Search Results (519)

Epstein–Barr virus (EBV) is a key oncogenic pathogen implicated in the development of lymphomas, particularly among HIV-positive and immunocompromised individuals. While the association between EBV and lymphoma is well established, the mechanisms underlying progression from infection to malignancy—especially in the head and neck region—remain incompletely understood. This review offers a comprehensive analysis of the pathophysiological pathways by which EBV and HIV contribute to lymphomagenesis, with an emphasis on latency patterns, immune evasion, and epigenetic “hit and run” oncogenesis. Notably, it integrates novel findings on the diagnostic implications of EBV latency proteins, explores HIV-mediated B-cell dysregulation, and evaluates the emerging landscape of targeted therapies, including monoclonal antibodies and lytic cycle inducers. By focusing specifically on head and neck lymphomas, this review underscores a clinically underrepresented domain and offers insights that may guide future diagnostics, surveillance, and treatment strategies in vulnerable patient populations. This review also highlights the pressing need for improved animal models and continued research into EBV-specific therapeutic targets. Full article

Introduction: A 3D endothelial spheroid model expressing mosaic gain-of-function KRAS mutations was established to further understand the molecular changes associated with sporadic brain arteriovenous malformations (AVMs). Methods: Repellent 96-well U-bottom plates were seeded with human cerebral microvascular endothelial cells and resultant spheroids transduced with recombinant adeno-associated virus expressing KRAS^G12V. Spheroids were monitored using live-cell imaging for extended culture periods. Results: In the early growth period, KRAS^G12V expression increased spheroid growth rates and enhanced spheroid sprouting on gel matrices consistent with known AVM characteristics. With extended culture, novel endothelial characteristics were observed. KRAS^G12V-expressing spheroids displayed dynamic blebbing associated with the formation of rounded, hypertrophic cells disposed to engage in spheroid escape. These cells displayed reduced cell–cell adherence with rapid plasma membrane blebbing characteristic of amoeboid-like migration and mesenchymal-to-amoeboid transition. Spheroid growth and blebbing were reversed with MEK and mTOR inhibitors; Rho/ROCK inhibition specifically targeted the blebbing phenotype. Conclusions: Endothelial spheroids expressing KRAS^G12V exhibit characteristic features associated with abnormal vessel development in brain AVMs as well as novel phenotypes not previously observed in 2D monolayers. The ability to extend culture periods in this simple 3D model may allow further phenotypic exploration of important AVM driver mutations. Full article

Bovine leukemia virus (BLV) is a retrovirus infecting several bovid species, notably Bos taurus, where it fulfills Koch’s postulates for pathogenicity. The virus primarily targets B-lymphocytes, establishing lifelong infections that remain mostly asymptomatic but can progress to lymphocytosis or lymphoma. Transmission occurs through live infected cells via blood, milk, or transplacental routes. Despite a robust antiviral immunity, BLV replicates by producing virions (i.e., the infectious cycle) or inducing mitosis of infected cells (i.e., clonal expansion). The immune system effectively controls the infectious cycle but fails to impede clonal expansion, leading to chronic immune activation and immunosuppression. BLV modifies the transcriptome of the host cell by expressing oncogenic factors (Tax), viral microRNAs and antisense RNAs. Leukemogenesis arises from cumulative alterations of the virus (e.g., 5′-end deletions of the integrated provirus and histone modifications of the LTR promoter) and the host cell (e.g., genomic mutations and favorable chromatin integration). This model underscores a unique persistence strategy, linking chronic infection, immune evasion, and slow multistep oncogenesis in the bovine host. Full article

Background: Climate change, urbanization, and global mobility increase the risk of emerging infectious diseases with pandemic potential. There is a need for rapid methods that can assess their long-term effects on human health. In silico approaches are particularly suited to study processes that may manifest years later, under the assumption that perturbed biomolecular interactions underlie these outcomes. Here we focus on viral oncogenicity—the ability of viruses to increase cancer risk—which accounts for about 15% of global cancer cases. Methods: We characterize viruses through multilayer representations of protein–protein interaction (PPI) networks reconstructed from the human interactome. Statistical analyses of topological features, combined with interpretable machine learning models, are used to distinguish oncogenic from non-oncogenic viruses and to identify proteins with potential central role in these processes. Results: Our analysis reveals clear statistical differences between the network properties of oncogenic and non-oncogenic viruses. Furthermore, the machine learning approach enables classification of virus–host interaction networks and identification of relevant subsets of proteins associated with oncogenesis. Functional enrichment analysis highlights mechanisms related to viral oncogenicity, including chromatin structure and other processes linked to cancer development. Conclusions: This framework enables virus classification and highlights mechanisms underlying viral oncogenicity, providing a foundation for investigating long-term health effects of emerging pathogens. Full article

