Search Results (159)

Porcine endogenous retroviruses (PERVs) are integrated into the genome of all pigs. As they can be released as infectious virus particles capable of infecting human cells in vitro, they pose a potential risk for xenotransplantation involving pig cells or organs. To assess whether pigs produce infectious human-tropic viruses, infection assays with human cells are required. There are three main types of assays. First is the incubation of human target cells with gamma-irradiated pig cells. This method ensures that viral transmission is assessed in the absence of replicating pig cells. However, gamma irradiation may alter gene expression in pig cells, potentially affecting the results. Second is the co-culture in a double-chamber system in which pig and human cells are separated by a porous membrane, preventing direct cell-to-cell contact. While this method allows for the detection of infection by free virus particles, it does not account for infection via cell-to-cell transmission, which is a common mode of retroviral infection. And third is the co-culture of pig cells with human cells expressing a resistance gene. The resistance gene allows selective elimination of pig cells upon the addition of a selection medium. This assay enables both free virus and cell-to-cell transmission as well as complete removal of pig cells, which may not be fully achieved in the first type of assay. The third assay best simulates the conditions of in vivo xenotransplantation. However, in all cases the selection of donor and recipient cells is crucial to the experimental outcome. Results only indicate whether a specific pig cell type releases PERVs and whether a specific human cell type is susceptible to infection. A negative infection result does not necessarily reflect the in vivo situation, in which a transplanted organ consists of multiple pig cell types interacting with a diverse range of human cells within a living organism. Knowledge of these limitations is important for authorities regulating clinical applications for xenotransplantation. Full article

DNA is inherently unstable and is susceptible to damage from both endogenous sources (such as reactive oxygen species) and exogenous factors (including UV, ionizing radiation, and chemicals). The accumulation of DNA damage manifests as genetic mutations, chromosomal instability, and the stalling of DNA replication and transcription processes. Accumulated DNA damage influences apoptosis and cell cycle checkpoints, serving as one of the key triggers for the manifestation of the senescent phenotype. Both aging and cancer are associated with the accumulation of mutations in somatic cells. Disruption of cell cycle control and uncontrolled proliferation are fundamental characteristics of any cancer cell, with the majority of anticancer drugs acting as inhibitors of cyclin-dependent kinases, thereby inducing a transition of cells into a senescent state. Consequently, disturbances in the dynamics and regulation of inflammatory responses, oxidative stress, cell proliferation, DNA damage repair, and epigenetic anomalies, along with the influence of retroviruses and transposons, lead to the accumulation of senescent cells within the human body, characterized by blocked replication and cell cycle, as well as a distinct secretory phenotype. The age-related or disease-associated accumulation of these senescent cells significantly alters the physiology of tissues and the organism as a whole. Many secondary metabolites of higher plants exhibit senolytic and senomorphic activities, although most of them are not fully characterized. In this review, we will explore the principal signaling pathways in mammalian cells that govern the cell cycle and cellular senescence, with a particular emphasis on how their dynamics, expression, and regulation have been modified through the application of senotherapeutic compounds. The second section of the review will identify key target genes for the metabolic engineering, primarily aimed at enhancing the accumulation of plant secondary metabolites with potential therapeutic benefits. Lastly, we will discuss the rationale for utilizing liver cells as a model system to investigate the effects of senolytic compounds on human physiology and health, as well as how senotherapeutic substances can be leveraged to improve gene therapy approaches based on CRISPR/Cas9 and prime-editing technologies. Full article

Human endogenous retroviruses (HERVs), as remnants of ancient exogenous retroviruses in the human genome, have received increased attention regarding their pathogenic effects caused by abnormal activation. In normal somatic cells, HERVs are tightly regulated by epigenetic mechanisms and are rarely expressed. In cancer cells, likely due to epigenetic dysregulation, HERVs become abnormally activated and are transcribed and expressed. The innate and adaptive immune responses triggered by HERV activation are closely associated with cancer initiation and progression. Melanoma, as a malignant tumor, often exhibits a poor prognosis in advanced-stage patients. HERVs have been found to be expressed in melanoma and linked to its malignant transformation. Here, we review the potential roles HERVs may play in melanoma development. As promising therapeutic targets for melanoma, research on HERVs could facilitate the development of novel treatment strategies. Full article

