Viruses

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Open AccessReview

Medicinal Mushrooms, Probiotics and Combination of Natural Compounds in the Management of HPV: A Comparative Look at Viral Clearance and Lesion Resolution

by Giuseppina Porcaro, Marco Calcagno and Andrea Tinelli

Viruses 2025, 17(7), 942; https://doi.org/10.3390/v17070942 - 2 Jul 2025

Abstract

Despite the fact that human papillomavirus (HPV) infections are common, there are currently no proven treatment approaches for persistent infections. A promising strategy to promote HPV clearance and the regression of caused lesions is dietary supplementation with natural compounds. This review evaluates available [...] Read more.

Despite the fact that human papillomavirus (HPV) infections are common, there are currently no proven treatment approaches for persistent infections. A promising strategy to promote HPV clearance and the regression of caused lesions is dietary supplementation with natural compounds. This review evaluates available supplement formulations proposed in HPV care, focusing on combinations of epigallocatechin gallate (EGCG), folic acid (FA), vitamin B12 (B12), and hyaluronic acid (HA), as well as medicinal mushrooms and probiotics. The combination of EGCG, FA, B12, and HA is supported by the most consistent evidence, which shows a high rate of HPV clearance and lesion resolution across several clinical investigations. Medicinal mushrooms and probiotics have also shown some evidence of beneficial effects, although the diverse designs of the reported clinical studies may limit the observed findings. Overall, natural molecule-based supplements showed promising safety and efficacy profiles in the management of HPV persistent infection, supporting their clinical use. Of course, further investigations through well-designed, large-scale, randomized controlled trials will be necessary to provide strong support. Full article

(This article belongs to the Section Human Virology and Viral Diseases)

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Open AccessArticle

In Silico Analysis of Mechanisms of Maribavir-Induced Inhibition and Drug Resistance Mutations in pUL97 Kinase Structural Prediction with AlphaFold2

by Jocelyne Piret and Guy Boivin

Viruses 2025, 17(7), 941; https://doi.org/10.3390/v17070941 - 2 Jul 2025

Abstract

Infections with cytomegalovirus (CMV) can result in increased morbidity and mortality in immunocompromised patients. The pUL97 kinase is a critical enzyme in the regulation of CMV replication. Although it does not phosphorylate deoxynucleosides, this enzyme is involved in the first phosphorylation step of [...] Read more.

Infections with cytomegalovirus (CMV) can result in increased morbidity and mortality in immunocompromised patients. The pUL97 kinase is a critical enzyme in the regulation of CMV replication. Although it does not phosphorylate deoxynucleosides, this enzyme is involved in the first phosphorylation step of ganciclovir (GCV), a viral DNA polymerase inhibitor. In contrast, maribavir (MBV) is a specific inhibitor of pUL97 kinase activity. In this paper, we analyzed the already-reported amino acid changes, conferring resistance to MBV and cross-resistance to GCV, in the pUL97 protein structure, predicted with AlphaFold2. Docking experiments suggest that MBV is a dual-site inhibitor, targeting ATP binding and substrate phosphorylation. Substitutions that confer resistance to MBV only may directly or indirectly alter the shape of the cavity in the vicinity of the invariant K355 in the putative ATP binding site, without affecting the viral growth. The most frequently encountered T409M substitution may correspond to a gatekeeper mutation. Substitutions that induce cross-resistance to MBV and GCV may directly or indirectly affect the environment of D456 and N461 residues in the catalytic loop, with reduced viral replicative capacity. These results have implications for the clinical use of MBV as well as for the design of novel pUL97 kinase inhibitors. Full article

(This article belongs to the Special Issue Mechanisms of Herpesvirus Resistance)

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4244 KiB

Open AccessArticle

Interactions Between Hantavirus Nucleoprotein and Glycoproteins: A Quantitative Fluorescence Microscopy Study

by Amit Koikkarah Aji, Titas Mandal and Salvatore Chiantia

Viruses 2025, 17(7), 940; https://doi.org/10.3390/v17070940 - 2 Jul 2025

Abstract

Orthohantaviruses are tri-segmented negative-sense RNA viruses that can cause severe pathologies in humans. Currently, limited information exists on the molecular interactions driving orthohantavirus assembly in infected cells. Specifically, it is not clear how its glycoproteins (i.e., Gn and Gc) interact with other viral [...] Read more.