Nucleic acid-based gene interfering and editing molecules, such as antisense oligonucleotides, ribozymes, small interfering RNAs (siRNAs), and CRISPR-Cas9-associated guide RNAs, are promising gene-targeting agents for therapeutic applications. Cancer’s heterogeneous and diverse nature demands gene-silencing technologies that are both specific and adaptable. RNase P ribozymes, called M1GS RNAs, are engineered constructs that link the catalytic M1 RNA from bacterial RNase P to a programmable guide sequence. This guide sequence directs the M1GS ribozyme to base-pair with a target RNA, inducing it to fold into a structure resembling pre-tRNA. Catalytic activity can be enhanced through in vitro selection strategies. In this review, we will discuss the application of M1GS ribozymes in targeting cancer-associated RNAs, focusing on the BCR-ABL transcript in leukemia, the internal ribosome entry site (IRES) of hepatitis C virus (HCV), and the replication and transcription activator (RTA) of Kaposi’s sarcoma-associated herpesvirus (KSHV). Together, these examples highlight the versatility of M1GS ribozymes across both viral and cellular oncogenic targets, underscoring their potential as a flexible synthetic biology platform for cancer therapy. Full article

Chronic hepatitis C virus (HCV) infection remains a major global health burden, responsible for substantial morbidity and mortality despite the advent of curative antiviral therapy. HCV induces hepatic injury and carcinogenesis through direct viral effects, persistent inflammation, oxidative stress, and metabolic disturbance. The introduction of direct-acting antivirals (DAAs) has revolutionized therapy, achieving sustained virologic response rates exceeding 95% and transforming HCV from a chronic, progressive disease into a curable infection. Nevertheless, viral eradication does not fully normalize hepatic or systemic risk. Patients with advanced fibrosis or cirrhosis continue to face an elevated incidence of hepatocellular carcinoma (HCC) and other complications, reinforcing the need for long-term monitoring. This review summarizes current knowledge of the molecular mechanisms underlying HCV-mediated carcinogenesis, the partial restoration of hepatic homeostasis following DAA-induced cure, and the clinical implications for surveillance and management in the post-HCV era. By integrating insights from molecular virology, immunopathogenesis, and clinical hepatology, the review highlights how persistent epigenetic and inflammatory footprints may sustain oncogenic potential even after viral clearance. A comprehensive understanding of these processes is essential for optimizing HCC prevention strategies, guiding surveillance policies, and advancing future therapeutic innovations aimed at complete hepatic recovery. Full article

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies. Full article

Nasopharyngeal carcinoma (NPC) is a head and neck malignancy strongly associated with Epstein–Barr virus (EBV) infection and characterized by high radiosensitivity but frequent therapy resistance. Despite advances in radiotherapy, chemotherapy, and immunotherapy, relapse and metastasis remain major challenges, underscoring the need for novel therapeutic approaches. This review aims to provide an integrated overview of the molecular mechanisms governing ferroptosis in NPC and to clarify how these pathways contribute to therapy resistance while revealing potential therapeutic vulnerabilities. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising target in NPC. Core regulators include the system xCT–GSH–GPX4 antioxidant axis, iron metabolism, and lipid remodeling enzymes such as ACSL4, with epigenetic modifiers (METTL3, IGF2BP2, HOXA9) and EBV-driven signaling further shaping ferroptosis responses. EBV-driven oncogenic programs substantially reshape ferroptosis sensitivity in NPC by activating the Nrf2/Keap1 antioxidant axis, stabilizing SLC7A11 and GPX4, and modulating iron and redox metabolism. These viral mechanisms suppress ferroptotic stress and contribute to both radioresistance and chemoresistance. Suppression of ferroptosis underlies both radioresistance and chemoresistance, whereas restoration of ferroptosis re-sensitizes tumors to treatment. Natural compounds including solasodine, berberine, cucurbitacin B, and celastrol-curcumin combinations, as well as pharmacologic modulators such as HO-1 inhibitors and GPX4 antagonists, have shown ferroptosis-inducing effects in preclinical models, although their translational potential remains to be clarified. Nanotechnology-based platforms (e.g., Bi₂Se₃ nanosheet hydrogels) further enhance efficacy and reduce toxicity by enabling controlled drug delivery. Biomarker discovery, encompassing ferroptosis-related gene signatures, epigenetic regulators, immune infiltration patterns, EBV DNA load, and on-treatment redox metabolites, provides a foundation for patient stratification. Integration of ferroptosis modulation with radiotherapy, chemotherapy, and immunotherapy represents a compelling strategy to overcome therapy resistance. In synthesizing these findings, this review highlights both the mechanistic basis and the translational promise of ferroptosis modulation as a strategy to overcome treatment resistance in NPC. Future directions include biomarker validation, optimization of drug delivery, early-phase clinical trial development, and multidisciplinary collaboration to balance ferroptosis induction in tumors while protecting normal tissues. Collectively, ferroptosis is emerging as both a vulnerability and a therapeutic opportunity for improving outcomes in NPC. Full article

