Search Results (1,959)

Highly pathogenic avian influenza H5N1 virus (H5N1 HPAIV) has long circulated in wild waterfowl and poultry and continues to cross species barriers, posing sustained threats to livestock productivity and public health. The 2024 outbreak of H5N1 HPAIV in dairy cattle across multiple U.S. states represents the first recognized large-scale transmission event of this virus in ruminants, reshaping our understanding of its host range and transmission ecology. This review summarizes recent advances in the epidemiology, virological characteristics, transmission, pathogenesis, surveillance, and control of dairy cattle-associated H5N1. The initial multistate outbreak was dominated by clade 2.3.4.4b genotype B3.13, whereas subsequent independent introductions of genotype D1.1 demonstrated that repeated avian-to-cattle spillover also contributes to the evolving outbreak ecology. A defining feature is efficient replication in bovine mammary epithelial cells, resulting in high viral titers in milk, supporting milk-associated exposure and milking-related contamination as plausible components of transmission, although the relative contribution of different routes remains unresolved. Infected cattle typically show reduced feed intake, a marked decline in milk production, abnormal milk, and mild systemic signs, whereas severe respiratory disease and mortality are uncommon. Mutations such as PB2-M631L, PA-K497R, and changes in NP and NS1 may promote replication and immune evasion in bovine cells, while genotype-specific PB2 adaptations highlight the potential for further mammalian adaptation. Human infections reported to date have been predominantly mild and associated with occupational exposure, with no evidence of sustained human-to-human transmission. Experimental vaccine studies have begun to demonstrate immunogenicity in cattle, although protection against mammary infection, viral shedding, and transmission remains to be established. Future priorities include clarifying mammary tropism and transmission dynamics, while strengthening diagnostics, farm biosecurity, vaccination, evaluating cattle vaccination strategies, and integrated One Health surveillance. Full article

Chronic hepatitis C virus (HCV) infection is an established risk factor for B-cell lymphoproliferative disorders and represents a paradigmatic model of infection-driven lymphomagenesis. Although direct-acting antivirals have markedly reduced the burden of HCV-related disease, HCV-associated lymphomas continue to occur. Moreover, HCV screening remains incomplete in some geographical areas and healthcare settings, leaving a substantial proportion of infected individuals unaware of their status. This narrative review integrates current evidence on the mechanisms linking chronic HCV infection to mixed cryoglobulinemia and overt B-cell non-Hodgkin lymphoma. HCV lymphotropism and persistent antigenic stimulation could initially promote the selection and expansion of autoreactive B-cell clones, while mixed cryoglobulinemia represents the most informative pre-lymphomatous risk condition. Cytokine-mediated survival signals, particularly those involving B-cell activating factor, reinforce clonal persistence and cooperate with host genetic susceptibility, impaired apoptotic control, and activation-induced cytidine deaminase-mediated genomic instability. The progressive acquisition of somatic driver mutations, copy-number alterations, and epigenetic and transcriptomic changes may enable selected clones to escape functional anergy and become increasingly independent of the original viral stimulus that, in turn, represents an initial trigger of the lymphoproliferative process. Recurrent abnormalities converge on NF-κB, NOTCH, chromatin-regulatory, apoptotic, and cell-cycle pathways, although HCV-associated lymphomas remain molecularly heterogeneous. Emerging microRNA profiles further contribute to the molecular characterization of the transition from chronic infection and cryoglobulinemia to lymphoma. Despite the availability of highly effective antiviral therapies, HCV-associated lymphomagenesis remains clinically relevant and continues to provide an especially informative model for understanding how chronic viral infection can drive human cancer development. Full article