Orthohantaviruses are tri-segmented negative-sense RNA viruses that can cause severe pathologies in humans. Currently, limited information exists on the molecular interactions driving orthohantavirus assembly in infected cells. Specifically, it is not clear how its glycoproteins (i.e., Gn and Gc) interact with other viral or host molecules. In this study, we use one- and two-color Number and Brightness fluorescence microscopy approaches to quantitatively characterize the interactions between orthohantavirus glycoproteins and the nucleoprotein in transfected cells. Our results indicate that orthohantavirus nucleoprotein homo-interactions are strongly affected by the host environment. Furthermore, we report evidence of Gc–nucleoprotein interactions, based on (i) the high fluorescence cross-correlation between these two proteins and (ii) the increased Gc-Gc interactions observed in the presence of nucleoprotein. Finally, experiments on a Gc deletion mutant suggest that the observed protein–protein interactions are mediated by the cytoplasmic tail of Gc. In conclusion, this study provides new insights into the role of the interactions between orthohantavirus glycoproteins and nucleoprotein in the context of viral assembly. Full article

(This article belongs to the Special Issue Microscopy Methods for Virus Research)

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3 pages, 651 KiB

Open AccessCorrection

Correction: Mbigha Donfack et al. Aedes Mosquito Virome in Southwestern Cameroon: Lack of Core Virome, But a Very Rich and Diverse Virome in Ae. africanus Compared to Other Aedes Species. Viruses 2024, 16, 1172

by Karelle Celes Mbigha Donfack, Lander De Coninck, Stephen Mbigha Ghogomu and Jelle Matthijnssens

Viruses 2025, 17(7), 939; https://doi.org/10.3390/v17070939 - 1 Jul 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Virus Bioinformatics 2024)

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22 pages, 6421 KiB

Open AccessArticle

Therapeutic Optimization of Pseudomonas aeruginosa Phages: From Isolation to Directed Evolution

by Sara Bolognini, Caterina Ferretti, Claudia Campobasso, Elisabetta Trovato, Magda Marchetti, Laura Rindi, Arianna Tavanti and Mariagrazia Di Luca

Viruses 2025, 17(7), 938; https://doi.org/10.3390/v17070938 - 30 Jun 2025

Abstract

Pseudomonas aeruginosa is a major opportunistic pathogen with high levels of antibiotic resistance. Phage therapy represents a promising alternative for the treatment of difficult infections both alone and in combination with antibiotics. Here, we isolated and characterized three novel lytic myoviruses, Cisa, Nello, [...] Read more.

Pseudomonas aeruginosa is a major opportunistic pathogen with high levels of antibiotic resistance. Phage therapy represents a promising alternative for the treatment of difficult infections both alone and in combination with antibiotics. Here, we isolated and characterized three novel lytic myoviruses, Cisa, Nello, and Moonstruck. Genomic analysis revealed that Cisa and Nello belong to the Pbunavirus genus, while Moonstruck is a novel Pakpunavirus species. All lacked lysogeny, virulence, or resistance-associated genes, supporting their therapeutic suitability. Phage Nello and Moonstruck were active against P. aeruginosa Pa3GrPv, isolated from a patient with lung infection candidate for phage therapy. Moonstruck exhibited superior lytic activity with ciprofloxacin sub-MIC value (0.125 µg/mL), achieving bacterial suppression for 48 h. However, to improve the lytic efficacy of the phages on the clinical isolate, phage adaptation via serial passage was investigated. The killing efficacy of Nello was enhanced, whereas Moonstruck showed a less consistent improvement, suggesting phage-specific differences in evolutionary dynamics. Sequencing of the evolved phages revealed point mutations in tail-associated genes, potentially linked to a better phage–host interaction. These results support the use of phage–antibiotic combinations and directed evolution as strategies to enhance phage efficacy against drug-resistant infections. Overall, these findings support the therapeutic potential of the newly isolated phages in treating P. aeruginosa lung infections. Full article

(This article belongs to the Section Bacterial Viruses)

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18 pages, 1262 KiB

Open AccessReview

Regulation and Deregulation of Viral Gene Expression During High-Risk HPV Infection

by Konstanze Schichl and John Doorbar

Viruses 2025, 17(7), 937; https://doi.org/10.3390/v17070937 - 30 Jun 2025

Abstract

Cervical cancer remains a global health burden, with persistent infection by high-risk human papillomaviruses (HR-HPVs) being the primary etiological factor. HR-HPVs target stem-like cells of the cervical epithelium to establish chronic infections. Upon infection of the cervical transformation zone (TZ)—a region adjacent to [...] Read more.