High-risk human papillomavirus (HR-HPV) types exhibit an uneven global distribution, with types 35, 51, 56, and 59 being more prevalent in Africa yet not covered by current L1-based vaccines. The genetic diversity of HR-HPV oncoproteins in Africa remains poorly characterized, despite their potential as alternative vaccine targets. This study investigates the genetic diversity of HR-HPV types 16, 18, 35, 51, 56, and 59 to inform vaccine development. We analyzed 14,332 sequences from the NCBI Virus database and 222 HPV reference sequences from the Papillomavirus Episteme (PaVE) database using phylogenetic analysis and variant identification. HPV16 and HPV35 exhibited close evolutionary relatedness, which may indicate shared traits relevant to vaccine design, although functional implications remain to be experimentally validated. A key finding of the study was the discovery of novel non-synonymous mutations, including E148K in HPV35 E6, S63C in HPV16 E7 and S495F in HPV18 L1, as well as known oncogenic variants such as L83V (E6) and N29S (E7) in HPV16. These findings highlight significant intra- and inter-type diversity among African HR-HPVs. This study provides new insights into the genetic diversity and evolutionary relationships of underrepresented HR-HPV types. The findings underscore the need for continued genomic surveillance and support efforts to develop region-specific vaccines that include HPV35, 51, 56, and 59 to address gaps in current vaccine coverage and help reduce the burden of HPV-related cancers in Africa. Full article

Oncogenic viruses are well-established contributors to cancer development in both humans and animals. While many animal oncogenic viruses exhibit strong host specificity, concerns remain about their potential to cross species barriers and impact human health. This article examines the classification and molecular mechanisms of oncogenic viruses, including retroviruses, papillomaviruses, herpesviruses, and hepadnaviruses, in animals. It explores historical cases of cross-species transmission, such as the contamination of early polio vaccines with simian virus 40 (SV40), which resulted from the use of rhesus monkey kidney cells and insufficient screening for latent simian viruses, and the hypothesised association between bovine leukaemia virus (BLV) and human breast cancer. To provide a broader comparative perspective, the discussion also includes examples of viruses with a lower economic impact, illustrating that zoonotic and oncogenic potential is not limited to commercially significant species. Biological barriers—including receptor specificity and immune defences—generally limit transmission; however, frequent human–animal interactions, consumption of contaminated food, and viral mutations may increase zoonotic risk. Advances in molecular diagnostics, such as polymerase chain reaction (PCR), next-generation sequencing (NGS), and serological testing, play a critical role in identifying emerging threats. Prevention strategies, including veterinary vaccination programs, biosafety protocols, and the One Health approach integrating human and veterinary medicine, are essential for mitigating risks. While current evidence indicates that oncogenic animal viruses do not significantly contribute to human cancers, ongoing surveillance and research remain crucial to detect emerging threats. Understanding viral oncogenesis in animals continues to provide valuable insights into cancer prevention and therapy in humans. Full article

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). The trans-activator protein Tax of HTLV-1 is thought to play a crucial role in the early-stage transformation of the virus-infected cells. Tax is a multi-functional protein and modulates cellular signaling pathways that promote proliferation and survival of HTLV-1-infected cells, primarily through the trans-activation of cellular target genes. Tax interacts with a variety of host cell factors including signal transducers and transcription factors, leading to the activation of transcription factors such as CREB, NF-κB, and SRF and activates both its own promoter and those of a variety of host cellular genes. Tax activates its own promoter mainly through CREB and host cellular genes through NF-κB, SRF, and CREB. Accumulating evidence indicates that the Tax-mediated trans-activation of target genes through NF-κB plays an essential role in the transformation of HTLV-1 infected cells. However, the repertoire of Tax target genes, especially those crucial for leukemogenesis, are not known in detail. In this review, we summarize transcriptional activation mechanisms and target genes of Tax, especially focusing on transformation, to facilitate understanding of the underlying mechanisms of leukemogenesis induced by HTLV-1 infection. Full article

