Viruses-Basel最新文献

Hepatitis D virus (HDV) is a very peculiar virus that shares many characteristics with plant viroids. One of its unique characteristics is the requirement for the presence of a helper virus for its replication, and in particular enveloping its virion, a role often played by the hepatitis B virus (HBV). Infection with HDV is frequently associated with more severe disease, which may present with fulminant hepatitis or a more rapid progression to cirrhosis and hepatocellular carcinoma (HCC), when compared to HBV mono-infection. HDV exhibits many peculiarities and enigmas, which have led to it being considered a neglected virus. This review aims to identify the most important gaps in knowledge and peculiarities in the study of this enigmatic virus, from virology to clinical implications.

Schizophrenia is a severe neurodevelopmental disorder with a complex and largely unresolved pathogenesis. Accumulating evidence indicates that mitochondrial dysfunction is a consistent pathological hallmark of schizophrenia, suggesting that impaired mitochondrial homeostasis may represent a convergent mechanism underlying disease vulnerability. BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is a critical regulator of mitochondrial integrity and apoptosis. However, its role in schizophrenia has not yet been elucidated. Human endogenous retroviruses W family envelope (ERVWE1) has been implicated as a potential risk factor in schizophrenia, but the molecular mechanisms by which it contributes to neuronal pathology remain poorly understood. In this study, we investigated whether ERVWE1 induces mitochondrial dysfunction and neuronal apoptosis through the regulation of BNIP3. Bioinformatic analysis of the public dataset GSE53987 revealed significantly elevated BNIP3 expression in the brain tissues of patients with schizophrenia, accompanied by enrichment of mitochondria-related pathways. Consistently, BNIP3 expression was also increased in the peripheral blood of schizophrenia patients and positively correlated with ERVWE1 levels. Mechanistically, ERVWE1 upregulated BNIP3 expression by suppressing miR-27b-3p, a microRNA that directly targets BNIP3. The resulting increase in BNIP3 led to marked mitochondrial structural and functional impairment, characterized by reduced mitochondrial aspect ratio, enhanced mitochondria permeability transition pore (mPTP) opening, and decreased mitochondrial DNA (mtDNA) copy number. These mitochondrial defects subsequently triggered cytochrome c release into the cytosol, activating the intrinsic mitochondrial apoptotic pathway. Collectively, this study provides the first evidence that the ERVWE1/miR-27b-3p/BNIP3 axis contributes to mitochondrial dysfunction and neuronal apoptosis in schizophrenia. Our findings identify a previously unrecognized molecular pathway linking endogenous retroviral activity to mitochondrial pathology, offering novel insights into the mechanisms and potential therapeutic targets for schizophrenia.

Over the past two decades, it has become clear that gene expression in eukaryotic cells is regulated by diverse RNA molecules. In this process, new RNAs have been discovered, and the roles of their modified molecules have been progressively elucidated. In this review, we first describe how RNA and its modifications function in virus-infected cells. We use adenovirus and several other viruses as models during the early stages of infection, which we believe determines the fate of infected cells. Next, we reviewed the process of identifying the early mRNA transcription initiation sites in adenovirus-infected cells. The results showed that the transcription initiation sites for the E1 and E4 mRNAs-known as adenovirus oncogenes-are highly complex. The same level of complexity in transcription initiation sites has been suggested for oncogenes in several other DNA tumor viruses, including SV40, polyomavirus, and papillomavirus. It is now understood that the transcription of the early adenovirus mRNA involves alternative splicing, rather than constitutive splicing, as we previously demonstrated. Furthermore, recent research indicates that the abnormal alternative splicing of intracellular mRNA may induce cellular carcinogenesis. Finally, we discuss whether alternative splicing plays a role in the carcinogenic effects of DNA tumor viruses, such as adenovirus. Additionally, we discuss that alternative splicing plays a crucial role in adenovirus replication.

The eradication of hepatitis C virus (HCV) with interferon-free direct-acting antivirals (DAAs) has transformed the management of chronic HCV infection. Chronic HCV infection is associated with an increased risk of type 2 diabetes mellitus (T2DM) and poor glycemic control. However, the magnitude and consistency of improvement in glycated hemoglobin (HbA1c) after DAA-induced sustained virologic response (SVR) in patients with established T2DM remain unclear. We conducted a systematic review and meta-analysis of six cohort studies comprising 2805 patients. Overall, DAA therapy was associated with a significant reduction in HbA1c after SVR, with a pooled random-effect mean difference of -0.45% (95% CI -0.74% to -0.16%; I² = 97.8%). This effect is highly heterogeneous but suggests that HCV may be a modifiable contributor to chronic hyperglycemia. These findings highlight the need for close glucose monitoring and individualized adjustment of antidiabetic therapy after SVR to optimize metabolic outcomes.