Cervical cancer remains a global health burden, with persistent infection by high-risk human papillomaviruses (HR-HPVs) being the primary etiological factor. HR-HPVs target stem-like cells of the cervical epithelium to establish chronic infections. Upon infection of the cervical transformation zone (TZ)—a region adjacent to the squamocolumnar junction (SCJ)—these viruses drive neoplastic transformation, which is due in part to the unique cellular composition and hormonal responsiveness of the TZ. Reserve cells, which can accumulate at the cervical crypt entrances of the TZ, are thought to be highly susceptible to HR-HPV infection because of their location beneath a single layer of columnar cells. Infection of the stratified ectocervical epithelium, in contrast, requires a wound to allow basal cell infection, replication, and the expression of early genes to adjust epithelial homeostasis while facilitating immune evasion. Persistent infection by HR-HPV types, particularly HPV16 and HPV18, can result in the deregulated expression of viral genes E6 and E7, driving cell cycle disruption, genomic instability, and subsequent viral genome integration. Differences in the microenvironment and transcriptional environment of the ectocervix compared with the TZ could explain the frequent deregulation of E6 and E7 at the latter site, which can drive disease progression towards cancer. Full article

(This article belongs to the Special Issue 15-Year Anniversary of Viruses)

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22 pages, 1198 KiB

Open AccessReview

Recent Progress in the Vaccine Development Against Epstein–Barr Virus

by Yihao Dai, Botian Zhang, Luming Yang, Shuo Tao, Yijing Yu and Conglei Li

Viruses 2025, 17(7), 936; https://doi.org/10.3390/v17070936 - 30 Jun 2025

Abstract

The Epstein–Barr virus (EBV) is the first human herpesvirus identified as an oncogenic agent, with approximately 95% of adults worldwide being latently infected. EBV infection is associated with multiple diseases, including nasopharyngeal carcinoma, Hodgkin’s lymphoma, infectious mononucleosis, and multiple sclerosis. Given significant EBV-associated [...] Read more.

The Epstein–Barr virus (EBV) is the first human herpesvirus identified as an oncogenic agent, with approximately 95% of adults worldwide being latently infected. EBV infection is associated with multiple diseases, including nasopharyngeal carcinoma, Hodgkin’s lymphoma, infectious mononucleosis, and multiple sclerosis. Given significant EBV-associated disease burden, developing effective vaccines against EBV remains a priority. In this review, we first presented the current understanding of EBV biology and pathogenesis, focusing on its biological structure and immune evasion mechanisms, and discussed key viral antigens—including gp350, gp42, gH/gL, and latency proteins—as potential targets for EBV vaccine development. We also summarized recent advances in various EBV vaccine platforms, including subunit, viral vector-based, nanoparticle-based, and mRNA vaccines, and discussed the related preclinical and clinical evidence, although no effective EBV vaccine has been approved for clinical use yet. In summary, this review provides an overview of the current landscape in EBV vaccine research, and sheds new light on developing new therapeutic approaches against EBV-associated diseases. Full article

(This article belongs to the Special Issue Molecular and Cellular Biology of Human Oncogenic Viruses)

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25 pages, 2250 KiB

Open AccessArticle

Antagonistic Trends Between Binding Affinity and Drug-Likeness in SARS-CoV-2 Mpro Inhibitors Revealed by Machine Learning

by Anacleto Silva de Souza, Vitor Martins de Freitas Amorim, Eduardo Pereira Soares, Robson Francisco de Souza and Cristiane Rodrigues Guzzo

Viruses 2025, 17(7), 935; https://doi.org/10.3390/v17070935 - 30 Jun 2025

Abstract

The SARS-CoV-2 main protease (Mpro) is a validated therapeutic target for inhibiting viral replication. Few compounds have advanced clinically, underscoring the difficulty in optimizing both target affinity and drug-like properties. To address this challenge, we integrated machine learning (ML), molecular docking, and molecular [...] Read more.

The SARS-CoV-2 main protease (Mpro) is a validated therapeutic target for inhibiting viral replication. Few compounds have advanced clinically, underscoring the difficulty in optimizing both target affinity and drug-like properties. To address this challenge, we integrated machine learning (ML), molecular docking, and molecular dynamics (MD) simulations to investigate the balance between pharmacodynamic (PD) and pharmacokinetic (PK) properties in Mpro inhibitor design. We developed ML models to classify Mpro inhibitors based on experimental IC₅₀ data, combining molecular descriptors with structural insights from MD simulations. Our Support Vector Machine (SVM) model achieved strong performance (training accuracy = 0.84, ROC AUC = 0.91; test accuracy = 0.79, ROC AUC = 0.86), while our Logistic Regression model (training accuracy = 0.78, ROC AUC = 0.85; test accuracy = 0.76, ROC AUC = 0.83). Notably, PK descriptors often exhibited opposing trends to binding affinity: hydrophilic features enhanced binding affinity but compromised PK properties, whereas hydrogen bonding, hydrophobic, and π–π interactions in Mpro subsites S2 and S3/S4 are fundamental for binding affinity. Our findings highlight the need for a balanced approach in Mpro inhibitor design, strategically targeting these subsites may balance PD and PK properties. For the first time, we demonstrate antagonistic trends between pharmacokinetic (PK) and pharmacodynamic (PD) features through the integrated application of ML/MD. This study provides a computational framework for rational Mpro inhibitors, combining ML and MD to investigate the complex interplay between enzyme inhibition and drug likeness. These insights may guide the hit-to-lead optimization of the novel next-generation Mpro inhibitors of SARS-CoV-2 with preclinical and clinical potential. Full article

