Search Results (173)

Porcine lymphotropic herpesviruses -1, -2, and -3 (PLHV-1, PLHV-2, and PLHV-3) are gammaherpesviruses that are widespread in pigs. These viruses are closely related to the human pathogens Epstein–Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV), both of which are known to cause severe diseases in humans. To date, however, no definitive association has been established between PLHVs and any disease in pigs. With the growing interest in xenotransplantation as a means to address the shortage of human organs for transplantation, the safety of using pig-derived cells, tissues, and organs is under intense investigation. In preclinical trials involving pig-to-nonhuman primate xenotransplantation, another porcine herpesvirus—porcine cytomegalovirus, a porcine roseolovirus (PCMV/PRV)—was shown to be transmissible and significantly reduced the survival time of the xenotransplants. In the present study, we examined donor pigs and their respective baboon recipients, all of which were part of preclinical pig heart xenotransplantation studies, for the presence of PLHV. PLHV-1, PLHV-2, and PLHV-3 were detected in nearly all donor pigs; however, no evidence of PLHV transmission to the baboon recipients was observed. Full article

Oncoviruses, such as Epstein–Barr virus (EBV), human papillomavirus (HPV), and Kaposi sarcoma-associated herpesvirus (KSHV), have been widely discussed for their oncogenic risk. Initially, the oral cavity was disregarded. In recent years, orientation has shifted to the importance of the oral cavity and cancer-related issues via Handbook 19 titled “Oral Cancer Prevention” by the International Agency for Research on Cancer, the WHO Global Oral Health Status Report 2022, and multiple other actions focused on reducing the oversight of this neglected area. Oncoviruses play a significant role in oral cavity malignancies by establishing persistent infections, evading host immune responses, and inducing cellular transformation through the disruption of normal regulatory pathways. Molecular biology and microbiome research have advanced our understanding of the complex interplay between oncoviruses and oral microbiota, demonstrating how coinfections and dysbiosis can enhance viral oncogenic potential. These findings improve the understanding of virus-induced oral cancers and support the development of novel diagnostic and therapeutic strategies. This narrative review focuses on the relationship between oncoviruses and the oral cavity by focusing on how a specific virus triggers tumorigenesis for each of the described viruses and how it affects oral cavity cancer development. Finally, we describe recent advances and future perspectives including vaccines and/or treatment. Full article

AIDS-related malignant lymphomas (ARLs) are the lymphomas that develop in association with HIV infection. According to the introduction of combination antiretroviral therapy (cART), the life expectancy of People Living with HIV (PLWH) has markedly improved; however, approximately one-third of PLWH have passed away from the complications of malignancies, even in well-controlled PLWH. HIV itself is not tumorigenic, and most of these tumors are due to co-infection with oncogenic viruses. γ-herpes viruses (Epstein–Barr virus: EBV and Kaposi sarcoma-associated herpesvirus: KSHV) are the most significant risk factors for ARLs. Immunodeficiency, chronic inflammation, accelerated aging, and genetic instability caused by HIV infection, as well as HIV accessory molecules, are thought to promote lymphomagenesis. The prognosis of ARLs is comparable to that of non-HIV cases in the cART era. Intensive chemotherapy with autologous stem cell transplantation is also available for relapsed/refractory ARLs. Since the early stage of HIV infection has no symptoms, significant numbers of HIV-infected individuals have not noticed HIV infection until the onset of AIDS (so-called Ikinari AIDS). Since the ratio of these patients is more than 30% in Japan, hematologists should carefully consider the possibility of HIV infection in cases of lymphoma. Even in an era of cART, ARL remains a critical complication in PLWH, warranting continuous surveillance. Full article