Background/Objectives: Adeno-associated virus (AAV) capsids undergo pH-dependent conformational gating at the 5-fold symmetry pore, but how these structural dynamics shape serotype-specific behavior and affinity-ligand recognition remains unclear, particularly for the clinically important serotypes AAV8 and AAV9. This study aimed to establish a pH-resolved structural framework linking 5-fold pore dynamics to peptide-ligand recognition and to translate this framework into sequence-based design principles for affinity capture of gene therapy vectors. Methods: AAV8 and AAV9 5-fold capsid assemblies were subjected to 500 ns molecular dynamics simulations under acidic (pH 5), neutral (pH 7), and basic (pH 9) conditions, with analysis of pore volume, inter-residue contact networks, electrostatic potential, and solvent-accessible surface area. In parallel, affinity chromatography using three mixed-mode peptide ligands (RVVAVYRI, TTFRAHHI, and TYHHHHII) was performed on clarified HEK293 lysates containing AAV8 or AAV9, with capsid yield, host-cell-protein clearance, and transduction activity assessed by ELISA, SEC-HPLC, and flow-cytometry-based transduction assays. Results: AAV8 displayed a heterogeneous, bimodal pore conformational landscape at pH 7, whereas AAV9 exhibited a discrete gate-like transition with maximal pore constriction at physiological pH; both serotypes showed pore-proximal contact remodeling with distinct network topologies. Experimentally, TYHHHHII achieved the highest selectivity for genome-containing capsids at pH 7, with transduction activity enrichment factors of 2.82 (AAV8) and 5.61 (AAV9), while TTFRAHHI provided the broadest operational pH range for bulk capsid recovery. Conclusions: These findings establish a structural framework linking pH-dependent pore dynamics to affinity ligand recognition and suggest practical sequence-design rules for ligand engineering: clustered histidines for neutral-pH selectivity, Arg-containing motifs for broad-pH robustness, and aromatic or hydrophobic residues for reinforcement of capsid binding. Full article

Banana bunchy top virus (BBTV) is a devastating pathogen threatening global banana production. The plant ubiquitin–proteasome system (UPS) governs immune signaling and is frequently subverted by invading viruses, yet the molecular mechanism through which BBTV interferes with host UPS remains unclear. Here, we show that BBTV nuclear shuttle protein (NSP) serves as the core viral effector to disrupt banana ubiquitination homeostasis. RT-qPCR time-series assays confirmed that BBTV infection dynamically remodels the transcription of eight phylogenetically divergent RING-type E3 ubiquitin ligases: four subfamily I E3-SIS3 paralogs and E3-HIP1 are significantly upregulated at 14 dpi and 21 dpi, while E3-BOI and E3-RHA1B are suppressed at 21 dpi. Transient expression screening of all six BBTV-encoded proteins verified that only NSP reproduces the UPS perturbation signature triggered by viral infection. Cross-species sequence alignment identified an evolutionarily conserved FNGSF motif within NSP orthologs of all Nanoviridae members. Alanine substitution mutagenesis (NSP^AAAAA) completely abolished NSP’s capacity to alter E3 ligase transcription. Western blot assays further validated that wild-type NSP induces massive accumulation of ubiquitinated host proteins, whereas the FNGSF-deficient mutant does not disrupt cellular ubiquitination. Phylogenetic analysis revealed that NSP-targeted E3 ligases share low overall sequence similarity but retain conserved catalytic RING domains, indicating that NSP exerts broad-spectrum regulatory effects on host UPS via the FNGSF motif. Collectively, this study reveals a novel pathogenic strategy whereby BBTV NSP recruits diverse host RING E3 ligases via its conserved FNGSF motif to dysregulate plant ubiquitination and elicit plant pathogenicity. Our findings provide two promising targets—the NSP FNGSF motif and defense-associated E3-SIS3 ligases—for developing antiviral agents and breeding BBTV-resistant banana germplasm. Full article

Background: Epstein–Barr virus (EBV) has long been linked to systemic lupus erythematosus (SLE), mainly through molecular mimicry, altered B-cell biology, defective antiviral immune surveillance and intermittent viral reactivation. However, the detection of EBV DNA in clinical samples does not necessarily indicate transcriptionally active infection or direct viral modulation of host pathways. Methods: Peripheral blood samples from 39 pediatric patients with SLE and 29 healthy controls were analyzed for host immune and apoptotic gene expression, including NFKB1, IL10, TLR3, BCL2, BAX and CASP3. EBV DNA was assessed in both patients and controls. In EBV DNA-positive SLE samples, the expression of EBV transcripts representative of latent, lytic and immunomodulatory programs, including LMP1, EBNA1, BZLF1, and viral IL-10, was also evaluated. Host gene expression was additionally compared between EBV DNA-positive and EBV DNA-negative patients with SLE. Results: EBV DNA was detected in 8 of 39 patients with SLE (20.5%) and in none of the 29 healthy controls (0%; Fisher’s exact test, p = 0.0171). None of the EBV DNA-positive samples showed detectable expression of LMP1, EBNA1, BZLF1 or viral IL-10. Compared with healthy controls, patients with SLE showed increased CASP3 expression that remained significant after FDR correction, whereas the reduction in IL10 expression was nominally significant only in the unadjusted analysis. NFKB1, TLR3, BCL2, and BAX did not differ significantly. In the exploratory comparison between EBV DNA-positive and EBV DNA-negative patients with SLE, no host gene remained significantly associated with EBV DNA status after false discovery rate correction. Conclusions: EBV DNA was detected more frequently in patients with SLE than in healthy controls, but this finding was not accompanied by detectable expression of the selected EBV transcripts under the analytical conditions used or by a consistent host transcriptional signature associated with EBV DNA positivity. These findings emphasize the importance of distinguishing EBV DNA detection from detectable viral transcript expression in SLE. Full article

