidating the implications of HERV activation in cancer and how targeting HERVs holds promise for anti-cancer treatments by modulating epigenetic plasticity and disrupting cancer initiation and progression.

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Human endogenous retroviruses (HERVs) are the result of retroviral infections acquired millions of years ago; nowadays, they compose around 8% of human DNA. Multiple mechanisms have been employed for endogenous retroviral deactivation, rendering replication and retrotransposition defective, while some of them have been co-opted to serve host evolutionary advantages. A pleiad of mechanisms retains the delicate balance of HERV expression in modern humans. Thus, epigenetic modifications, such as DNA and histone methylation, acetylation, deamination, chromatin remodeling, and even post-transcriptional control are recruited. In this review, we aim to summarize the main HERV silencing pathways, revisit paradigms of human disease with a HERV component, and emphasize the human immunodeficiency virus (HIV) and HERV interactions during HIV infection.

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Human endogenous retroviruses (HERVs), which are conserved sequences of ancient retroviruses, are widely distributed in the human genome. Although most HERVs have been rendered inactive by evolution, some have continued to exhibit important cytological functions. HERVs in the human genome perform dual functions: on the one hand, they are involved in important physiological processes such as placental development and immune regulation; on the other hand, their aberrant expression is closely associated with the pathological processes of several diseases, such as cancers, autoimmune diseases, and viral infections. HERVs can also regulate a variety of host cellular functions, including the expression of protein-coding genes and regulatory elements that have evolved from HERVs. Here, we present recent research on the roles of HERVs in viral infections and cancers, including the dysregulation of HERVs in various viral infections, HERV-induced epigenetic modifications of histones (such as methylation and acetylation), and the potential mechanisms of HERV-mediated antiviral immunity. We also describe therapies to improve the efficacy of vaccines and medications either by directly or indirectly targeting HERVs, depending on the HERV.

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Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies.

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Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some clinical features overlapping with Kawasaki disease (KD). Our research group and others have highlighted that the spike protein of SARS-CoV-2 can trigger the activation of human endogenous retroviruses (HERVs), which in turn induces inflammatory and immune reactions, suggesting HERVs as contributing factors in COVID-19 immunopathology. With the aim to identify new factors involved in the processes underlying KD and MIS-C, we analysed the transcriptional levels of HERVs, HERV-related genes, and immune mediators in children during the acute and subacute phases compared with COVID-19 paediatric patients and healthy controls. The results showed higher levels of HERV-W, HERV-K, Syn-1, and ASCT-1/2 in KD, MIS-C, and COV patients, while higher levels of Syn-2 and MFSD2A were found only in MIS-C patients. Moreover, KD and MIS-C shared the dysregulation of several inflammatory and regulatory cytokines. Interestingly, in MIS-C patients, negative correlations have been found between HERV-W and IL-10 and between Syn-2 and IL-10, while positive correlations have been found between HERV-K and IL-10. In addition, HERV-W expression positively correlated with the C-reactive protein. This pilot study supports the role of HERVs in inflammatory diseases, suggesting their interplay with the immune system in this setting. The elevated expression of Syn-2 and MFSD2A seems to be a distinctive trait of MIS-C patients, allowing to distinguish them from KD ones. The understanding of pathological mechanisms can lead to the best available treatment for these two diseases, limiting complications and serious outcomes.

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In this review, we summarized the results of experimental and clinical studies about three human endogenous retroviruses and their products-syncytin-1, syncytin-2, and suppressyn in human physiology and pathophysiology. We summed up the described connection with various pathological processes and diseases, mainly with pregnancy-induced hypertensive diseases such as preeclampsia, oncogenesis, gestational trophoblastic disease, and multiple sclerosis. Supposed mechanisms of action and the potential of clinical applications are also described.

