Search Results (340)

Autophagy is a conserved cellular degradation pathway that plays important roles in insect–virus interactions. In the MED cryptic species of Bemisia tabaci, cotton leaf curl Multan virus (CLCuMuV) can persist upon acquisition, yet this vector fails to transmit the virus. However, whether autophagy contributes to this antiviral response in MED whiteflies remains unknown. In this study, we show that CLCuMuV acquisition activates autophagy in MED whiteflies, as evidenced by increased LC3-I to LC3-II conversion, enhanced LC3-positive puncta formation in the gut, and dynamic transcriptional regulation of multiple autophagy-related genes. Functional investigations using RNAi-mediated silencing of Atg3 and Atg9, two essential autophagy genes, revealed that their knockdown elevated viral DNA accumulation by 1.4-fold at 48 h post-acquisition. Consistently, pharmacological blockade of autophagic flux with bafilomycin A1 led to a 1.0-, 2.2-, and 1.0-fold increase in viral loads across 24, 48, and 72 h post-acquisition, respectively, whereas treatment with rapamycin, an autophagy inducer, decreased viral DNA accumulation by 46.4% and 33.3% relative to control levels at 24 and 48 h post-acquisition, respectively. Together, these loss- and gain-of-function experiments demonstrate that autophagy functions as a host restriction mechanism that limits CLCuMuV persistence in MED whiteflies, providing molecular insights into the immune competence of this non-vector species. Full article

Infectious bovine rhinotracheitis virus (IBRV) causes highly contagious bovine respiratory disease and threatens the global cattle industry. Ferroptosis, an iron-dependent regulated cell death, is involved in multiple viral infections, but its role and mechanism in IBRV infection remain unclear. This study investigated IBRV-induced ferroptosis and the NFKB1-SLC39A8 axis in MDBK cells and examined the effect of ferroptosis on IBRV replication. Ferroptotic phenotypes and molecules were detected by biochemical assays, qPCR, Western blotting and TEM. Gain- and loss-of-function assays were performed to modulate gene expression, and their transcriptional relationship was verified by dual-luciferase assay. IBRV induced typical ferroptosis in MDBK cells, including Fe²⁺ overload, excessive ROS and MDA accumulation, GSH depletion and mitochondrial damage. Ferrostatin-1 reversed these changes and reduced viral titers, suggesting that ferroptosis contributes to IBRV replication. SLC39A8 overexpression aggravated ferroptosis, whereas its knockdown suppressed it. Mechanistically, our data support that NFKB1 positively regulates SLC39A8 transcription, and NFKB1 silencing inhibited IBRV-induced ferroptosis. In conclusion, this in vitro study shows that IBRV induces ferroptosis in MDBK cells via the NFKB1-SLC39A8 axis, and ferroptosis may contribute to viral replication. These findings provide insights into IBRV–host cellular interaction and identify potential candidate molecular targets for future antiviral research. Full article

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and play a fundamental role in host response to viral infections. SARS-CoV-2 has been shown to dysregulate host miRNA expression, potentially as a mechanism to modulate cellular pathways for its own replication or to evade immune responses. However, evidence from the literature related to the specific miRNA landscape in SARS-CoV-2 infection is conflicting and unclear. We employed an integrative multi-model approach using human nasal lung epithelial cell lines and pulmonary organoids to map miRNA expression dynamics after SARS-CoV-2 infection. Data obtained from the CALU-3 miRNAome were successively validated in other two cellular models (hAEC and hLORG), and from this comparative analysis, two miRNAs, miR-141-3p and miR-33a-5p, were found to be significantly dysregulated. These miRNAs are involved in critical pathways, including cytokine-mediated signalling, apoptotic processes and epithelial cell junction integrity. High-throughput miRNA profiling was followed by functional enrichment analysis of their predicted targets to delineate affected biological pathways. By highlighting candidate miRNAs and regulatory pathways that may contribute to disease pathogenesis, we identified robust, infection-associated hallmarks across cell models, establishing a foundation for future therapeutic strategies for COVID-19 based on the development of miRNA-guided approaches. Full article

