Search Results (52)

To this day, the etiology of multiple sclerosis has yet to be fully comprehended by the scientific community. However, the knowledge on mechanisms leading to the development of this neurodegenerative autoimmune disorder increases daily, along with the development of new disease-modifying treatments. A correlation between Epstein–Barr Virus infection and the disease incidence has recently shed light on possible innovative antiviral therapies. Here, we review the literature on Human Endogenous Retroviral sequences as emerging actors for the impairment of remyelination as a major challenge in disease progression. Our primary focus is the HERV-W envelope protein, which has been found at elevated levels in individuals affected by this condition and is suggested here as a potential therapeutic target. We then continue analyzing the clinical cases where antiretroviral drugs have been tested to treat multiple sclerosis patients and, from successes and failures, we finally narrow down our therapeutic hypothesis to the administration of Nucleoside-analog Reverse Transcriptase Inhibitors to target the HERV-W envelope protein, possibly leading to remyelination and significantly improving the condition of those affected by the disease. The main purpose of this review is to present a rationale for the therapeutic potential of this drug class and offer a new perspective for therapeutic options against multiple sclerosis. Full article

Human endogenous retroviruses (HERVs) represent 8% of our genome. They are remnants of ancient infections of germinal cells. HERVs are no longer infectious, but their enhanced expression is implicated in several diseases, including neuropsychiatric disorders. Their transcription is regulated by TRIM28 and SETDB1, which are involved in the regulation of epigenetic processes, in neural cell differentiation, and brain inflammation. We explored the expressions of HERVs and TRIM28/SETDB1 in adolescents affected by anorexia nervosa (AN). Through real-time PCR, we assessed the transcription levels of pol genes of HERV-H, -K, and -W, of env genes of Syncytin 1 (SYN1), Syncytin 2 (SYN2), and of HERV-W, and of TRIM28 and SETDB1 in whole blood of 37 adolescents with AN and in healthy controls (HCs) of comparable age. HERV-H-pol, HERV-K-pol and SETDB1 transcriptional levels were significantly higher in adolescents with AN as compared with HCs, while HERV-W-pol and -env were downregulated in the former. No differences were observed for SYN1, SYN2, and TRIM28 between the two groups. The observed expression pattern of HERVs is specific for AN as compared to other neuropsychiatric disorders. These aberrant expressions suggest a potential role of retroviral elements in the pathophysiology of AN, opening the way for innovative diagnostic and therapeutic strategies. Full article

Human endogenous retroviruses (HERVs), remnants of ancient germline infections, constitute ~8% of the human genome. Although mostly silenced, these elements can be expressed and play physiological or pathological roles. We investigated HERV expression dynamics, proviral load, and systemic inflammatory status in young and older adults, as well as the impact of regular physical exercise. PBMC and serum samples were collected from 30 young controls (YC), 30 inactive older adults (INAC) and 30 regularly exercising older adults (REG). Expression of HERV-W, -K, -H, Syncytin-1 and -2 was assessed by qPCR using the −2ΔΔCt method, and proviral load (HERV-W, -K, -H) was estimated by relative copy number. Serum cytokines (IL-1β, IL-6, IL-17, TNF-α, IFN-γ, IL-10) were quantified by ELISA. Statistical significance was set at p < 0.05. INAC participants showed higher proviral load of HERV-K, -W and -H compared to YC (p = 0.025), but overall lower HERV expression, except for HERV-K. REG presented increased expression of HERV-W (~1.5-fold, p < 0.0001), HERV-H (~1.8-fold, p < 0.0001; higher than YC p = 0.01), HERV-K (vs. YC p = 0.02) and Syncytin-1 (~1.4-fold vs. INAC and YC, p < 0.01). HERV-K was the most upregulated element in INAC. HERV-W and HERV-H expression were strongly correlated in all groups. INAC showed a pro-inflammatory profile, with elevated IL-6/IL-10, IL-1β/IL-10, and IFN-γ/IL-10 ratios. Older adults exhibit higher HERV proviral load, suggesting possible age-related insertions. Regular physical exercise modulates HERV expression, whereas inactivity is associated with reduced expression and increased inflammation. HERV-W and HERV-H maintain coordinated expression across ages, indicating interplay between inflammatory balance, aging, and retroviral activity. Full article

Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder caused by genetic and epigenetic alterations at chromosome 11p15.5. Increasing evidence suggests that imprinting defects may be accompanied by broader epigenomic perturbations affecting repetitive elements such as human endogenous retroviruses (HERVs). We quantified the transcriptional levels of the HERV-H, HERV-K, and HERV-W-pol genes, the HERV-derived env genes, Syncytin-1 (SYN1) and Syncytin-2 (SYN2), and the epigenetic regulators, TRIM28 and SETDB1, in whole blood from children and adolescents with BWS, stratified by molecular subtype (ICR2 loss of methylation, n = 14; UPD(11)pat, n = 10), and compared with age-matched healthy controls using quantitative real-time PCR. The BWS samples showed significantly increased transcription of HERV-H and HERV-K relative to controls, whereas HERV-W was unchanged. The SYN1 transcripts were significantly higher in UPD(11)pat compared with controls, while SYN2 did not differ between groups. TRIM28 and SETDB1 were significantly overexpressed in BWS, irrespective of molecular subtype, and no significant differences were observed between ICR2 and UPD(11)pat for HERV-H, HERV-K, HERV-W, TRIM28, or SETDB1. These findings indicate selective dysregulation of endogenous retroelements and key repressors in BWS, consistent with epigenetic alterations extending beyond canonical imprinted loci. Full article

Systemic lupus erythematosus (SLE) is characterized by chronic immune activation, enhanced type I interferon signaling, and epigenetic dysregulation, conditions that may promote the reactivation of human endogenous retroviruses (HERVs). Whether HERV activation in SLE is global or selective, however, remains unclear. We analyzed the expression of HERV-H, HERV-K, and HERV-W, along with the HERV-derived envelope genes Syncytin-1 and Syncytin-2, in samples from lupus patients and healthy controls. In parallel, we assessed the expression of the epigenetic repressors TRIM28 and SETDB1. HERV-H expression was comparable between groups, whereas HERV-K and HERV-W were significantly overexpressed in lupus patients. Syncytin-1 and HERV-W env transcripts were markedly increased in SLE, while Syncytin-2 expression was unchanged. Lupus patients showed reduced TRIM28 and increased SETDB1 expression, consistent with altered regulation of HERV repression pathways. Notably, HERV-H and HERV-W pol expression correlated with the type I interferon score, suggesting an association between interferon signaling and selective HERV activation. These findings indicate that SLE is associated with the selective activation of immunostimulatory HERV families, particularly HERV-W. The observed associations with interferon signaling suggest that HERV-W-related transcripts may represent disease-associated molecular signatures, warranting further mechanistic investigation. Full article

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into various connective tissue cell types. Adipose tissue provides a rich source of MSCs (ADSCs), which can differentiate into osteoblasts, adipocytes, and chondroblasts. Pluripotency factors such as SOX2, NANOG, and OCT4 maintain MSC stemness, whereas human endogenous retroviruses (HERVs) and their epigenetic regulators TRIM28 and SETDB1 have been implicated in transcriptional regulation and cell fate decisions. This study investigated the transcriptional expression of HERV-H, -K, and -W, TRIM28, SETDB1, and pluripotency markers (NANOG, OCT4, SOX2) during chondrogenic differentiation of ADSCs using Real-Time PCR. Chondrogenesis was confirmed by aggrecan (ACAN) upregulation and aggrecan immunostaining. Although no statistically significant differences were observed for HERV-H, HERV-K, or HERV-W, HERV-K and HERV-W showed a trend toward decreased expression in differentiated cells, consistent with the overall shift in transcriptional profile during lineage commitment. TRIM28 expression was significantly reduced, while SETDB1 showed a decreasing trend. Among pluripotency markers, OCT4 was significantly downregulated, whereas NANOG and SOX2 remained stable. Correlation analyses revealed that in differentiated ADSCs, HERV-W expression correlated negatively with TRIM28 and positively with SETDB1, while no correlations were found for HERV-H or HERV-K. These findings suggest that specific HERV families and their epigenetic regulators may undergo coordinated modulation during chondrogenic differentiation, supporting a complex and family-specific interplay between retroelement regulation, pluripotency factors, and MSC lineage commitment. Full article