(This article belongs to the Special Issue Advances in Small-Molecule Viral Inhibitors)

14 pages, 589 KiB

Open AccessArticle

Adoptive JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy: Experience from Two Italian Centers

by Maria Magdalena Pocora, Paola Bini, Giulia Berzero, Elisa Vegezzi, Luca Diamanti, Matteo Gastaldi, Paola Cinque, Gaia Catalano, Matteo Paoletti, Anna Pichiecchio, Fulvio Tartara, Sabrina Basso, Fausto Baldanti, Milena Furione, Patrizia Comoli and Enrico Marchioni

Viruses 2025, 17(7), 934; https://doi.org/10.3390/v17070934 - 30 Jun 2025

Abstract

Background: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease caused by John Cunningham virus (JCV) in immunocompromised individuals, with no effective antiviral treatment currently available. This study aimed to evaluate the feasibility of adoptive JCV-specific T lymphocyte therapy in patients with [...] Read more.

Background: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease caused by John Cunningham virus (JCV) in immunocompromised individuals, with no effective antiviral treatment currently available. This study aimed to evaluate the feasibility of adoptive JCV-specific T lymphocyte therapy in patients with PML. Methods: Nineteen patients meeting the 2013 consensus criteria for “definite PML” were included, and JCV-specific T lymphocytes expanded from autologous or allogeneic peripheral blood mononuclear cells (PBMCs) using JCV antigen-derived peptides were administered. Clinical outcomes were monitored through neuroimaging and biological markers. Results: The mean age at diagnosis was 56.5 years, with a mean time to treatment of three months. Patients received a median of two infusions. At 12 months, six patients (31.6%) survived, while 13 (68.4%) had died, primarily due to PML progression. Survivors had a higher median baseline Karnofsky performance scale (KPS) score (50% vs. 30%, p = 0.41) and a significantly shorter diagnosis delay. MRI assessment showed a reduced disease burden in survivors, and JCV-DNA copy numbers decreased overall. One case of immune reconstitution inflammatory syndrome (IRIS) was observed. Conclusions: Adoptive JCV-specific T lymphocytes may represent a safe therapeutic option for PML patients, and the MRI burden and JCV-DNA copy may serve as biomarkers for disease monitoring. Full article

(This article belongs to the Special Issue Emerging Controversies and Advances in Neurovirology)

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14 pages, 3918 KiB

Open AccessArticle

Beta-Sitosterol Enhances Classical Swine Fever Virus Infection: Insights from RNA-Seq Analysis

by Yayun Liu, Dongdong Yin, Jieru Wang, Yin Dai, Xuehuai Shen, Lei Yin, Bin Zhou and Xiaocheng Pan

Viruses 2025, 17(7), 933; https://doi.org/10.3390/v17070933 - 30 Jun 2025

Abstract

Beta-sitosterol (BS), a naturally occurring phytosterol abundant in plants, has been reported to exhibit diverse biological activities, including immunomodulatory and antiviral effects. Classical swine fever virus (CSFV), a member of the Pestivirus genus, remains a persistent threat to the swine industry worldwide, causing [...] Read more.

Beta-sitosterol (BS), a naturally occurring phytosterol abundant in plants, has been reported to exhibit diverse biological activities, including immunomodulatory and antiviral effects. Classical swine fever virus (CSFV), a member of the Pestivirus genus, remains a persistent threat to the swine industry worldwide, causing considerable economic damage. Our research found that BS significantly enhances the replication of both the CSFV-Shimen strain and the attenuated C-strain vaccine virus in PK-15 cells. Additionally, transcriptomic profiling (RNA-Seq) identified 175 differentially expressed genes (DEGs) following BS exposure, comprising 53 upregulated and 122 downregulated genes. Further results demonstrated that treatment with β-sitosterol suppressed IκBα expression, thereby activating the NF-κB pathway, and that knockdown of endogenous IκBα significantly promoted CSFV replication. These findings contribute to a deeper understanding of how BS influences the CSFV infection process, suggesting its role as a host lipid-associated factor facilitating viral propagation. Full article

(This article belongs to the Section Animal Viruses)

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57 pages, 750 KiB

Open AccessReview

The Role of Hematophagous Arthropods, Other Than Mosquitoes and Ticks, in Arbovirus Transmission

by Bradley J. Blitvich

Viruses 2025, 17(7), 932; https://doi.org/10.3390/v17070932 - 30 Jun 2025

Abstract

Arthropod-borne viruses (arboviruses) significantly impact human, domestic animal, and wildlife health. While most arboviruses are transmitted to vertebrate hosts by blood-feeding mosquitoes and ticks, a growing body of evidence highlights the importance of other hematophagous arthropods in arboviral transmission. These lesser-known vectors, while [...] Read more.