Influenza A virus (IAV) remains a major threat to global public health because of its capacity for antigenic drift, reassortment, zoonotic transmission, and pandemic emergence. Viral transcription and genome replication are carried out by the influenza virus RNA-dependent RNA polymerase (FluPol), a heterotrimeric complex composed of polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA), which functions together with nucleoprotein (NP) within viral ribonucleoprotein complexes (vRNPs). FluPol activity is regulated not only by viral determinants and host cofactors but also by diverse post-translational modifications. Among these, ubiquitination has emerged as a particularly versatile regulatory mechanism because it can control protein stability, polymerase assembly, subunit interactions, conformational dynamics, NP–RNA interactions, and innate immune signaling. Depending on the modified substrate, ubiquitin linkage type, acceptor residue, and responsible E3 ligase or deubiquitinase, ubiquitination may either restrict IAV replication or be exploited by the virus to enhance polymerase function and vRNP activity. This review summarizes recent advances in ubiquitination-mediated regulation of FluPol and NP, focusing on the responsible E3 ubiquitin ligases, deubiquitinases, ubiquitination sites, ubiquitin-chain types, and host restriction mechanisms. We further discuss the crosstalk between ubiquitination and other post-translational modifications, highlight unresolved mechanistic questions, and evaluate the therapeutic potential and challenges of targeting ubiquitin-dependent pathways for antiviral intervention. Collectively, this review provides a conceptual framework for understanding how ubiquitination shapes IAV replication and identifies E3 ligases and DUBs as potential targets for host-directed antiviral strategies. Full article

The innate immune system provides the first line of defense against invading pathogens and relies on tightly regulated mechanisms to initiate and resolve inflammatory responses. In addition to transcriptional control, post-transcriptional regulation of messenger RNA (mRNA) plays a critical role in determining the magnitude and duration of immune responses. Among those key regulators, the ZFP36 family of CCCH-type zinc-finger RNA-binding proteins, including ZFP36, ZFP36L1, and ZFP36L2, plays a central role in controlling the stability and translation of inflammatory, immune-related, and viral RNAs. This review focuses on the ZFP36 family of RNA-binding proteins and highlights their emerging roles in inflammation, immune cell development and differentiation, and antiviral immunity, with a particular focus on ZFP36L1 and ZFP36L2. Recent evidence has identified ZFP36L1 as a broad-spectrum antiviral factor that restricts multiple RNA viruses through distinct molecular mechanisms. A detailed understanding of the molecular mechanisms underlying ZFP36L1- and ZFP36L2-mediated antiviral activity and immune regulation will facilitate rational development of host-directed antiviral therapeutics and their strategic integration with vaccination strategies to limit viral replication, shedding, and transmission, thereby improving the control of emerging and re-emerging viral diseases. Full article

Hepatitis B virus (HBV) infection remains a major global health burden, with chronic infection leading to severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). HBV-encoded X protein (HBx) plays a critical role in viral replication and pathogenesis by modulating host cellular processes, including autophagy and lysosomal function. However, the molecular mechanisms by which HBx disrupts lysosomal biogenesis and autophagic degradation remain elusive. In this study, we show that HBx downregulates the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, which leading to impaired lysosomal acidification and autophagosome–lysosome fusion. Mechanistically, HBx-mediated TFEB downregulation involves the CUL4A (Cullin 4A)/CUL4B (Cullin 4B)-DDB1 (DNA damage-binding protein 1) E3 ubiquitin ligase complex and is dependent on the DDB1-interacting motif in HBx. HBx mutants defective in DDB1 binding (HBx^R96E and HBx^ΔDBD) fail to downregulate TFEB or impair lysosomal function. Collectively, our findings identify a pathway by which HBx disrupts lysosomal function via CUL4A/CUL4B–DDB1-dependent TFEB downregulation, providing insights into HBV-associated liver pathogenesis and highlighting potential targets for therapeutic intervention. Full article

Infectious laryngotracheitis virus (ILTV), formally known as Gallid alphaherpesvirus 1, represents a prominent alphaherpesvirus that poses a significant threat to the global poultry industry. Current routine vaccination strategies fail to eliminate latent infection. Host–pathogen interaction networks have become a key focus in antiviral research. Our previous study demonstrated that activation of the MEK/ERK signaling pathway upon ILTV infection restricts host cellular metabolic activity to mount protective host antiviral responses, yet the underlying molecular mechanism remains unclear. The present work systematically dissects the contribution of MEK/ERK signaling to intrinsic host defense against ILTV. The results show that ILTV infection activates the MEK/ERK pathway, which in turn promotes the expression, activation, and nuclear translocation of the transcription factor Fos. As a core transcriptional regulator, Fos represses host metabolic gene expression, thereby restricting viral replication and proliferation. Integrated multi-omics analyses further demonstrate that the MEK/ERK-Fos-metabolic regulatory axis operates uniformly during infection with avian, human, and porcine alphaherpesviruses, suggesting a broadly conserved host antiviral mechanism. This consistent cross species signaling pattern points toward an evolutionarily conserved host antiviral strategy and provides potential molecular targets for the development of broad-spectrum antiviral strategies against alphaherpesviruses. Full article