Background: Human endogenous retroviruses (HERVs) are remnants of ancestral retroviral infections integrated into the human genome, some of which maintain a residual active expression and retain physiological relevance. HIV-1 infection and antiretroviral therapy (ART) are known to modulate HERV expression, yet their specific effects during pregnancy remain poorly understood. This study aimed to investigate the peripartum transcriptional activity of selected HERV sequences in HIV-1-positive women receiving ART and their newborns exposed to the therapy and HIV-1-negative healthy controls. Methods: We quantified the expression of pol regions of HERV-H, -K, and -W and of Syncytin 1 and Syncytin 2 in peripheral blood samples collected at delivery using real-time PCR. Results: In HIV-1-positive mothers on ART therapy, we observed a significant downregulation in the pol gene expression of HERV-H, HERV-K, and HERV-W, as well as of Syncytin 1 and Syncytin 2, compared to healthy mothers. In contrast, no differences in the expression of the different targets were found in the two groups of newborns. All the HERV genes analyzed were also found to be expressed at significantly higher levels in the newborns compared to their mothers. Discussion: The results obtained suggest that antiretroviral therapy may influence and modulate HERV expression during pregnancy in both the mother and the fetus. Full article

Human Endogenous Retroviruses comprise approximately 8% of the human genome, serving as fragments of ancient retroviral infections. Although they are generally maintained in a silenced state by robust epigenetic mechanisms, specific HERV groups, particularly HERV-W and HERV-K, can become derepressed under specific pathological conditions, thereby contributing to the initiation and progression of neuroinflammatory and neurodegenerative processes. Preclinical studies and clinical trials, such as those investigating monoclonal antibodies, indicate that directly targeting these elements may offer a novel therapeutic strategy. In this review, we provide an overview of HERVs′ biology, examine their role in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer′s disease, and Parkinson′s disease, and explore their therapeutic prospects, highlighting both the challenges and the potential future research directions needed to translate these approaches into clinical interventions. Full article

Crohn’s disease (CD) is a multifactorial polygenic inflammatory bowel disease linked to aberrant immune response. Mycobacterium paratuberculosis (MAP) has been associated with CD; however, detecting MAP in CD tissues remains highly challenging. Recently, Human Endogenous Retroviruses (HERVs) differential gene expression has been reported in CD, but little is known about the involvement of MAP and HERVs in CD pathology. This study aimed to characterize the humoral response against HERV-K, HERV-W, and MAP antigens using an indirect ELISA in plasma samples from CD patients and age- and gender-matched healthy controls (HCs). We observed a significant antibody response against HERV-K and HERV-W epitopes in CD patients in comparison to MAP epitopes, as well as a higher overall antibody response in patients compared to HCs. This study is the first to report the presence of humoral immune response against HERVs antigens in CD. Considering the pro-inflammatory nature of CD, HERVs may contribute to the development or progression of disease in genetically predisposed individuals. However, further research is needed to better understand the complex role of HERVs in CD. Full article

Human endogenous retroviruses (HERVs) constitute about 8% of the human genome. The overexpression of HERVs has been detected in various inflammatory disorders like neuro-inflammation disorders and cancer. Interestingly, it has been reported that stress conditions facilitate HERV expression. Space travel exposes astronauts to microgravity environments (a stress condition), which may result in the activation of HERVs and might influence pathogenic outcomes during and after space flight. This study aimed to elucidate the transcriptional activity of three HERV families (W, K, and H) and cytokine genes (IL-1, IL-6, and TNF-α) in different cell lines under microgravity (μg) conditions and compare them with the results obtained under normal gravity (ng; 1g). We evaluated the expression of HERVs (HERV-K env, HERV-K gag, HERV-W env, and HERV-H env) and cytokine gene expression (IL-1, IL-6, and TNF-α) in neuroblastoma (SH-SY5Y), HEp-2, and Caco-2 cell lines under simulated μg and 1g conditions. In SH-SY5Y cells, the expression level of the IL-1, IL-6, HERV-H env, HERV-K env, HERV-K gag, and HERV-W env genes was significantly increased when exposed to short-term μg (3 and 6 h). The expression of TNF-α remained unchanged throughout all time points. Additionally, in Caco-2 cells, the expression of the HERV-K env, HERV-K gag, and IL-1 genes was significantly higher after 6 h of incubation in μg conditions compared to 1g. There was no statistically significant difference in the expression levels of the HERV-W env, HERV-H env, IL6, and TNF-α genes between the μg and 1g conditions. Moreover, in HEp-2 cells, the expression of the IL-1, IL6, TNF-α, HERV-H env, HERV-K env, HERV-K gag, and HERV-W env genes significantly increased following short-term incubation in μg (3 h, 6 h) and then decreased to levels comparable to those observed in the 1g condition. Taken together, the dysregulation of cytokine and HERV gene expression was observed under the simulated μg condition. The patterns of these dysregulations varied throughout cell lines, which demands further investigation for human health protection in space. Full article