Arthropod-borne viruses (arboviruses) significantly impact human, domestic animal, and wildlife health. While most arboviruses are transmitted to vertebrate hosts by blood-feeding mosquitoes and ticks, a growing body of evidence highlights the importance of other hematophagous arthropods in arboviral transmission. These lesser-known vectors, while often overlooked, can play crucial roles in the maintenance, amplification, and spread of arboviruses. This review summarizes our understanding of hematophagous arthropods, other than mosquitoes and ticks, in arboviral transmission, as well as their associations with non-arboviral viruses. Thirteen arthropod groups are discussed: bat flies, blackflies, cimicids (bat bugs, bed bugs, and bird bugs), Culicoides midges, fleas, hippoboscid flies, lice, mites, muscid flies (including horn flies and stable flies), phlebotomine sandflies, tabanids (including deer flies and horse flies), triatomines, and tsetse flies. Some of these arthropods are regarded as known or likely arboviral vectors, while others have no known role in arbovirus transmission. Particular attention is given to species associated with arboviruses of medical and veterinary significance. As the burden of arboviruses continues to grow, it is critical not to overlook the potential contribution of these lesser-known vectors. Full article

(This article belongs to the Section Invertebrate Viruses)

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Open AccessArticle

Evaluation of Treatment Response in Chronic Hepatitis C Patients Receiving Sofosbuvir/Velpatasvir/Voxilaprevir: A Multicenter Real-World Experience from Türkiye

by Umut Devrim Binay, Faruk Karakeçili, Bilgehan Aygen, Ayşin Kılınç Toker, İlhami Çelik, Neşe Demirtürk, Tuğçe Şimşek Bozok, Leyla Dursun, Fethiye Akgül, Güle Çınar, Özgür Günal, Ali Asan, Eyüp Arslan, Fatma Yılmaz Karadağ, Orçun Barkay, İrem Akdemir, Funda Şimşek, Emine Türkoğlu Yılmaz, Zeynep Ravza Eğilmez, Süda Tekin and The Viral Hepatitis Study Group of the Turkish Society of Clinical Microbiology and Infectious Diseases (KLİMİK) Show full author list Hide full author list

Viruses 2025, 17(7), 931; https://doi.org/10.3390/v17070931 - 30 Jun 2025

Abstract

The combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is recommended as a salvage therapy for treatment-experienced chronic hepatitis C (CHC) patients. However, it is used in our country for treatment-naïve and treatment-experienced patients. This study aims to present real-world data from Türkiye on CHC patients treated [...] Read more.

The combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is recommended as a salvage therapy for treatment-experienced chronic hepatitis C (CHC) patients. However, it is used in our country for treatment-naïve and treatment-experienced patients. This study aims to present real-world data from Türkiye on CHC patients treated with SOF/VEL/VOX. The present study was conducted by the Viral Hepatitis Study Group of the Turkish Society of Clinical Microbiology and Infectious Diseases (KLİMİK). It was a multicenter, retrospective, observational study. The data were collected from patients receiving SOF/VEL/VOX therapy at 12 medical centers in Türkiye between 1 June 2022 and 31 December 2024. The patients had received the treatment for 8 to 12 weeks. Of the 139 patients enrolled, 63.3% (n = 88) were male, with a mean age of 54.4 years. Most patients were non-cirrhotic (94.2%, n = 131) and treatment-naïve (92%, n = 128); 49.6% (n = 69) were infected with genotype 1b. Early virologic response (EVR) could be assessed in 126 patients, with an EVR rate of 82.5% (n = 104). End-of-treatment data were available for 113 patients, all achieving an end-of-treatment response. Among the 80 patients for whom week-12 post-treatment data were available, 97.5% sustained virologic response at week 12 (SVR12). Significant improvements were observed in AST, ALT, and platelet levels, along with reductions in APRI and FIB-4 scores (p = 0.001).” No serious adverse events leading to treatment discontinuation were reported. Mild adverse events included pruritus (2.1%, n = 3), fatigue (2.1%, n = 3), and nausea (1.4%, n = 2). The SOF/VEL/VOX combination is a highly effective and well-tolerated treatment option in treatment-naïve CHC patients, achieving an SVR12 rate of 97.5%. Full article

(This article belongs to the Special Issue Recent Advances in Anti-HCV, Anti-HBV and Anti-Flavivirus Agents, 2nd Edition)

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18 pages, 9016 KiB

Open AccessArticle

GCRV-II Triggers B and T Lymphocyte Apoptosis via Mitochondrial ROS Pathway

by Jie Wang, Wen-Jing Dong, Chang-Song Wu, Tian-Tian Tian, Xu-Jie Zhang and Yong-An Zhang

Viruses 2025, 17(7), 930; https://doi.org/10.3390/v17070930 - 30 Jun 2025

Abstract

Grass carp reovirus (GCRV), particularly the highly prevalent genotype II (GCRV-II), is known to infect peripheral blood leukocytes (PBLs) of grass carp. However, it is unclear whether GCRV-II can induce apoptosis in bystander lymphocytes within infected PBLs. Here, we have shown that GCRV-II [...] Read more.