Although efficiently managed by cART, chronic HIV infection remains associated with a high incidence of malignant lymphomas. This diverse group of tumors presents considerable challenges in research, diagnosis, and treatment due to their complex pathogenesis, heterogeneous tumor microenvironment, and frequently aggressive clinical behavior. In this review, we examine the multifactorial pathogenesis of lymphomas arising in people living with HIV (PLWH), encompassing both direct and indirect oncogenic mechanisms. We summarize the key histopathological features and microenvironmental characteristics that may influence therapeutic responses. Current treatment strategies approved for the treatment of lymphomas in PLWH are showing outcomes comparable with those observed in patients without HIV. Notably, the immune reconstitution achieved through cART has renewed interest in immunotherapeutic approaches for HIV-associated lymphomas, with several strategies under clinical investigation. However, progress in the diagnosis and management of these malignancies is hindered by fragmented research efforts and the frequent exclusion of PLWH from pivotal clinical trials. Coordinated efforts are essential to overcome these barriers, reduce lymphoma incidence, and improve survival outcomes in this vulnerable population. Full article

Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is regulated by key mediators including glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes latency-associated nuclear antigen (LANA), a multifunctional protein critical for viral persistence. Although studies reported that KSHV infection enhanced cellular resistance to ferroptosis, the specific role of LANA in this process remains unexplored. Here, we demonstrate that LANA unexpectedly promotes ferroptosis. In KSHV-positive iSLK.219 cells, LANA knockdown significantly attenuated RSL-3-induced ferroptosis, whereas LANA overexpression sensitized HeLa cells to ferroptotic death. Quantitative analysis revealed that LANA-depleted cells exhibited significantly elevated ROS accumulation (p < 0.01), whereas LANA-overexpressing cells maintained reduced ROS levels during challenge with the ferroptosis inducer RSl-3. Mechanistically, LANA suppressed glutathione peroxidase 4 (GPX4) expression, reduced nuclear factor erythroid 2-related factor 2 (Nrf2) expression and impaired its nuclear translocation, and upregulated mouse double minute 2 homolog (MDM2) expression. Pharmacological inhibition of Nrf2 (ML385) or MDM2 (nutlin3a) reversed the ferroptotic effects of LANA knockdown or overexpression, respectively. These findings reveal a pro-ferroptotic role of LANA via Nrf2/GPX4 suppression and MDM2 activation. Full article

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus. There are no vaccines or antiviral therapies for KSHV. Identifying the cellular metabolic pathways that KSHV manipulates can broaden the knowledge of how these pathways contribute to sustaining lytic infection, which can be targeted in future therapies to prevent viral spread. In this study, we performed an untargeted metabolomic analysis of KSHV infected telomerase-immortalized gingival keratinocytes (TIGK) cells at 4 h post-infection compared to mock-infected cells. We found that the metabolomic landscape of KSHV-infected TIGK differed from that of the mock. Specifically, a total of 804 differential metabolic features were detected in the two groups, with 741 metabolites that were significantly upregulated, and 63 that were significantly downregulated in KSHV-infected TIGK cells. The differential metabolites included ornithine, arginine, putrescine, dimethylarginine, orotate, glutamate, and glutamine, and were associated with pathways, such as the urea cycle, polyamine synthesis, dimethylarginine synthesis, and de novo pyrimidine synthesis. Overall, our untargeted metabolomics analysis revealed that KSHV infection results in marked rapid alterations in the metabolic profile of the oral epithelial cells. We envision that a subset of these rapid metabolic changes might result in altered cellular functions that can promote viral lytic replication and transmission in the oral cavity. Full article

In addition to its classical role in calcium and phosphate metabolism regulation, vitamin D also has an important impact on immunity modulation. Vitamin D regulates the immune response, shifting from a proinflammatory state to a more tolerogenic one by increasing the release of anti-inflammatory cytokines while downregulating proinflammatory cytokines. Thus, low levels of vitamin D have been associated with an increased risk of developing autoimmune diseases like multiple sclerosis and type 1 diabetes. Furthermore, this prohormone also enhances the release of well-known antimicrobial peptides, like cathelicidin LL-37 and β-defensins; therefore, it has been proposed that vitamin D serum levels might be related to the risk of well-known pathogen infections, including herpesviruses. These are a group of widely spread viral pathogens that can cause severe encephalitis or tumors like Kaposi’s sarcoma and Burkitt lymphoma. However, there is no consensus on the minimum levels of vitamin D or the recommended daily dose, making it difficult to establish a possible association between these two factors. This narrative non-systematic review will analyze the mechanisms by which vitamin D regulates the immune system and recent studies about whether there is an association between vitamin D serum levels and herpesvirus infections. Full article