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Chronic lymphocytic leukemia (CLL) is one of the most diagnosed forms of leukemia worldwide and it is usually classified into two forms: indolent and aggressive. These two forms are characterized by distinct molecular features that drive different responses to treatment and clinical outcomes. In this context, a better understanding of the molecular landscape of the CLL forms may potentially lead to the development of new drugs or the identification of novel biomarkers. Human endogenous retroviruses (HERVs) are a class of transposable elements that have been associated with the development of different human cancers, including different forms of leukemias. However, no studies about HERVs in CLL have ever been reported so far. Here, we present the first locus-specific profiling of HERV expression in both the aggressive and indolent forms of CLL. Our analyses revealed several dysregulations in HERV expression occurring in CLL and some of them were specific for either the aggressive or indolent form of CLL. Such results were also validated by analyzing an external cohort of CLL patients and by RT-qPCR. Moreover, in silico analyses have shown relevant signaling pathways associated with them suggesting a potential involvement of the dysregulated HERVs in these pathways and consequently in CLL development.

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Human endogenous retroviruses (HERVs) comprise about 8.3% of the human genome and are capable of producing RNA molecules that can be sensed by pattern recognition receptors, leading to the activation of innate immune response pathways. The HERV-K (HML-2) subgroup is the youngest HERV clade with the highest degree of coding competence. Its expression is associated with inflammation-related diseases. However, the precise HML-2 loci, stimuli, and signaling pathways involved in these associations are not well understood or defined. To elucidate HML-2 expression on a locus-specific level, we used the retroelement sequencing tools TEcount and Telescope to analyze publicly available transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data sets of macrophages treated with a wide range of agonists. We found that macrophage polarization significantly correlates with modulation of the expression of specific HML-2 proviral loci. Further analysis demonstrated that the provirus HERV-K102, located in an intergenic region of locus 1q22, constituted the majority of the HML-2 derived transcripts following pro-inflammatory (M1) polarization and was upregulated explicitly in response to interferon gamma (IFN-γ) signaling. We found that signal transducer and activator of transcription 1 and interferon regulatory factor 1 interact with a solo long terminal repeat (LTR) located upstream of HERV-K102, termed LTR12F, following IFN-γ signaling. Using reporter constructs, we demonstrated that LTR12F is critical for HERV-K102 upregulation by IFN-γ. In THP1-derived macrophages, knockdown of HML-2 or knockout of MAVS, an adaptor of RNA-sensing pathways, significantly downregulated genes containing interferon-stimulated response elements (ISREs) in their promoters, suggesting an intermediate role of HERV-K102 in the switch from IFN-γ signaling to the activation of type I interferon expression and, therefore, in a positive feedback loop to enhance pro-inflammatory signaling. IMPORTANCE The human endogenous retrovirus group K subgroup, HML-2, is known to be elevated in a long list of inflammation-associated diseases. However, a clear mechanism for HML-2 upregulation in response to inflammation has not been defined. In this study, we identify a provirus of the HML-2 subgroup, HERV-K102, which is significantly upregulated and constitutes the majority of the HML-2 derived transcripts in response to pro-inflammatory activation of macrophages. Moreover, we identify the mechanism of HERV-K102 upregulation and demonstrate that HML-2 expression enhances interferon-stimulated response element activation. We also demonstrate that this provirus is elevated in vivo and correlates with interferon gamma signaling activity in cutaneous leishmaniasis patients. This study provides key insights into the HML-2 subgroup and suggests that it may participate in enhancing pro-inflammatory signaling in macrophages and probably other immune cells.

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Endogenous retroviruses (ERVs), or LTR retrotransposons, are a class of transposable elements that are highly represented in mammalian genomes. Human ERVs (HERVs) make up roughly 8.3% of the genome and over the course of evolution, HERV elements underwent positive selection and accrued mutations that rendered them non-infectious; thereby, the genome could co-opt them into constructive roles with important biological functions. In the past two decades, with the help of advances in sequencing technology, ERVs are increasingly considered to be important components of the innate immune response. While typically silenced, expression of HERVs can be induced in response to traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts and under certain circumstances, proteins, including functionally active reverse transcriptase and viral envelopes. The biological activity of HERVs in the context of the innate immune response can be based on the functional effect of four major viral components: (1) HERV LTRs, (2) HERV-derived RNAs, (3) HERV-derived RNA:DNA duplexes and cDNA, and (4) HERV-derived proteins and ribonucleoprotein complexes. In this review, we will discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states.