Grass carp reovirus (GCRV), particularly the highly prevalent genotype II (GCRV-II), is known to infect peripheral blood leukocytes (PBLs) of grass carp. However, it is unclear whether GCRV-II can induce apoptosis in bystander lymphocytes within infected PBLs. Here, we have shown that GCRV-II infection induces apoptosis via the mitochondria-dependent caspase-3 pathway in infected PBLs. GCRV-II infection was also found to induce a significant increase in reactive oxygen species (ROS) accumulation in leukocytes and lymphocytes, accompanied by increased apoptosis in IgM⁺ B and CD4⁺ T lymphocyte subsets. Further studies have demonstrated that the targeted inhibition of mitochondrial ROS production can effectively attenuate apoptosis in neighboring B and T lymphocytes within infected PBLs, suggesting that GCRV-II-induced pro-apoptotic effects on bystander lymphocytes largely require the involvement of the mitochondrial-dependent ROS pathway. Taken together, our study reveals the underlying mechanism by which GCRV-II induces apoptosis in bystander B and T lymphocytes through ROS production, providing new insights into understanding the virus-induced pro-apoptotic mechanism in specific immune cells and a potential strategy for viral immune escape. Full article

(This article belongs to the Section Animal Viruses)

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14 pages, 7004 KiB

Open AccessArticle

Predictive Value of Hepatitis B Core-Related Antigen for Multiple Recurrence Outcomes After Treatment Cessation in Chronic Hepatitis B: A Meta-Analysis Study

by Guoyang Yu, Meiqi Cheng, Yuxin Duan, Minrong Kang, Ning Jiang, Wei Yan and Jianhua Yin

Viruses 2025, 17(7), 929; https://doi.org/10.3390/v17070929 - 30 Jun 2025

Abstract

Background: Hepatitis B core-related antigen (HBcrAg), a novel serum biomarker reflecting the activity of intrahepatic covalently closed circular DNA (cccDNA), has generated conflicting evidence regarding its clinical utility for predicting post-antiviral therapy relapse in chronic hepatitis B (CHB) patients. Methods: We systematically analyzed [...] Read more.

Background: Hepatitis B core-related antigen (HBcrAg), a novel serum biomarker reflecting the activity of intrahepatic covalently closed circular DNA (cccDNA), has generated conflicting evidence regarding its clinical utility for predicting post-antiviral therapy relapse in chronic hepatitis B (CHB) patients. Methods: We systematically analyzed 13 studies (15 cohorts, n = 1529 patients) from PubMed, Web of Science, Wanfang, and CNKI (through April 2025). A bivariate model evaluated HBcrAg’s predictive performance for relapse outcomes, including virological relapse, clinical relapse, and hepatitis flares. Results: HBcrAg demonstrated a pooled sensitivity of 0.81 (95% CI: 0.75–0.86) and specificity of 0.72 (95% CI: 0.67–0.76) for relapse prediction, with a diagnostic odds ratio of 10.66 (95% CI: 7.36–15.42) and summary AUC of 0.83 (95% CI: 0.80–0.86). Subgroup analysis identified threshold effects as the primary source of heterogeneity, which resolved (I² < 13%) after excluding studies with outlier cutoff values. Meta-regression established that HBcrAg’s predictive value was unaffected by age, sex, hepatitis B e antigen status, or detection methods (p > 0.05). Conclusions: HBcrAg is validated as a robust non-invasive biomarker to optimize treatment cessation strategies, with high sensitivity providing strong negative predictive value in CHB populations. Future research should prioritize multi-marker models to enhance prediction accuracy. Full article

(This article belongs to the Special Issue Hepatitis B Core-Related Antigen)

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23 pages, 2511 KiB

Open AccessArticle

The Role of Prion Protein in Reelin/Dab1 Signaling: Implications for Neurodegeneration

by Irene Giulia Rolle, Anna Burato, Merve Begüm Bacınoğlu, Fabio Moda and Giuseppe Legname

Viruses 2025, 17(7), 928; https://doi.org/10.3390/v17070928 - 29 Jun 2025

Abstract

The cellular prion protein (PrP^C) is studied in prion diseases, where its misfolded isoform (PrP^Sc) leads to neurodegeneration. PrP^C has also been implicated in several physiological functions. The protein is abundant in the nervous system, and it is [...] Read more.