Chronic hepatitis B virus (HBV) infection remains one of the main causes of hepatocellular carcinoma (HCC), even though vaccination and long-term viral suppression have reduced new infections and circulating viral replication. This residual cancer risk suggests that serum HBV DNA alone does not capture the full biology of HBV-related carcinogenesis. Hepatitis B virus X protein (HBx) is a relevant entry point because it maintains the transcriptional competence of covalently closed circular DNA (cccDNA), engages host chromatin regulators, and may persist in tumors as cccDNA-derived, integration-derived, full-length, truncated, or fusion forms. This review focuses on a specific question: does the available literature support HBx-associated reactivation of the IGF2 locus in chronic HBV infection and HBV-related hepatocarcinogenesis, and, if so, at which regulatory layer is the claim defensible? The most direct evidence remains promoter-proximal. Classic mechanistic work shows acute HBx-dependent activation of IGF2 promoter P4 through Sp1- and PKC/ERK-dependent signaling. Human tissue and cell-based studies also support a broader fetal-promoter compartment, including P3/P4 transcript enrichment, local promoter hypomethylation, MBD2-HBx-CBP/p300 recruitment, and increased histone H3/H4 acetylation. These observations do not, however, establish HBV exclusivity, uniform loss of imprinting, or direct HBx-mediated rewiring of the human IGF2/H19 topological domain. Recent integration-aware and long-read studies further argue against treating tumor-stage HBx as a single biological variable. In the present evidence framework, HBx-associated IGF2 locus reactivation is therefore more appropriately viewed as a stage-aware, promoter-resolved, biomarker-oriented hypothesis than as a universal mechanism or a treatment algorithm for HBV-related HCC. Full article

Oncogenic viruses are responsible for between 12% and 20% of human cancers worldwide. They trigger tumorigenesis by integrating into host-cell genomes, altering cell cycle pathways, and evading immune detection. Oncoviral cancers exhibit low rates of mutation, implicating alternative splicing as an underappreciated alternative mechanism for oncogene and oncogenic pathway activation in oncoviral pathogenesis and progression. In order to create alternatively spliced viral proteins for replication and viral genome maintenance, oncoviruses take advantage of host-cell splicing machinery. Some of these proteins inhibit major host-cell tumor suppressors to promote the proliferation of DNA-damaged host-cells in order to facilitate persistent infection, whilst others interact with and de-regulate the expression and activity of host-cell splicing factors to alter host transcript splice site selection. The latter reprograms host-cell transcriptomes to express aberrant, sometimes oncogenic protein isoforms, which interact with oncoviral proteins to promote host-cell transformation and subsequent tumor progression to metastatic disease. In this article, we review oncovirus-induced alternative splicing as a fundamental, underappreciated, oncogenic and tumor-promoting mechanism. We present detailed descriptions of individual human oncoviruses. We compare how these oncoviruses hijack host-cell splicing mechanisms, how specific aberrant alternatively spliced host-cell protein isoforms, induced by oncoviruses, influence tumor pathogenesis and progression, organized with respect to the hallmarks of cancer, and provide a section on therapeutic perspectives. This approach not only crystallizes the complexity of how oncovirus-induced host-cell alternative splicing can influence cancer pathogenesis and progression but also reveals novel potential therapeutic opportunities. Full article