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3/A3) family of cytosine deaminases serves as a key innate immune barrier against invading retroviruses and endogenous retroelements. The A3 family’s restriction activity against these parasites primarily arises from their ability to catalyze cytosine-to-uracil conversions, resulting in genome editing and the accumulation of lethal mutations in viral genomes. Additionally, non-editing mechanisms, including deaminase-independent pathways, such as blocking viral reverse transcription, have been proposed as antiviral strategies employed by A3 family proteins. Although viral factors can influence infection progression, the determinants that govern A3-mediated restriction are critical in shaping retroviral infection outcomes. This review examines the interactions between retroviruses, specifically human immunodeficiency virus type 1 and human T-cell leukemia virus type 1, and A3 proteins to better understand how editing and non-editing activities contribute to the trajectory of these retroviral infections. Full article

Irritable bowel syndrome (IBS) is a common disease, whose etiopathogenesis is poorly understood. Human endogenous retroviruses (HERVs) originate from ancient infections of germinal cells and represent 8% of our DNA. Most HERVs have become defective due to the accumulated mutations; some can, however, still be activated, and their altered expressions have been associated with a number of chronic inflammatory and immune-mediated disorders, including gastrointestinal diseases. Retroviral transcription is modulated by TRIM28 and SETDB1, which also participate in the regulation of epigenetic mechanisms and in shaping the immune system. Expressions of HERVs and TRIM28/SETDB1 have not been investigated in patients affected by IBS. Using a PCR real-time Taqman amplification assay, we explored the RNA levels of HERV-H-pol, HERV-K-pol, and HERV-W-pol; syncytin 1 (SYN1), SYN2, and HERV-W-env; and TRIM28 and SETDB1 in the peripheral blood of 37 IBS patients and healthy controls (HCs) of similar age. The transcript levels were higher in IBS patients than in HCs for all HERVs except for HERV-W-pol, with significant p-values for HERV-H-pol, HERV-K-pol, and SYN1 and borderline p-values for SYN2 and HERV-W-env. The RNA levels of SETDB1 were significantly enhanced in IBS patients, while those of TRIM28 were in the normal range. Patients with severe disease had significant upregulation of SETDB1 compared to those with mild or moderate symptoms. These findings suggest that overexpression of HERVs and SETDB1 may contribute to the development of IBS and open the way to innovative therapeutic strategies. Full article