The cellular prion protein (PrP^C) is studied in prion diseases, where its misfolded isoform (PrP^Sc) leads to neurodegeneration. PrP^C has also been implicated in several physiological functions. The protein is abundant in the nervous system, and it is critical for cell signaling in cellular communication, where it acts as a scaffold for various signaling molecules. The Reelin signaling pathway, implicated both in Alzheimer’s and prion diseases, engages Dab1, an adaptor protein influencing APP processing and amyloid beta deposition. Here, we show, using Prnp knockout models (Prnp^0/0), that PrP^C modulates Reelin signaling, affecting Dab1 activation and downstream phosphorylation in both neuronal cultures and mouse brains. Notably, Prnp^0/0 mice showed reduced responsiveness to Reelin, associated with altered Dab1 phosphorylation and Fyn kinase activity. Even though no direct interaction between PrP^C and Reelin/ApoER2 was found, Prnp^0/0 neurons showed lower NCAM levels, a well-established PrP^C interactor. Prion infection further disrupted the Reelin signaling pathway, thus downregulating Dab1 and Reelin receptors and altering Reelin processing, like Alzheimer’s disease pathology. These findings emphasize PrP^C indirect role in Dab1 signaling via the NCAM and Fyn pathways, which influence synaptic function and neurodegeneration in prion diseases. Full article

(This article belongs to the Special Issue 15-Year Anniversary of Viruses)

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28 pages, 854 KiB

Open AccessReview

H5N1 Avian Influenza: A Narrative Review of Scientific Advances and Global Policy Challenges

by Alison Simancas-Racines, Claudia Reytor-González, Melannie Toral and Daniel Simancas-Racines

Viruses 2025, 17(7), 927; https://doi.org/10.3390/v17070927 - 29 Jun 2025

Abstract

The H5N1 avian influenza virus continues to evolve into genetically diverse and highly pathogenic clades with increased potential for cross-species transmission. Recent scientific advances have included the development of next-generation vaccine platforms, promising antiviral compounds, and more sensitive diagnostic tools, alongside strengthened surveillance [...] Read more.

The H5N1 avian influenza virus continues to evolve into genetically diverse and highly pathogenic clades with increased potential for cross-species transmission. Recent scientific advances have included the development of next-generation vaccine platforms, promising antiviral compounds, and more sensitive diagnostic tools, alongside strengthened surveillance systems in both animals and humans. However, persistent structural challenges hinder global readiness. Vaccine production is heavily concentrated in high-income countries, limiting equitable access during potential pandemics. Economic and logistical barriers complicate the implementation of control strategies such as vaccination, culling, and compensation schemes. Gaps in international coordination, public communication, and standardization of protocols further exacerbate vulnerabilities. Although sustained human-to-human transmission has not been documented, the severity of confirmed infections and the rapid global spread among wildlife and domestic animals underscore the urgent need for robust preparedness. International organizations have called for comprehensive pandemic response plans, enhanced multisectoral collaboration, and investment in targeted research. Priorities include expanding surveillance to asymptomatic animal hosts, evaluating viral shedding and transmission routes, and developing strain-specific and universal vaccines. Strengthening global cooperation and public health infrastructure will be critical to mitigate the growing threat of H5N1 and reduce the risk of a future influenza pandemic. Full article

(This article belongs to the Special Issue Controlling Zoonotic Viral Diseases from One Health Perspective 2025)

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21 pages, 1889 KiB

Open AccessArticle

Investigation of Avian Reovirus Evolution and Cross-Species Transmission in Turkey Hosts by Segment-Based Temporal Analysis

by Cheng-Shun Hsueh, Michael Zeller, Amro Hashish, Olufemi Fasina, Pablo Piñeyro, Ganwu Li, Jianqiang Zhang, Mohamed El-Gazzar and Yuko Sato

Viruses 2025, 17(7), 926; https://doi.org/10.3390/v17070926 - 28 Jun 2025

Abstract

Avian reovirus (ARV) has emerged as an important pathogen in turkeys, causing economic losses through tenosynovitis, necrotizing hepatitis, immunosuppression, and enteric disease. Despite its ubiquity, the evolutionary history of ARV cross-species transmission among chickens, turkeys, and wild birds remains poorly understood, hindering effective [...] Read more.