Background/Objectives: As important post-transcriptional and epigenetic regulators of gene expression, miRNAs play a pivotal role in modulating host–virus interactions. While prior reviews have addressed either direct miRNA–HIV genome interactions or miRNA-mediated immune modulation in isolation, the integrated dual functionality of these molecules has not been systematically characterized. This review aimed to comprehensively explore how miRNAs that target the HIV-1 genome simultaneously modulate key innate and adaptive host immune signaling pathways. The conceptual novelty of this study is determined not by the identification of previously unknown miRNA-target gene pairs, but by the systemic integration of two regulatory levels (direct inhibition of the viral genome and modulation of the host cell immune signaling pathways) within a unified analytical framework. Such an integrated approach reveals a proviral regulatory network that remains non-obvious when each of these levels is examined separately. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar (all years through 2025). In Stage 1, publications reporting experimentally confirmed interactions between host miRNAs and the HIV-1 genome were identified, yielding a curated set of 15 miRNAs. In Stage 2, target genes for each miRNA were retrieved from miRTarBase, TarBase (experimentally validated) and TargetScan 8.0 (in silico predicted). In Stage 3, target genes were manually mapped to key immune signaling pathways (TLR, NF-κB, JAK-STAT). In Stage 4, targeted literature searches were performed for each miRNA–target gene pair to identify direct experimental evidence of interaction. All stages were performed by two independent researchers, with discrepancies resolved by a third. Results: Fifteen host miRNAs with experimentally confirmed binding to the HIV-1 genome were identified, targeting viral genes including nef, pol, vpr, gag, env, vif, and the 3′-UTR. Thirteen of these miRNAs were found to regulate components of major immune pathways. miR-92a-3p, miR-29a/b-3p, miR-150-5p, and miR-125b-5p emerged as the most pleiotropic regulators, simultaneously suppressing TLR signaling (TLR3, TLR7, TLR8, MyD88, TRAF3/6, IRAK1/4), NF-κB components (REL, RELA, NFKB1), JAK-STAT effectors (STAT1–3, STAT5A/B, JAK2), and negative regulators of cytokine signaling (SOCS and PIAS family proteins). miR-133b and miR-196b-5p were found to selectively regulate SOCS/PIAS proteins without involvement in other analyzed pathways, suggesting potential for selective therapeutic targeting. Conclusions: The analyzed miRNAs exhibit functional dualism, acting as direct post-transcriptional suppressors of the HIV-1 genome while simultaneously functioning as epigenetic modulators of host immune signaling. These two modes of action are not independent but together form a conceptual framework of a self-reinforcing proviral regulatory network that, based on the synthesis of published evidence, is proposed to promote viral latency and immune evasion. The identified miRNAs represent promising, albeit complex, targets for novel therapeutic strategies aimed at eliminating latent HIV reservoirs. Full article

Human papillomaviruses (HPVs) comprise more than 200 types associated with diverse clinical outcomes, ranging from benign lesions caused by low-risk types to cancers driven by high-risk types. These differences are partly driven by variation in the Long Control Region (LCR), a non-coding element that regulates viral gene expression through interactions with viral and host transcription factors (TFs). Although individual TF binding sites have been mapped in a few well-studied HPV types, the broader regulatory differences between high-risk and low-risk HPVs remain poorly defined. Here, we systematically analyzed LCR sequences from 207 HPV types using TF motif scanning and identified 104 TFs with significantly different binding site densities between risk groups. Integration with TCGA transcriptomics data showed that 50 of 69 TF enriched in high-risk types are expressed in HPV-positive head and neck tumors (HNSC) and 53 in HPV-positive cervical tumors (CESC). Analysis of published ChIP-seq datasets further confirmed LCR occupancy for seven of these TFs in HPV18-positive cells. In addition, conservation analysis across clinical isolates of HPV-16 and HPV-18 identified highly conserved TF binding sites overlapping multiple high-risk-enriched TF motifs, suggesting functional constraint on key regulatory elements. Together, these findings reveal distinct TF binding landscapes associated with HPV risk groups and identify candidate host regulators that may contribute to differences in viral transcriptional programs and oncogenic potential across HPV types. Full article

Persistence of human papillomavirus (HPV) infection leading to cervical carcinogenesis can be attributed to the action of high-risk HPVs, but there are still some unclear factors involved in the mechanisms of either viral clearance or persistence. Although many infections may be self-limiting and cleared successfully by the immune response of the infected individuals, other infections result in persistent HPV infection. Recent studies indicate that microbiota in the gut and cervicovaginal tract modulate host immune status, mucosal inflammation, and epithelial barrier integrity. All these factors determine susceptibility to persistent infection. Inflammation, overproduction of reactive oxygen species (ROS), genomic instability, and impaired antiviral transcription pathways are associated with dysbiosis. In parallel, redox imbalance contributes to mitochondrial dysfunction, impairing mitochondrial antiviral signaling (MAVS)-dependent interferon responses and attenuating induction of interferon-stimulated genes. Additionally, extracellular vesicles (EVs) further promote immune evasion, metabolic programming, and epigenetic regulation by facilitating the intercellular exchange of viral constituents, microRNAs, and signaling molecules. Through this interconnected network of mechanisms, microbial dysbiosis, mitochondrial disruption, and EV signaling collectively shape a niche conducive to persistence. Unlike previous reviews that primarily examine microbiome alterations, oxidative stress (OS), mitochondrial dysfunction, extracellular vesicles, or immune responses as separate processes, this review integrates clinical and omics findings into a systems-based conceptual framework of HPV persistence. By emphasizing the potential interactions among these interconnected biological systems, we aim to identify points of biological convergence, generate mechanistic hypotheses, and highlight opportunities for future biomarker development and therapeutic intervention. Full article