The Spodoptera frugiperda Sf9 insect cell line is used in the baculovirus expression vector system for the development of various viral vaccines and some gene therapy products. Early studies indicated that Sf9 cells produced a reverse transcriptase (RT) activity that was detected using a sensitive PCR-enhanced reverse transcriptase (PERT) assay. Since RT is generally associated with retrovirus particles, we undertook the investigation of the physical properties and infectious nature of the extracellular RT activity that was constitutively expressed from Sf9 cells or induced after the chemical treatment of the cells with drugs known to activate endogenous retroviruses. A density gradient analysis indicated that the peak RT activity corresponded to a low buoyant density of about 1.08 g/mL. Ultracentrifugation and size filtration of cell-free Sf9 supernatant indicated that different particle sizes were associated with the RT activity. This was confirmed by transmission electron microscopy and cryoEM, which revealed a diversity in particle size and type, including viral-like and extracellular vesicles. The treatment of Sf9 cells with 5-iodo-2′-deoxyuridine (IUdR) induced a 33-fold higher RT activity with a similar low buoyant density compared to untreated cells. Infectivity studies using various target cells (human A204, A549, MRC-5, and Raji, and African green monkey Vero cells) inoculated with cell-free supernatant from untreated and IUdR-treated Sf9 cells showed the absence of a replicating retrovirus by PERT-testing of cell-free supernatant during the 30 day-culturing period. Additionally, there was no evidence of virus entry by whole genome analysis of inoculated MRC-5 cells using high-throughput sequencing. This is the first study to identify extracellular retroviral-like particles in Spodoptera. Full article

HERVs (Human endogenous retroviruses) are remnants of ancient exogenous retroviruses that have integrated into the human genome, particularly in germ-line cells. Among these, the envelope protein gene HERV-W env (Human endogenous retroviruses W family envelope protein), located on chromosome 7 and primarily expressed in the human placenta, has been closely linked to various neuropsychiatric disorders, including schizophrenia, as well as autoimmune diseases and cancer. Recent studies have highlighted the abnormal expression of cytokines as a key factor in the pathophysiology of schizophrenia. Notably, elevated serum levels of IL-1β (interleukin 1 beta) in schizophrenia, a cytokine associated with inflammation, are a characteristic feature of pyroptosis—a form of pro-inflammatory programmed cell death. Although previous research has observed significant upregulation of pyroptosis-related genes such as CASP1 (Caspase-1), NLRP3 (NLR family pyrin domain containing 3), and IL1B (interleukin 1 beta) in the serum of schizophrenia patients, and extensive neuron pyroptosis has been documented in various neuropsychiatric disorders, including Alzheimer’s disease, epilepsy, and multiple sclerosis, the occurrence of neuron pyroptosis in schizophrenia remains uncertain. Furthermore, the mechanisms underlying pyroptosis in schizophrenia and its potential connection with HERV-W env have yet to be fully elucidated. In this study, we found that the expression levels of pyroptosis-related genes, specifically CASP1, GSDMD (Gasdermin D), and IL1B, were significantly elevated in patients with schizophrenia compared to healthy controls. Furthermore, our analysis revealed a strong positive correlation between HERV-W env expression and the levels of CASP1/GSDMD/IL1B in these patients. Experimental evidence further demonstrated that HERV-W env promoted the activation of Caspase-1 and the cleavage of Gasdermin D, leading to increased release of LDH (lactate dehydrogenase) and IL-1β. Importantly, inhibitors targeting NLRP3, CASP1, and GSDMD significantly reduced the releases of LDH and IL-1β induced by HERV-W env, whereas BID (BH3 interacting domain death agonist) inhibitors did not have a notable effect. This suggests that HERV-W env induces CASP1–GSDMD-dependent pyroptosis through the NLRP3–CASP1–GSDMD signaling pathway. As pyroptosis is increasingly recognized for its connection to neurodegenerative diseases, this study provides insights into the molecular mechanisms of neuronal pyroptosis mediated by the NLRP3 inflammasome in the context of HERV-W env. Additionally, it explores the potential facilitation of HERV-W env in the development of schizophrenia via pyroptosis, proposing that certain pyroptosis indicators could serve as potential biomarkers for schizophrenia. Based on our existing research results and the findings of previous researchers, we infer that HERV-W env acts as a bridge in the onset and progression of schizophrenia. Furthermore, HERV-W env may serve as a potential target for the clinical treatment of schizophrenia, suggesting that monoclonal antibody therapy targeting HERV-W env could represent a novel approach to managing this disease. Full article