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INTRODUCTION: HERVs are human endogenous retroviruses, which represent about 8% of the human genome, and have various physiological functions, especially in pregnancy, embryo development and placenta formation. However, their involvement in diseases is not well defined. Some studies have observed changes in HERV expression according to age. OBJECTIVE: Therefore, the aim of this systematic review was to analyze their role in pathogenesis and usage as diagnosis or prognosis biomarkers in aging disorders. METHODS: In this study, a search on the Pubmed interface was performed for papers published from January 1953 to June 1st, 2021. RESULTS: 45 articles have been included, which matched the eligibility criteria and evaluated the following diseases: breast cancer, prostate cancer, amyotrophic lateral sclerosis (ALS), osteoarthritis, Alzheimer's disease, immuno-senescence, cognitive impairment, cataract, glaucoma and hypertension. CONCLUSION: In conclusion, the results suggested that HERVs play a role in the pathogenesis and can be used as biomarkers for the diagnosis or prognosis of aging disorders.

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Human Endogenous Retroviruses (HERVs) are viral sequences integrated into the human genome, resulting from the infection of human germ-line cells by ancient exogenous retroviruses. Despite losing their replication and retrotransposition abilities, HERVs appear to have been co-opted in human physiological functions while their aberrant expression is linked to human disease. The role of HERVs in multiple malignancies has been demonstrated, however, the extent to which HERV activation and expression participate in the development of cancer is not yet fully comprehended. In this review article, we discuss the presumed role of HERVs in carcinogenesis and their promising diagnostic and prognostic implications. Additionally, we explore recent data on the HERVs in cancer therapeutics, either through the manipulation of their expression, to induce antitumor innate immunity responses or as cancer immunotherapy targets. Finally, more precise and higher resolution high-throughput sequencing approaches will further elucidate HERV participation in human physiological and pathological processes.

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BACKGROUND: Putative pathogenic effects mediated by human endogenous retroviruses (HERVs) in neurological and psychiatric disorders in humans have been extensively described. HERVs may alter the development of the brain by means of several mechanisms, including modulation of gene expression, alteration of DNA stability, and activation of immune system. We recently demonstrated that autistic children and their mothers share high expression levels of some HERVs and cytokines in peripheral blood mononuclear cells (PBMCs) ex vivo, suggesting a close mother-child association in Autism Spectrum Disorder (ASD). RESULTS: In the present study, PBMCs from autistic children and their parents were exposed to stimulating factors (Interleukin-2/Phytohaemagglutinin) or drugs, as Valproic acid and Efavirenz. The results show that HERVs and cytokines expression can be modulated in vitro by different stimuli in PBMCs from autistic children and their mothers, while no significant changes were found in PBMCs ASD fathers or in controls individuals. In particular, in vitro exposure to interleukin-2/Phytohaemagglutinin or valproic acid induces the expression of several HERVs and cytokines while Efavirenz inhibits them. CONCLUSION: Herein we show that autistic children and their mothers share an intrinsic responsiveness to in vitro microenvironmental changes in expressing HERVs and pro-inflammatory cytokines. Remarkably, the antiretroviral drug Efavirenz restores the expression of specific HERV families to values similar to those of the controls, also reducing the expression of proinflammatory cytokines but keeping the regulatory ones high. Our findings open new perspectives to study the role of HERVs in the biological mechanisms underlying Autism.

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Human Endogenous Retroviruses (HERVs) are derived from ancient exogenous retroviral infections that have infected our ancestors' germline cells, underwent endogenization process, and were passed throughout the generations by retrotransposition and hereditary transmission. HERVs comprise 8% of the human genome and are critical for several physiological activities. Yet, HERVs reactivation is involved in pathological process as cancer and autoimmune diseases. In this review, we summarize the multiple aspects of HERVs' role within the human genome, as well as virological and molecular aspects, and their fusogenic property. We also discuss possibilities of how the HERVs are possibly transactivated and participate in modulating the inflammatory response in health conditions. An update on their role in several autoimmune, inflammatory, and aging-related diseases is also presented.