Suppressors of cytokine signaling (SOCSs) are negative feedback regulators of the JAK-STAT pathway and are often exploited by viruses to evade host antiviral immunity. Unlike other SOCS members, the role of SOCS2 in viral infection remains poorly understood. Here, we report that overexpression of silkworm SOCS2 isoforms, SOCS2L and SOCS2S, promotes Bombyx mori nucleopolyhedrovirus (BmNPV) replication at multiple stages, including viral DNA replication, late gene (VP39) transcription, and virion egress, while their knockdown suppresses these processes. Overexpression of SH2 domain mutants (R123Q in SOCS2S, R142Q in SOCS2L) reduced viral DNA replication to baseline and VP39 expression below baseline, drastically decreased infectious progeny titers, but unexpectedly increased viral DNA release to wild-type levels, suggesting that the SH2 domain may differentially regulate distinct steps of viral replication. Furthermore, SOCS2 isoforms, alone or cooperatively with BmNPV, modulate the mRNA levels of SOCS-STAT network members in an isoform-, dose-, and target-specific manner. Collectively, this study reveals for the first time the multiple proviral functions of silkworm SOCS2 isoforms, with differential effects on distinct stages of the viral life cycle, and highlights their potential as transcriptional modulators exploited by viruses for immune evasion. Full article

Paraspeckles are subnuclear ribonucleoprotein condensates that regulate host stress responses, including those triggered by viral infection. In vitro studies using non-neuronal cells have shown the involvement of specific paraspeckle components in facilitating the replication of certain viruses, including Herpes Simplex Virus 1 (HSV-1), but these processes have not been investigated in human neuronal cells, which represent a relevant target of the virus. We employed human neural precursor cells (NPCs), neurons, and brain organoids derived from hiPSCs to investigate the previously unexplored dynamics of paraspeckle components in HSV-1-infected human neuronal cells. Our results reveal cell-type-specific differences in the expression of paraspeckle genes in response to HSV-1 infection. Unlike other viruses, HSV-1 orchestrates a previously unreported redistribution of paraspeckle proteins, leading to their accumulation in viral replication compartments (VRCs). Importantly, the expression of the paraspeckle proteins NONO and SFPQ correlates with HSV-1 permissiveness in human neuronal cells and may be required to establish a nuclear environment favoring viral transcription/replication. This enhances our understanding of how stress-response pathways in cells can be exploited by viruses in a cell-type-specific manner. Full article

Despite prolonged viral inhibition with combination antiretroviral therapy (ART), HIV-1 survives as genetically intact, replication-capable proviruses within durable CD4+ T-cell fractions, involving central memory, transitional memory, and stem cell-like memory populations, as well as within tissue-resident compartments including lymphoid follicles and gut-associated lymphoid tissue. Reservoir stability is preserved via clonal growth of infected cells and epigenetic processes that impose proviral transcriptional silencing. As a result, current therapeutic approaches seek to either directly alter proviral survival or to improve immune-driven elimination of infected cells. At the molecular level, investigational strategies such as CRISPR–Cas9 and CRISPR–Cas12 gene-editing systems are intended to remove or induce inactivating mutations inside embedded proviral DNA, as well as alter host entrance co-receptors such as CCR5 to provide cellular resistance to infection. In addition, pharmacologic latency regulation is being studied via histone deacetylase inhibitors, protein kinase C agonists, and bromodomain inhibitors to reverse latency, along with Tat inhibitors and other transcriptional repressors aimed to persistently silence proviral expression. Moreover, immunological techniques aim to counteract inefficient endogenous antiviral defenses. Broadly neutralizing antibodies with tailored Fc-driven effector functions are under examination for both neutralization and antibody-dependent cellular cytotoxicity. Therapeutic vaccine approaches seek to elevate polyfunctional HIV-specific CD8+ T-cell responses, while adoptive cellular approaches, involving CAR-T cells aiming HIV envelope epitopes, remain in early clinical research. Immune checkpoint blockade is also being investigated to reverse T-cell depletion inside reservoir-rich tissues. Nevertheless, the key obstacles continue to be the diverse reservoir composition, restricted tissue penetration, viral escape, and safety limitations. The molecular and translational obstacles that characterize attempts toward an HIV cure must be addressed through ongoing multidisciplinary research. Full article