Although tomato mosaic virus (ToMV) is an economically important tobamovirus, the physiological and molecular events occurring during the asymptomatic phase of infection remain poorly understood. In this study, we investigated the early responses of Nicotiana tabacum cv. Samsun to ToMV infection using an integrated physiological, biochemical, photosynthetic, and molecular approach. Viral accumulation was quantified via RT-PCR. Oxidative stress markers, antioxidant systems, photosynthetic performance, and gene expression were analyzed at 7 days post inoculation (DPI), before visible symptoms developed. Although infected plants remained symptomless, ToMV was detected in 80% of inoculated plants. Early infection induced oxidative stress, evidenced by increased malondialdehyde content, reduced free amino acid levels, and enhanced activities of superoxide dismutase and peroxidase. Total glutathione, phenolic compounds, and phenylpropanoids remained unchanged, whereas flavonoid content decreased significantly. ToMV infection also impaired the photosynthetic apparatus, resulting in reduced chlorophyll and carotenoid contents, decreased electron transport efficiency, and increased energy dissipation within photosystem II. Gene expression analysis revealed significant upregulation of defense- and stress-related genes (WRKY1, HSP70, GR, and DHAR), as well as chloroplast-associated genes (psaA and rbcL). Correlation analyses demonstrated coordinated relationships among viral accumulation, oxidative stress, antioxidant responses, and photosynthetic performance. These findings provide new insights into the asymptomatic phase of ToMV infection and identify potential early markers of host responses to viral infection. Full article

Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus’s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility. Full article

Ticks are prominent hosts for many viruses that are pathogenic to humans on almost every continent. Despite the documented historical association of ticks with viral disease in humans, clinical case reports are low, likely due to under-recognition of these pathogens. A key feature of understanding tick-borne virus transmission to humans lies in the natural invertebrate and vertebrate hosts supporting ecological maintenance. As humans are often infected as incidental hosts during the tick–virus life cycle, determining relevant ticks and mammals involved in maintenance can inform prevention strategies, surveillance priorities, and diagnostic assay development. This review aims to cover common trends in tick-borne virus ecology, including the wide breadth of implicated tick species, an unclear role for definitive vertebrate reservoirs, and the focal distributions of these viruses closely linked to these host ecological features. Here we also provide examples of prominent tick-borne viruses causing human disease between the Old (Africa, Asia, Europe) and New (Americas) Worlds, highlighting parallels in initial discoveries, vectors, and vertebrates including tick-borne encephalitis, Crimean–Congo hemorrhagic fever, severe fever with thrombocytopenia syndrome, Colorado Tick fever, and Powassan, Heartland, and Bourbon viruses. Full article

A secreted protein toxin encoded by a satellite dsRNA-enabled dissection of the genetic control of replication and expression of a single-segment dsRNA virus, the first Totivirus, L-A. Among the then-novel findings were i. “head-full replication”, ii. a supposedly forbidden “T = 2” capsid symmetry based on an asymmetric dimer, iii. a host N-acetyltransferase whose modification of the coat protein is necessary for packaging, iv. Kex1 and Kex2 pro-toxin peptidases leading to discovery of the pre-pro-insulin processing enzymes, and v. specific viral (+) strand sites/structures needed for RNA packaging and (-) strand synthesis. L-A viral (+) strands made in the particle are extruded to the cytoplasm. Those destined for translation are 5′ 7meGMP-capped by a coat protein activity that steals the cap from cellular mRNAs. (+) strands destined for encapsidation in new coats are not capped. Three host-encoded anti-viral systems were found, one based on blocking translation of the viral non-polyA mRNAs (Ski2,3,8 complex), another a 5′->3′ exoribonuclease specific for uncapped molecules (such as the viral (+) strands)(Ski1/Xrn1), and the third a mitochondrial nuclease released in cells undergoing meiosis/sporulation (Nuc1). All of these systems protect cells from virus-induced pathology and have clear animal homologs. The 3′ polyA of yeast mRNAs is dispensable for translation in ski2Δ slh1Δ cells, and such cells are healthy unless the L-A and M dsRNAs are present, suggesting that this polyA is primarily a device allowing cells to distinguish viral and cellular mRNAs. We suggest that the ribosome-associated Ski2,3,8 proteins block 60S subunit joining on polyA⁻ mRNAs. Recent evidence of roles for other cellular components controlling viral expression and replication suggests that yeast viruses will continue to be a fertile area for study of viral pathogenesis and host anti-viral systems. Full article