Despite notable progress in cancer therapy, immune evasion remains a major obstacle to effective treatment outcomes. In the context of spaceflight, astronauts are exposed to unique environmental stressors—particularly microgravity and radiation—that profoundly affect cellular and immune homeostasis. Emerging evidence suggests that microgravity alters key cellular processes, including proliferation, apoptosis, adhesion, and oncogenic signaling pathways such as NF-κB and ERK1/2. Concurrently, microgravity (µg) disrupts immune regulation, potentially facilitating both tumor progression and treatment resistance. Of particular concern is the upregulation of human endogenous retroviruses (HERVs), especially HERV-K and HERV-W, under µg conditions, which may exacerbate inflammatory responses and immune system dysregulation. While some studies indicate that µg may impair tumor growth, others reveal enhanced immune evasion and reduced antitumor immunity. Importantly, insights from µg research extend beyond space medicine and provide translational opportunities for terrestrial oncology, including the development of physiologically relevant 3D tumor models for drug screening, the identification of mechano-sensitive pathways (FAK/RhoA, YAP/TAZ) as therapeutic targets, and novel immunotherapeutic strategies involving epigenetic modulation and checkpoint inhibition. This review critically examines the dual role of µg in modulating cancer progression and immune function. We synthesize findings on how µg shapes immune responses, alters tumor–immune system interactions, and impacts the efficacy of immunotherapeutic approaches. Finally, we highlight translational opportunities and challenges for optimizing cancer immunotherapy and precision oncology in both spaceflight and Earth-based environments. 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

This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow-up, which provided a secondary diagnosis of Multiple Sclerosis (MS) eight years later. The most impactful result was his response to rituximab treatment after the systematic failure of prior treatments. Although the expression of endogenous retroviral proteins has been associated with autoimmunity, the patient did not show increased expression of the toxic protein HERV (human endogenous retrovirus)-W ENV, a target of the ongoing clinical trials with temelimab in MS and long COVID-19 cases. However, genome-wide HERV transcriptome analysis by high density microarrays clearly revealed a distinct profile in the patient’s blood supportive of an altered immune system. Limitations of the study include sub-optimal frequency of magnetic resonance imaging to monitor lesion progression, and similarly for reassessment of HERV profiles after rituximab. Overall, the coincidence of HERV alterations and the impactful response to rituximab presents the possibility of additional, more specific, therapeutic targets encoded by other HERV elements yet to be discovered. 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

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

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

Inflammatory bowel disease (IBD) includes patients affected by Crohn’s disease or ulcerative colitis. IBD is thought to be a chronic immune-mediated disease, but its origin remains elusive, and this limits new therapeutic approaches. Human endogenous retroviruses (HERVs) originate from ancestral infections and represent 8% of the human genome. HERVs are no longer infectious, but some retroviral sequences can be activated, and their aberrant expressions have been implicated in inflammatory and autoimmune disorders. HERV transcription is regulated by TRIM28 and SETDB1, which are also directly involved in epigenetic processes and modulation of the immune response. Using a PCR real-time Taqman amplification assay, we assessed, for the first time, the transcription levels of pol genes of HERV-H, -K, and -W families of env genes of syncytin 1 (SYN1), SYN2, and HERV-W, as well as of TRIM28 and SETDB1 in the whole blood of 48 patients with Crohn’s disease (CD), 20 with ulcerative colitis (UC), and in healthy controls (HC) of comparable age. The transcriptional levels of HERV-H-pol (p = 0.0003) and HERV-K-pol (p = 0.001) were significantly higher in IBD patients compared with HC, with no differences between patients with CD and UC. No significant differences were found for the remaining HERVs between IBD patients and HC. The transcript levels of TRIM28 were significantly downregulated in IBD patients (p < 0.001), without differences between CD and UC, while the SETDB1 levels were preserved. The enhanced transcription of HERV-H-pol and HERV-K-pol, as well as the impaired activation of TRIM28, were not influenced by clinical disease activity and type of treatment. The overexpression of HERVs and impaired transcription of TRIM28 in patients affected by CD or UC suggest that they might be the main actors in the pathophysiology of IBD, opening the way to innovative targeted interventions. Full article