The phages used to treat bacterial infections in phage therapy are commonly chosen based on their abilities to form plaques on the infecting bacterium-on host range. In practice, phage therapy is not always successful, leaving room for improvement. Here, we use computational models to investigate whether some standard phage properties (burst size, lysis rate, adsorption rate constant, intrinsic decay rate, and growth rate) might serve as predictors of treatment success. As our measure of treatment success, we deviate from many other approaches by calculating the number of phages needed to suppress bacterial densities 100-fold in the short term, given that the patient's immune system is expected to regain control once bacterial numbers are reduced. Numerical analysis of single-phage trials across 2400 combinations of phage phenotypes reveals that, on average, adsorption rate constant and growth rate provide the most useful predictive values, decay rate provides some value, whereas burst size and lysis time offer essentially little or no value. Bacterial density is especially informative of the number of phages required for treatment. There is nonetheless often considerable variation around average behavior for a single phenotype. These results raise the possibility that the adsorption rate constant and growth rate may be especially important in phage therapy performance for both high and low bacterial densities. Given that therapeutic phages are often evolved in vitro for broad host ranges rather than for individual hosts, it should be considered that selection for broad host range may have a downside of compromising adsorption to and growth rate on individual bacterial hosts.

Long-acting injectable HIV pre-exposure prophylaxis (LAI-PrEP) demonstrates superior efficacy to oral PrEP but faces a critical implementation challenge: 47% of patients fail to receive their first injection during the "bridge period" between prescription and initiation. We developed a clinical decision support tool with an external configuration architecture synthesizing evidence from major LAI-PrEP trials (HPTN 083, HPTN 084, PURPOSE) and implementation studies. The tool provides population-specific risk stratification, barrier identification, and evidence-based intervention recommendations from a library of 21 interventions with mechanism diversity scoring to prevent redundant recommendations. We conducted progressive validation on four scales: 1000 (functional), 1,000,000 (large-scale), 10,000,000 (ultra-large-scale) and 21,200,000 patients (UNAIDS PrEP target), with comprehensive unit testing achieving a test pass rate of 100% (18/18 edge cases). Progressive validation demonstrated convergence and increasing precision: 1K (±2.6 pp), 1M (±0.09 pp), 10M (±0.028 pp), and 21.2M (±0.018 pp). At UNAIDS 2025 PrEP target (21.2 million) scale, the tool predicted baseline bridge period success rate of 23.96% (95% CI: 23.94-23.98%), with evidence-based interventions improving success to 43.50% (95% CI: 43.48-43.52%)-an absolute improvement of 19.54 pp (or 81.6% relative improvement), representing 4.1 million additional successful transitions globally. Population disparities were substantial: People who inject drugs (PWID) showed 10.36% baseline success versus 33.11% for men who have sex with men (MSM)-a 22.75 pp gap. Regional disparities were equally significant: Sub-Saharan Africa (serving 62% of global patients) achieved 21.69% baseline versus 29.33% in Europe/Central Asia-a 7.64 pp gap. However, evidence-based interventions disproportionately benefited vulnerable populations. PWID experienced +265% relative improvement, and adolescents experienced +147% relative improvement, demonstrating that systematic implementation support can narrow rather than widen health equity gaps at UNAIDS 2025 PrEP target (21.2 million) scale. The tool demonstrates predictive validity with policy-grade statistical precision. Using published epidemiologic parameters (HIV incidence 2-5% among indicated users, LAI-PrEP efficacy 96%), our model translates the 4.1 million additional successful transitions into approximately 80,000-100,000 prevented HIV infections annually (midpoint: 100,000), corresponding to an estimated USD 40 billion in averted lifetime treatment costs.