Human papillomavirus (HPV) infection is a primary driver of cervical cancer. Integration of HPV into the human genome causes persistent expression of viral oncogenes E6 and E7, which promote carcinogenesis and disrupt host genomic function. However, the impact of integration on host gene expression remains incompletely understood. We used multimodal RNA sequencing, combining total RNA-seq and Cap Analysis of Gene Expression (CAGE), to clarify virus–host interactions after HPV integration. HPV-derived transcripts were detected in 17 of 20 clinical samples. In most specimens, transcriptional start sites (TSSs) showed predominant early promoter usage, and transcript patterns differed with detectable E4 RNA region. Notably, the high RNA expressions of E4 region and viral-human chimeric RNAs were mutually exclusive. Chimeric RNAs were identified in 13 of 17 samples, revealing 16 viral integration sites (ISs). CAGE data revealed two patterns of TSS upregulation centered on the ISs: a two-sided pattern (43.8%) and a one-sided pattern (31.3%). Total RNA-seq showed upregulation of 12 putative cancer-related genes near ISs, including MAGI1-AS1, HAS3, CASC8, BIRC2, and MMP12. These findings indicate that HPV integration drives transcriptional activation near ISs, enhancing expression of adjacent oncogenes. Our study deepens understanding of HPV-induced carcinogenesis and informs precision medicine strategies for cervical cancer. Full article

Bovine leukemia virus (BLV), an oncogenic retrovirus of the genus Deltaretrovirus, causes enzootic bovine leukosis (EBL), the most prevalent neoplastic disease in cattle and a major source of economic loss. While BLV prevalence has been studied in commercial breeds, data on native Latin American cattle remain limited. This study assessed BLV infection and proviral load in 244 animals from six native breeds: Argentine Creole (CrAr), Patagonian Argentine Creole (CrArPat), Pampa Chaqueño Creole (CrPaCh), Bolivian Creole from Cochabamba (CrCoch), Saavedreño Creole (CrSaa), and Siboney (Sib), sampled across Argentina, Bolivia, Paraguay, and Cuba. BLV-CoCoMo-qPCR-2 assay detected BLV provirus in 76 animals (31.1%), with a mean load of 9923 copies per 10⁵ cells (range: 1–79,740). Infection rates varied significantly by breed (9.8% in CrAr to 83.8% in CrPaCh) and country (15.6% in Argentina to 83.8% in Paraguay) (p = 9.999 × 10⁻⁵). Among positives, 57.9% exhibited low proviral load (≤1000 copies), and 13.2% showed moderate levels (1001–9999), suggesting potential resistance to EBL progression. This is the first comprehensive report of BLV proviral load in Creole cattle across Latin America, offering novel epidemiological insights and highlighting the importance of native breeds in BLV surveillance. Full article

Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year. HTLV-1 also causes inflammatory disorders, including HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. The estimated lifetime risks of ATLL and HAM/TSP in HTLV-1 carriers are 3–5% and 0.25–1.8%, respectively. Although there is uncertainty about other health effects of HTLV-1, a recent meta-analysis showed an association between HTLV-1 and cardiovascular, cerebrovascular, and metabolic diseases and a 57% increased risk of early mortality in HTLV-1 carriers, independent of ATLL or HAM/TSP. Furthermore, emerging studies in endemic areas show that outcomes for common cancers, such as cervical cancer and lymphoma (non-ATLL), are inferior in HTLV-1 carriers compared to publicly reported data. Thus, the impact of HTLV-1 may be greater and more diverse than currently understood. This review provides an outline of the prevalence and impact of HTLV-1 and associated disorders in the US, focused on—but not limited to—ATLL, with an emphasis on the social determinants of health that can affect the success of screening and prevention strategies. We also discuss the mechanisms by which HTLV-1 drives the pathogenesis of ATLL and potential strategies for early diagnosis and intervention. Finally, we conclude by suggesting approaches to designing and implementing community-informed research initiatives in HTLV-1 and ATLL. Full article

Organ transplantation significantly enhances the survival and quality of life for recipients. However, multiple dependent and independent variables can adversely affect life expectancy after transplantation. Cancer is one of the most common causes of morbidity and mortality for long-term organ transplant recipients. The incidence of cancer in transplanted tissues can be twice as high in approximately 32 distinct cancer types. Oncogenic viruses present in graft tissues may contribute to the etiology of various cancers in transplant recipients. Such oncogenic viruses include hepatitis viruses, papillomaviruses, Epstein–Barr virus, Kaposi’s sarcoma, Merkel cell virus, JC virus, BK virus, and human T-lymphotropic virus type 1, all of which have been associated with various malignancies in these patients. To mitigate this risk, a comprehensive viral screening protocol should be integrated into the transplantation process. Depending on the type of graft, diagnostic methods, control strategies, and post-transplantation care may vary considerably. To efficiently implement any strategy to inhibit viral oncogenicity, a comprehensive understanding of viral–host interactions involving oncogenic viruses within graft tissue is essential. The current view of tumor biology is that changes in the tumor microenvironment and immune signaling influence evolutionary selection pressures. Such interactions ultimately promote conditions that favor uncontrolled host–cell proliferation and malignant transformation. This review examines these viral–host interactions and their role in cancer development among transplant recipients. Full article