COVID-19 remains a relevant area of biomedical investigation because its pathogenesis involves complex virus–host interactions. This study aimed to explore, through purely in silico and hypothesis-generating insights, the predicted molecular associations between benzyl isothiocyanate (BITC) from Salvadora persica and COVID-19-associated host-response pathways. BITC-associated targets were collected from compound-target databases, while COVID-19-associated targets were obtained from disease-gene databases and transcriptomic datasets. Overlapping targets were analyzed using protein–protein interaction network construction, hub-gene prioritization, Gene Ontology and KEGG enrichment analyses, and molecular docking. A total of 271 unique BITC-associated targets and 1890 COVID-19-associated targets were identified, with 36 candidate targets overlapping. PPI analysis generated a connected network of 24 nodes and 39 edges. Hub-gene analysis prioritized ACE, JUN, MAOA, CDK1, MAOB, HCK, CCNA2, ACHE, GADD45A, and ADRA2A. Enrichment analysis indicated associations with inflammatory response, vascular regulation, calcium homeostasis, monoamine oxidase activity, NF-κB signaling, serotonergic synapse, and tryptophan metabolism. Validated active-site docking of six targets yielded comparative Vina scores ranging from −5.380 to −6.437 kcal/mol. These preliminary findings provide theoretical target–pathway associations supporting further investigation of BITC as a potential immunomodulatory candidate within COVID-19-related host-response pathways. Full article

Curcumin derivatives (curcuminoids) exhibit considerable antiparasitic and antiviral activities. In this study, EF24-like bis-2-fluorobenzylidene piperidone derivatives were synthesized and evaluated for antiprotozoal activity and inhibition of the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT)-associated RNase H (HIV-1 RNase H). A series of bis-arylidene piperidones and tetrahydro(thio)pyranones bearing halogen or nitro substituents were tested against Leishmania major (promastigotes and amastigotes) and Toxoplasma gondii. L. major promastigotes were the most sensitive parasitic model, with several compounds exhibiting low-nanomolar IC₅₀ values, while ortho- or para-halogenated analogues demonstrated submicromolar activity against T. gondii. Among them, 3,4-dichlorophenyl (HPip-DC) and 4-bromophenyl (HPip-4Br) derivatives showed potent activity against L. major and HIV-1 RNase H. The entropy-uncorrected MM-GBSA effective binding energy estimates were −33.41, −9.29, −8.37, and −4.27 kcal/mol for the predicted L. major squalene monooxygenase–HPip-DC, bovine cytochrome bc₁–DiFiD (2,4-difluorophenyl derivative), RNase H–HPip-4NO (4-nitrophenyl derivative), and RNase H–HPip-DC complexes, respectively. During 300 ns simulations, the ligands remained associated with their binding pockets. The Arg557 residue was crucial for HPip-4NO-mediated RNase H inhibition while the inhibitory activity of HPip-DC was much less dependent on this amino acid. These findings identify EF24-like curcuminoids with potent in vitro antiprotozoal activity and biochemical inhibition of HIV-1 RNase H. Antiviral activity was observed but confounded by host cell toxicity. Full article

Epstein–Barr virus (EBV) is causally associated with various malignancies and autoimmune diseases. It establishes a lifelong latent infection in host B-lymphocytes, and can strategically manipulate host cell metabolism and cell-to-cell communication via extracellular particles (EPs). While EBV-induced changes in fatty acid and mevalonate pathways are documented, the role of the sphingolipid network in this process remains poorly understood. In this study, we characterized both the EP and the cellular sphingolipid signatures of three EBV-infected (EBV+) lymphoblastoid cell lines compared to three EBV-negative (EBV−) counterparts. Lipidomic analysis revealed a profound metabolic redirection in EBV+ cells, characterized by reduced ceramide and sphingomyelin levels, and a significant upregulation of glycosphingolipids (GSLs), particularly hexosylceramide and globotrialosylceramide. Furthermore, EBV+ cells released larger, more heterogeneous EPs that are significantly enriched in GSLs and in the viral non-coding RNA EBER1. Our findings suggest that EBV-induced reshaping of sphingolipid metabolism correlates with altered physical properties of the secretome, potentially contributing to viral pathogenesis and microenvironmental manipulation. Full article