Organoid technology has transformed experimental virology by offering physiologically relevant 3D human models that bridge the gap between conventional 2D cell cultures and complex in vivo systems. Derived from pluripotent or adult stem cells, organoids self-organize into multicellular structures that recapitulate native tissue architecture and function, enabling more accurate modeling of host-virus interactions and disease mechanisms. This review outlines the evolution and application of organoid-based systems across neural, intestinal, hepatic, pulmonary, and renal tissues for studying a broad range of human viruses that remain a public health burden. These models can reproduce viral tropism, immune signaling, and host variability, offering new molecular insights into infection dynamics. Integration with single-cell transcriptomics, CRISPR editing, and antiviral screening has expanded the translational utility of organoids, establishing them as a powerful platform for antiviral discovery, vaccine testing, and precision medicine.

This study constructed a bioinformatics prediction algorithm for human enterovirus uncoating receptors based on amino acid sequences and physicochemical properties. Based on the availability of uncoating receptor information and three-dimensional (3D) structural data, human enterovirus serotypes were classified into training, validation, and prediction datasets. Using amino acid sequences of receptor-binding sites and their physicochemical properties as model features, a prediction model was constructed using the Naive Bayes algorithm and bioinformatic network analysis method. The results showed that both the training and validation datasets achieved a prediction accuracy of 100%. Among the 56 serotypes in the prediction dataset, the vast majority utilized seven known types of uncoating receptors (e.g., SCARB2, CAR, and ICAM-1), while a minority of serotypes may share the same novel, unknown receptor. This study indicates that uncoating receptors can be accurately predicted based on the amino acid sequences and physicochemical properties of human enteroviruses. Furthermore, the three-dimensional structural features at receptor-binding sites can be reflected through corresponding amino acid sequences and their physicochemical properties. This study facilitates a more in-depth investigations of enterovirus pathogenic mechanisms and provides important insights for the development of vaccines and antiviral drugs.

Viruses of the family Anelloviridae represent a predominant component of the human virome across various anatomical sites, yet their clinical significance remains poorly understood. This review summarizes current data on the dynamics and functional interactions of anelloviruses with the immune system in the context of human immune deficiency virus (HIV) infection. Existing studies indicate that an individual's complement of anelloviruses (their "anellome") serves as a highly sensitive indicator of immunocompetence. In the absence of antiretroviral therapy (ART), the viral load and taxonomic diversity of anelloviruses (genera Alphatorquevirus, Betatorquevirus, and Gammatorquevirus) demonstrate a rapid increase, correlating with HIV viral load, a decline in CD4+ T-lymphocyte count, and the CD4/CD8 ratio, reflecting weakened immune surveillance. Upon initiation of antiretroviral therapy (ART), a decrease in anellovirus viral load is observed; however, it likely does not revert to the pre-HIV infection baseline. At the same time, a high baseline level of Torque teno virus (TTV) is associated with incomplete immune recovery and the risk of ART non-response. Anelloviruses exhibit a dual role as both activators of the immune system (via APOBEC3, antibody production, and pro-inflammatory cytokines resulting from Toll-like receptor (TLR) activation) and disruptors of certain signaling pathways (through micro-RNAs and proteins encoded by ORF2). Thus, monitoring the anellome represents a promising non-invasive approach for assessing immune status, risk stratification, and personalizing therapy in patients with HIV infection. Future research should focus on the practical application of anellovirus viral load and diversity as markers of immune status and on clarifying the consequences of the aggregate interaction between HIV modulator proteins and anelloviruses during co-infection.

Coronaviruses pose a global pandemic threat, making development of a pan-coronavirus inhibitor crucial for preparedness and containment in the event of a new coronavirus outbreak. The 3C-like protease (3CL^pro) is a key target for antiviral development, as it is essential for viral replication and conserved across human coronaviruses. We previously developed an assay to monitor SARS-CoV-2 3CL^pro activity in cells. This assay uses a single vector that coexpresses the 3CL^pro enzyme and the reporter, which consists of two luciferase fragments linked by a 3CL^pro cleavage site. Cleavage of this site by 3CL^pro decreases luciferase activity, whereas inhibition of 3CL^pro increases the luciferase activity. Here, we adapted this assay to examine 3CL^pro activity from six other human coronaviruses: SARS-CoV, MERS-CoV, HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1. We further determined the effects of different cleavage sites to improve the signal-to-background ratio. The Nsp4-Nsp5 site and super-active substrate (SAS) resulted in the largest dynamic range for most coronaviruses in our assay. Using the broad-spectrum 3CL^pro inhibitor GC376, we observed increased reporter activity, indicating the assay's efficacy for identifying inhibitors across multiple coronaviruses. The adaptation and improvement of the assay can facilitate the development of inhibitors against 3CL^pro from multiple or novel coronaviruses.