Despite the high prevalence of latent Kaposi’s sarcoma-associated herpesvirus (KSHV) infections in patients from endemic areas with a high human immunodeficiency virus (HIV) prevalence, KSHV lytic reactivation in the context of other co-infections is not well understood. Lytic KSHV infections can contribute to severe inflammatory symptoms and KSHV-associated pathogenesis. We have previously reported on KSHV reactivation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure in a non-hospitalised cohort of people living with HIV (PLWH). From this cohort, we identified a 34-year-old male who presented for routine HIV care in May 2021 with an unusually high KSHV viral load (VL) of 189,946.3 copies/10⁶ cells, before SARS-CoV-2 infection. The patient was invited into a 2-year follow-up study where his peripheral blood was analysed for selected virological, clinical, and inflammatory parameters every 6 months. He remained highly viremic for KSHV throughout the 2-year study period, during which he was infected with SARS-CoV-2 and developed disseminated tuberculosis, with steadily increasing levels of the inflammatory markers C-reactive protein (CRP), and interleukin-6 (IL-6). His HIV VL remained controlled (<1000 copies/mL) and his CD4 count bordered immunosuppression (±200 cells/µL), suggesting some responsiveness to antiretroviral treatment (ART). However, the patient’s uncontrolled lytic KSHV infection may increase his risk for developing a KSHV-associated pathology manifesting with inflammation which should be closely monitored beyond the study period. Full article

Repressor element-1 silencing transcription factor or neuron-restrictive silencer factor (REST/NRSF) is an extensively studied neuronal gene regulator both in neuronal cells and non-neuronal cells. Even though the role of REST in host cellular gene regulation is well established, its role in the establishment of viral infections and its capability to stabilize and destabilize such viral infections are scarcely studied. Co-repressor and DNA modifiers are involved in REST-mediated repressive action of its target genes. The role of REST and co-repressors together or individually in the regulation of viral as well as host genes has been unraveled in a few viruses such as HIV and influenza as well as two of the herpesvirus family members, namely herpes simplex virus type 1 (HSV-1) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Here, we summarize all such virus studies involved with REST to gain a better insight into REST biology in virus infections. We also focus on unraveling the possible RE-1 binding sites in the Epstein–Barr virus (EBV) genome, a well-known human oncogenic herpesvirus that is associated with infectious mononucleosis and neoplasms such as B-cell lymphomas, nasopharyngeal carcinoma, gastric carcinoma, etc. An in silico-based approach was employed towards the prediction of such possible RE-1 binding elements in the EBV genome. This review advances the present knowledge of REST in virus infection which will aid in future efforts towards a better understanding of how REST acts in herpesviruses and other viruses for their infections and pathogenesis. Full article

Kaposi’s Sarcoma Herpesvirus (KSHV) is the causative agent of several human diseases. There are few effective treatments available to treat infection and KSHV oncogenesis. Disrupting the KSHV infectious cycle would diminish the viral spread. The KSHV lytic phase and production of new virions require efficient copying and packaging of the KSHV genome. KSHV encodes its own lytic DNA replication machinery, including the processivity factor (PF-8), which presents itself as an attractive target for antiviral development. We characterized PF-8 at the single molecule level using transmission electron microscopy to identify key molecular interactions that mediate viral DNA replication initiation. Our results indicate that PF-8 forms oligomeric ring structures (tetramer, hexamer, and/or dodecamer) similar to the related Epstein–Barr virus processivity factor (BMRF1). Our DNA positional mapping revealed high-frequency binding locations of PF-8 within the lytic origin of replication (OriLyt). A multi-variable analysis of PF-8 DNA-binding activity with three mutant OriLyts provides new insights into the mechanisms that PF-8 associates with viral DNA and complexes to form multi-ring-like structures. Collectively, these data enhance the mechanistic understanding of the molecular interactions (protein–protein and protein-DNA) of an essential KSHV DNA replication protein. Full article