Hepatitis B virus (HBV) exploits host proteins to reshape cellular physiology and metabolism, thereby supporting its replication. Transgelin (TAGLN), an actin-binding protein highly expressed in HBV-associated hepatocellular carcinoma, has a poorly defined role in HBV infection. HBV infection upregulated TAGLN expression both in vitro and in vivo. Silencing TAGLN suppressed HBV replication, increased mitochondrial fission, and elevated intracellular ATP levels. Mitochondrial proteomic analysis identified optic atrophy 1 (OPA1), a mitochondrial dynamin protein, as differentially expressed, with higher levels in HBV-positive HepG2.2.15 cells than in parental HepG2 cells. TAGLN deficiency was associated with reduced OPA1 expression. Similarly, modulation of OPA1 expression was associated with corresponding changes in TAGLN levels and HBV replication. Collectively, these findings indicate an association between TAGLN and OPA1 in the context of HBV replication. However, the precise regulatory hierarchy and molecular basis of this association remain to be determined. Full article

The emergence of SARS-CoV-2 variants and antiviral resistance highlights the need for improved therapeutic strategies against COVID-19 and other coronavirus infections. By pairing direct-acting antivirals with repurposed host-modulating drugs, combination therapy approaches may enhance antiviral efficacy while mitigating inflammation. In this study, we evaluated the effects of combining Nirmatrelvir (a SARS-CoV-2 main protease inhibitor) with Ivermectin, Azithromycin or Doxycycline—using a murine hepatitis virus (MHV) infection model of RAW264.7 macrophages. Checkerboard assays demonstrated that the Nirmatrelvir–Ivermectin combination exhibited strongly synergistic antiviral activity. This combination achieved potent inhibition of live virus titer of at least 5 to 6 log₁₀ and reduction in viral RNA load of 3 log₁₀, at drug concentrations much lower than the respective monotherapies. The Nirmatrelvir–Ivermectin combination treatment affected the coronavirus replication cycle at the same time-point of 8 h as Nirmatrelvir monotherapy. Moreover, multiplex cytokine protein profiling revealed that Nirmatrelvir–Ivermectin markedly suppressed key pro-inflammatory cytokines and chemokines associated with the cytokine storm, including IL-6, TNF-α, IL-1β, and MCP-1. Conversely, the combinations of Nirmatrelvir with Azithromycin or Doxycycline exhibited only additive or mildly additive effects, with alterations in certain cytokine levels. These findings support the potential of Nirmatrelvir–Ivermectin as a promising novel combination therapy with both antiviral and anti-inflammatory benefits, warranting further in vivo validation and clinical investigation. Full article

Historically, mpox was thought to be a geographically constrained ‘disease of poverty,’ leading to decades of neglect by global health actors. Waning population immunity from the cessation of smallpox vaccination and prolonged scientific neglect created conditions that enabled the monkeypox virus (MPXV) to adapt cryptically. This ultimately contributed to the emergence of unprecedented global public health crises. This review aims to systematically trace the history, epidemiology, genomic evolution, and reservoir ecology of mpox in West Africa from 1970 to 2025. Following PRISMA guidelines, 110 articles met the inclusion criteria and were synthesized to map the virus’s trajectory. For nearly four decades, an “Era of Silence” (1970–2016) masked the silent enzootic circulation of MPXV within West African wildlife, primarily rodents and small mammals. This epidemiological quiescence ended with the 2017 re-emergence in Nigeria, which signaled a fundamental paradigm shift. The disease profile transitioned from sporadic, rural paediatric infections to sustained, urban and secondary transmission among young adult males. This shift was often associated with sexual networks, especially among men who have sex with men, and was characterized by novel clinical presentations, including genital and perianal lesions. Genomic analyses revealed that clade II diverged from clade I approximately 3500 years ago and is uniquely defined by the deletion of virulence factors, such as the complement-binding protein. Importantly, the clade IIb lineage, which triggered the 2022 global outbreak, exhibits accelerated microevolution consistent with APOBEC3-mediated hypermutation. This host-driven mutational signature provides genomic evidence supporting the hypothesis that clade IIb circulated cryptically within human-to-human transmission chains in West Africa as early as 2014. Ecologically, while no definitive reservoir has yet been identified, evidence suggests diverse rodents and an expanding host range. The transformation of mpox from a rare zoonosis to a global threat underscores the severe consequences of delayed intervention, demanding robust, integrated “One Health” surveillance. Full article