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Bisphenol A (BPA), a recognized endocrine-disrupting chemical, is used in the production of epoxy and polycarbonate resins. Since human exposure to BPA has been associated with increased cancer susceptibility, the market has shifted to products often labeled as "BPA free" containing BPA analogs such as bisphenol F (BPF) and bisphenol S (BPS). However, the European legislation on BPF and BPS is still unclear. This study analyzed the effects of BPA, BPF, and BPS exposure on human peripheral blood mononuclear cells by using in vitro micronucleus assay. Furthermore, it investigated the impact of bisphenols exposure on human endogenous retroviruses (HERVs) expression, which is implicated with the pathogenesis of several human diseases. The micronucleus assay revealed a significant genotoxic effect in peripheral blood cells after exposure to BPA and BPF at concentrations of 0.1, 0.05, and 0.025 µg/ml, and to BPS at 0.1 and 0.05 µg/ml. In addition, BPA exposure seems to upregulate the expression of HERVs, while a downregulation was observed after BPF and BPS treatments. Overall, our data showed the toxic effect of BPA and its analogs on circulating cells in the blood and demonstrated that they could modulate the HERVs expression.

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Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths worldwide. Among its subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the most common, accounting for more than 85% of lung cancer diagnoses. Despite the incredible efforts and recent advances in lung cancer treatments, patients affected by this condition still have a poor prognosis. Therefore, novel diagnostic biomarkers are needed. Recently, a class of transposable elements called human endogenous retroviruses (HERVs) has been found to be implicated in cancer development and later employed as novel biomarkers for several tumor types. In this study, we first ever characterized the expression of HERVs at genomic locus-specific resolution in both LUAD and LUSC cohorts available in The Cancer Genome Atlas (TCGA). Precisely, (i) we profiled the expression of HERVs in TCGA-LUAD and TCGA-LUSC cohorts; (ii) we identified the dysregulated HERVs in both lung cancer subtypes; (iii) we evaluated the impact of the dysregulated HERVs on signaling pathways using neural network-based predictions; and (iv) we assessed their association with overall survival (OS) and relapse-free survival (RFS). In conclusion, we believe this study may help elucidate another layer of dysregulation that occurs in lung cancer involving HERVs, paving the way for identifying novel lung cancer biomarkers.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a "decentralized" information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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ABSTRACT Interferon-gamma (IFN-γ) plays a crucial role in viral infections by preventing viral replication and in the promotion of innate and adaptive immune responses. However, IFN-gamma can exert distinct effects in different persistent viral infections. The long-term overproduction of IFN-γ in retroviral infections, such as the human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1), and human endogenous retroviruses (HERVs), resulting in inflammation, may cause neuronal damage. This review is provocative about the role of IFN-γ during persistent retroviral infections and its relationship with the causation of some neurological disorders that are important for public health.

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Genomic incorporation of viruses as human endogenous retroviruses (HERVs) are components of our genome that possibly originated by incorporating ancestral of exogenous viruses. Their roles in the evolution of the human genome, gene expression, and the pathogenesis of autoimmune diseases (ADs) and neoplastic phenomena are the subject of intense research. This review analyzes the evolutionary and virological aspects of HERVs and other viruses that incorporate their genome into the human genome and have known role in the genesis of ADs. These insights are helpful to understand further the possible role in autoimmunity genesis of HERVs, other ancestral viruses no HERVs and modern viruses with the ability to incorporate into the human genome or interact with HERVs.

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Human endogenous retroviruses (HERVs) represent ∼8% of human genome, deriving from exogenous retroviral infections of germ line cells occurred millions of years ago and being inherited by the offspring in a Mendelian fashion. Most of HERVs are nonprotein-coding because of the accumulation of mutations, insertions, deletions, and/or truncations. It has been long thought that HERVs were "junk DNA". However, it is now known that HERVs are involved in various biological processes through encoding proteins, acting as promoters/enhancers, or lncRNAs to affect human health and disease. In this review, we summarized recent findings about HERVs, with implications in embryonic development, pluripotency, cancer, aging, and neurodegenerative diseases.