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus and the etiological agent of several diseases. These include the malignancies Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD), as well as the inflammatory disorder KSHV inflammatory cytokine syndrome (KICS). The KSHV lifecycle is characterized by two phases: a default latent phase and a lytic replication cycle. During latency, the virus persists as an episome within host cells, expressing a limited subset of viral genes to evade immune surveillance while promoting cellular transformation. The lytic phase, triggered by various stimuli, results in the expression of the full viral genome, production of infectious virions, and modulation of the tumor microenvironment. Both phases of the KSHV lifecycle play crucial roles in driving viral pathogenesis, influencing oncogenesis and immune evasion. This review dives into the intricate world of the KSHV lifecycle, focusing on the molecular mechanisms that drive its latent and lytic phases, their roles in disease progression, and current therapeutic strategies. Full article

This study aims to analyze the whole-genome DNA methylation differences in Yili horses before and after racing, with the goal of identifying differentially methylated genes associated with racing performance and exploring the epigenetic mechanisms underlying exercise in horses. Blood samples were collected from the jugular veins of the top 3 Yili horses in a 5000 m race, which included 25 competitors, both prior to and within 5 min after the race. Genomic DNA was extracted, followed by sequencing using Whole-Genome Bisulfite Sequencing (WGBS) to assess DNA methylation levels, differentially methylated regions (DMRs), and differentially methylated genes (DMGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the identified DMGs to select candidate genes potentially associated with equine exercise. A total of 18,374 differentially methylated CG regions, 254 differentially methylated CHG regions, and 584 differentially methylated CHH regions were identified. A total of 4293 DMGs were anchored in gene bodies and 2187 DMGs in promoter regions. Functional analysis revealed that these DMGs were mainly enriched in terms related to binding and kinase activity, as well as pathways such as PI3K-Akt signaling and Kaposi sarcoma-associated herpesvirus infection. Further analysis indicated that genes such as IFNAR2, FGF4, and DGKH could be potential candidate genes associated with equine athletic performance. The findings of this study contribute to understanding the epigenetic regulatory mechanisms of equine athletic performance, providing a reference for further in-depth research on horse racing. Full article

Kaposi Sarcoma (KS) is a vascular tumor originating from endothelial cells and is associated with human herpesvirus 8 (KSHV) infection. It disproportionately affects populations facing health disparities. Although antiretroviral therapy (ART) has improved KS control in people with HIV (PWH), treatment options for advanced KS remain limited. This study investigates the tumor microenvironment (TME) of KS through whole-transcriptomic profiling, analyzing changes over time and differences based on HIV status. The TME was categorized into four subtypes: immune-enriched (IE), non-fibrotic, immune-enriched/fibrotic (IE/F), fibrotic (F) and immune-depleted (D). Nine KS patients (four HIV-negative and five HIV-positive) were enrolled in the study. Longitudinally collected KS samples from three patients (one HIV-negative and two HIV-positive) allowed for the investigation of dynamic TME changes within individual patients. The immune cellular composition was determined using deconvolution and compared to a cohort of non-KS patients. Our findings revealed that all KS samples, regardless of HIV status, were enriched in endothelial cells. Compared to non-KS tissues, the KS samples contained a higher percentage of NK and CD8+ T cells. HIV-negative KS samples displayed the IE and IE/F TME subtypes, while HIV-positive samples exhibited IE, IE/F, and F subtypes. Over the course of the disease, a decrease in angiogenic signatures was observed in two HIV-positive KS patients. Notably, HIV-negative KS samples showed alterations in NK cell-mediated immunity and cytotoxic response pathways, whereas HIV-positive samples exhibited changes in growth regulation and protein kinase activity pathways at the time of initial diagnosis. The gene expression of immune checkpoints, including CD274 (PD-L1) and PDCD1LC2 (PD-L2), was comparable between HIV-positive and HIV-negative KS samples at diagnosis. Furthermore, sequencing identified a shared TCRβ chain in all patients analyzed, indicating a T-cell immune response to a common antigen. This study demonstrates unique transcriptomic features and TME subtypes in KS that differ based on HIV status. Additionally, it illustrates longitudinal dynamic changes in the gene signatures and TME subtypes in individual patients. The identification of a shared TCRβ chain suggests that immune T cells in KS patients may target a common antigen. Future studies should further explore the immune microenvironment and unique T cell clonotypes, which could pave the way for the development of novel therapeutic strategies for KS patients. Full article

Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), which are the only members of the gamma(γ) herpesviruses, are oncogenic viruses that significantly contribute to the development of various human cancers, such as Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s lymphoma, Kaposi’s sarcoma, and primary effusion lymphoma. Oncogenesis triggered by γ-herpesviruses involves complex interactions between viral genetics, host cellular mechanisms, and immune evasion strategies. At the genetic level, crucial viral oncogenes participate in the disruption of cell signaling, leading to uncontrolled proliferation and inhibition of apoptosis. These viral proteins can modulate several cellular pathways, including the NF-κB and JAK/STAT pathways, which play essential roles in cell survival and inflammation. Epigenetic modifications further contribute to EBV- and KSHV-mediated cancerogenesis. Both EBV and KSHV manipulate host cell DNA methylation, histone modification, and chromatin remodeling, the interplay of which contribute to the elevation of oncogene expression and the silencing of the tumor suppressor genes. Immune factors also play a pivotal role in the development of cancer. The γ-herpesviruses have evolved intricate immune evasion strategies, including the manipulation of the major histocompatibility complex (MHC) and the release of cytokines, allowing infected cells to evade immune detection and destruction. In addition, a compromised immune system, such as in HIV/AIDS patients, significantly increases the risk of cancers associated with EBV and KSHV. This review aims to provide a comprehensive overview of the genetic, epigenetic, and immune mechanisms by which γ-herpesviruses drive cancerogenesis, highlighting key molecular pathways and potential therapeutic targets. Full article

Kaposi sarcoma-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV-8), is the primary etiologic cause of Kaposi sarcoma (KS) and KSHV Inflammatory Cytokine Syndrome (KICS). Patients with KICS demonstrate symptoms of systemic inflammation, high KSHV viral load, elevation of inflammatory markers, and increased mortality. Management requires rapid diagnosis, treatment of underlying HIV, direct treatment of KS, and addressing the hyperimmune response. While a case definition based on clinical presentation, imaging findings, laboratory values, KSHV viral load, and lymph-node biopsy has been proposed, some of the required investigations are frequently unavailable in resource-constrained settings. Due to these challenges, KICS likely remains underdiagnosed and undertreated in these settings. We report a case of a 19-year-old woman living with HIV, and intermittent adherence to her ART, who presented with hypotension and acute hypoxemic respiratory failure. She was found to have high KSHV and HIV viral loads, low CD4 count, anemia, thrombocytopenia, hypoalbuminemia, and elevated inflammatory markers. On bedside ultrasound, she was found to have bilateral pleural effusions, ascites, an enlarged spleen, and hyperechoic splenic lesions. The diagnosis of KICS was made based on this constellation of findings. Weighing the risk and benefits of steroid administration in KS patients, the patient was successfully treated by the continuation of ART and the initiation of paclitaxel chemotherapy and steroids. We propose an adapted case definition relevant to the resource-constrained context. Due to the dual burden of KSHV and HIV in sub-Saharan Africa, additional cases of KICS are likely, and this syndrome will contribute to the burden of early mortality in newly diagnosed HIV patients. Addressing the diagnostic and therapeutic challenges of KICS must be a part of the overall management of the HIV pandemic. Full article