Avian reovirus (ARV) has emerged as an important pathogen in turkeys, causing economic losses through tenosynovitis, necrotizing hepatitis, immunosuppression, and enteric disease. Despite its ubiquity, the evolutionary history of ARV cross-species transmission among chickens, turkeys, and wild birds remains poorly understood, hindering effective control and surveillance. This study investigates ARV temporal phylogenetics with an emphasis on interspecies transmission in turkeys. Whole genome sequences (WGSs) from seventy-seven turkey cases and one quail case at the Iowa State University Veterinary Diagnostic Laboratory, along with 74–136 segment sequences per gene from GenBank (1970–2023), were analyzed. Temporal phylogenetic analyses identified chickens as the ancestral host, with spillover into turkeys beginning in the mid-20th century, followed by stable transmission within turkey populations. Migration analyses revealed predominantly unidirectional transmission from chickens to turkeys. WGS analyses showed high variability in the M2 and σC-encoding region of the S1 segment, suggesting selective pressure on outer capsid proteins. M2, S1 σC, and L3 had the highest substitution rates, implicating their role in adaptation and antigenic diversity. These findings highlight the complexity of ARV evolution across hosts and underscore the need for robust genotyping schemes and surveillance strategies to mitigate outbreaks in poultry. Full article

(This article belongs to the Special Issue Avian Reovirus)

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11 pages, 1137 KiB

Open AccessArticle

Characterisation of Orthohantavirus Serotypes in Human Infections in Kazakhstan

by Nur Tukhanova, Anna Shin, Abhishek Bakuli, Lyazzat Yeraliyeva, Nurbek Maikanov, Guenter Froeschl, Zauresh Zhumadilova, Gulnara Tokmurziyeva, Edith Wagner, Sandra Essbauer and Lukas Peintner

Viruses 2025, 17(7), 925; https://doi.org/10.3390/v17070925 - 28 Jun 2025

Abstract

Orthohantavirus infection is a zoonotic disease transmitted to humans through contact with infected rodents. In Eurasia, Old World Orthohantaviruses can cause haemorrhagic fever with renal syndrome (HFRS), while in the Americas, New World Orthohantaviruses are responsible for hantavirus cardiopulmonary syndrome (HCPS). In Kazakhstan, [...] Read more.

Orthohantavirus infection is a zoonotic disease transmitted to humans through contact with infected rodents. In Eurasia, Old World Orthohantaviruses can cause haemorrhagic fever with renal syndrome (HFRS), while in the Americas, New World Orthohantaviruses are responsible for hantavirus cardiopulmonary syndrome (HCPS). In Kazakhstan, the first recorded cases of HFRS appeared in the West Kazakhstan region in 2000, which has since then been established as an endemic area due to the presence of stable rodent reservoirs and recurring human infections. Routine diagnosis of HFRS in this region relies primarily on immunoassays. To enhance diagnostic precision, we aimed to implement both serological and molecular methods on samples from suspected HFRS cases in the endemic West Kazakhstan region and non-endemic Almaty City. A total of 139 paired serum, saliva, and urine samples were analysed using IgM/IgG ELISA, immunoblot assays, and qPCR. Our findings confirm that suspected HFRS cases in West Kazakhstan are associated with the Puumala virus serotype. Full article

(This article belongs to the Special Issue Hantavirus 2024)

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10 pages, 3437 KiB

Open AccessArticle

Phylogenetic and Mutation Analysis of Hemagglutinin Gene from Highly Pathogenic Avian Influenza Virus H5 Clade 2.3.4.4b in South America

by Alfredo Bruno, Domenica de Mora, Miguel Angel Garcia-Bereguiain and Juan Cristina

Viruses 2025, 17(7), 924; https://doi.org/10.3390/v17070924 - 28 Jun 2025

Abstract

The Highly Pathogenic Avian Influenza Virus (HPAIV) H5 clade 2.3.4.4b has caused severe outbreaks in domestic and wild birds worldwide since its emergence in 2014, and especially since 2020, with outbreaks in Europe and North America. The introduction of the virus into South [...] Read more.

The Highly Pathogenic Avian Influenza Virus (HPAIV) H5 clade 2.3.4.4b has caused severe outbreaks in domestic and wild birds worldwide since its emergence in 2014, and especially since 2020, with outbreaks in Europe and North America. The introduction of the virus into South America was reported for the first time in Colombia in October 2022, followed by outbreaks in other South American countries affecting poultry, wild birds, mammals, and humans. In this study, a phylogenetic and mutation analysis of the hemagglutinin (HA) gene of HPAIV H5N1 2.3.4.4b viruses isolated in South America was performed to analyze its evolution and its transmission and zoonotic potential. The analysis shows an increase in the viral effective population size between April and June 2022, which was followed by multiple outbreaks of HPAIV H5N1 clade 2.3.4.4b in South America. Moreover, the virus variants evolved from a recent common ancestor estimated to have existed in June 2017. The mean rate of evolution of the HA gene was 6.95 × 10⁻³ substitutions per site per year, and the sequence analysis of HA identified a mutation (D171N) located at antibody binding sites and viral oligomerization interfaces, with implications for immune response evasion and new host species infection. Additionally, viral strains from South America share the substitutions L104M, T156A, P181S, and V210A, compared to the vaccine strain A/chicken/Ghana/AVL763/2021. Understanding the dynamics of viral evolution and transmission is essential for effective prevention strategies to mitigate future outbreaks. Full article

(This article belongs to the Special Issue H5N1 Influenza Viruses)

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