The human endogenous retroviruses (HERVs) are ancient exogenous retroviruses that were embedded in the germline over 30 million years ago and underwent an endogenization process. They make up roughly 8% of the human genome. HERVs exhibit many physiological and non-physiological functions; for example, they play a role in the development of many diseases. They have been shown to affect carcinogenesis by modifying the expression of host genes through their functions as enhancers and promoters. Additionally, some molecules derived from HERVs may stimulate the immune system. Recently research has been focused on the effect of human endogenous retroviruses on the development of neurodegenerative diseases, including Alzheimer’s disease (AD), which is the most common cause of dementia. AD is also linked to a significant deterioration in quality of life. The article aims to highlight the potential role of HERVs in neurodegenerative diseases such as Alzheimer’s disease and senescence. Moreover, it is estimated that HERVs may be potential targets for diagnosis and therapy of AD. Full article

Increasing evidence indicates that human endogenous retroviruses (HERVs) are important to human health and are an underexplored component of many diseases. Certain HERV families show unique expression patterns and immune responses in autism spectrum disorder (ASD) patients compared to healthy controls, suggesting their potential as biomarkers. Despite these interesting findings, the role of HERVs in ASD needs to be further investigated. In this review, we discuss recent advances in genetic research on ASD, with a particular emphasis on the implications of HERVs on neurodevelopment and future genomic initiatives aimed at discovering ASD-related genes through Artificial Intelligence. Given their pro-inflammatory and autoimmune characteristics, the existing literature suggests that HERVs may contribute to the onset or worsening of ASD in individuals with a genetic predisposition. Therefore, we propose that investigating their fundamental properties could not only improve existing therapies but also pave the way for new therapeutic strategies. Full article

Human endogenous retroviruses (HERVs) are genomic fragments integrated into human DNA from germline infections by exogenous retroviruses that threatened primates early in their evolution and are inherited vertically in the germline. So far, HERVs have been studied in the context of extensive immunopathogenic, neuropathogenic and even oncogenic effects within their host. In particular, in our paper, we elaborate on the aspects related to the possible correlation of transposable HERV elements’ activation and SARS-CoV-2 spike protein’s presence in cells of COVID-19 patients or upon COVID-19 vaccination with implications for natural and adaptive immunity. In particular, the release of cytokines TNF-α, IL-1β and IL-6 occurs in such cases and plays a notable role in sustaining chronic inflammation. Moreover, well-known interindividual variations of HERVs might partially account for the interpersonal variability of COVID-19 symptoms or unwanted events post-vaccination. Accordingly, further studies are required to clarify the SARS-CoV-2 spike protein’s role in triggering HERVs. Full article

Papillary thyroid cancer (PTC) is one of the fastest-growing cancers worldwide, lacking established causal factors or validated early diagnostics. Human endogenous retroviruses (HERVs), comprising 8% of human genomes, have potential as PTC biomarkers due to their comparably high baseline expression in healthy thyroid tissues, indicating homeostatic roles. However, HERV regions are often overlooked in genome-wide association studies because of their highly repetitive nature, low sequence coverage, and decreased sequencing quality. Using targeted whole-genome sequence analysis in conjunction with high sequencing depth to overcome methodological limitations, we identified associations of specific HERV variants with PTC. Analyzing WGS data from 138 patients with PTC generated through The Cancer Genome Atlas project and 2015 control samples from the 1000 Genomes Project, we examined the mutational variation in HERVs within a 20 kb radius of known cancer predisposition genes (CPGs) differentially expressed in PTC. We discovered 15 common and 13 rare germline HERV variants near or within 20 CPGs that distinguish patients with PTC from healthy controls. We identified intragenic–intronic HERV variants within RYR2, LRP1B, FN1, MET, TCRVB, UNC5D, TRPM3, CNTN5, CD70, RYR1, RUNX1, CRLF2, and PCDH1X, and three variants downstream of SERPINA1 and RUNX1T1. Sanger sequencing analyses of 20 thyroid and 5 non-thyroid cancer cell lines confirmed associations with PTC, particularly for MSTA HERV-L variant rs200077102 within the FN1 gene and HERV-L MLT1A LTR variant rs78588384 within the CNTN5 gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of CNTN5. In addition, we identified 16 variants that modified the poly(A) region in Alu elements, potentially altering the potential to retrotranspose. In conclusion, this study serves as a proof-of-concept for targeted variant analysis of HERV regions and establishes a basis for further exploration of HERVs in thyroid cancer development. Full article