Viruses

12 pages, 787 KB

Open AccessArticle

Vitamin D Status, CMV Seropositivity, and Viral Cytokine Expression in Pregnancy

by Adalvan D. Martins, Jennifer Woo, Brandi Falley and Juliet V. Spencer

Viruses 2025, 17(9), 1203; https://doi.org/10.3390/v17091203 - 31 Aug 2025

Cytomegalovirus (CMV) is the leading infectious cause of birth defects and has been linked to increased risk of preterm birth (PTB). CMV establishes lifelong latency and is more prevalent among Black and Hispanic/Latina women, populations already at higher risk for adverse pregnancy outcomes. [...] Read more.

Cytomegalovirus (CMV) is the leading infectious cause of birth defects and has been linked to increased risk of preterm birth (PTB). CMV establishes lifelong latency and is more prevalent among Black and Hispanic/Latina women, populations already at higher risk for adverse pregnancy outcomes. Vitamin D deficiency, also common in these groups, has been linked to impaired immune function and increased susceptibility to infections, including CMV. In this cross–sectional study of 63 pregnant minority women (50 CMV+, 13 CMV−), we evaluated associations among serum 25(OH)D levels, CMV serostatus, and cmvIL–10, the CMV–encoded interleukin–10 homolog that modulates host immune responses. While vitamin D insufficiency and CMV seropositivity were both highly prevalent, we found no statistically significant associations between 25(OH)D levels and CMV serostatus or cmvIL–10 levels. These findings highlight the need for further investigation into how vitamin D deficiency and CMV infection may independently or synergistically contribute to maternal and neonatal health disparities. Full article

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

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13 pages, 1531 KB

Open AccessArticle

Long-Term Genomic Surveillance and Immune Escape of SARS-CoV-2 in the Republic of Korea, with a Focus on JN.1-Derived Variants

by Il-Hwan Kim, Eun Ju Lee, Jin Sun No, Ji Yeong Noh, Chae Young Lee, Sang Won O, Yong Jun Choi, Jeong-Ah Kim, Bo Min An, Jeong-Hyun Nam, Jeong-Min Kim, Jee Eun Rhee and Eun-Jin Kim

Viruses 2025, 17(9), 1202; https://doi.org/10.3390/v17091202 - 31 Aug 2025

Abstract

Since the onset of the COVID-19 pandemic, the Republic of Korea has experienced continuous waves of SARS-CoV-2 variants. The current study aimed to analyze the long-term trends of variant prevalence and associated changes in immune responses within the country. Whole-genome sequencing was performed [...] Read more.

Since the onset of the COVID-19 pandemic, the Republic of Korea has experienced continuous waves of SARS-CoV-2 variants. The current study aimed to analyze the long-term trends of variant prevalence and associated changes in immune responses within the country. Whole-genome sequencing was performed on confirmed patient samples collected from December 2020 to May 2025, and variant distribution, genetic diversity, and neutralization were compared. As a result of analyzing a total of 157,962 gene sequences, various Omicron sub-lineages, including BA.1, BA.2, BA.5, followed by JN.1, KP.3, and NB.1.8.1, were seen to circulate sequentially over time. The nucleotide diversity of the SARS-CoV-2 genome gradually increased after the JN.1 outbreak. Of the tested variants, hamster antiserum neutralization analysis indicated that Omicron NB.1.8.1, which began to circulate in 2025, exhibited the lowest neutralization activity, with an approximately 6.6-fold decrease compared to JN.1. This suggests a potential expansion in the dominance of new variants with enhanced immune evasion. As the transmission of SARS-CoV-2 continues, new variants with novel characteristics may emerge; therefore, continuous national genomic surveillance and immunological characterization are considered crucial for early detection of emerging variants and for guiding effective public health responses. Full article

(This article belongs to the Section Coronaviruses)

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35 pages, 654 KB

Open AccessArticle

Time Series Analysis of Dengue, Zika, and Chikungunya in Ecuador: Emergence Patterns, Epidemiological Interactions, and Climate-Driven Dynamics (1988–2024)

by José Daniel Sánchez, Carolina Álvarez Ramírez, Emilio Cevallos Carrillo, Juan Arias Salazar and César Barros Cevallos

Viruses 2025, 17(9), 1201; https://doi.org/10.3390/v17091201 - 31 Aug 2025

Abstract

Background: Ecuador presents a unique epidemiological laboratory for studying arboviral dynamics due to its diverse ecological zones and exposure to climatic variability. Methods: We conducted a comprehensive 36-year analysis (1988–2024) of dengue (DENV), Zika (ZIKV), and chikungunya (CHIKV) using national surveillance data from [...] Read more.

Background: Ecuador presents a unique epidemiological laboratory for studying arboviral dynamics due to its diverse ecological zones and exposure to climatic variability. Methods: We conducted a comprehensive 36-year analysis (1988–2024) of dengue (DENV), Zika (ZIKV), and chikungunya (CHIKV) using national surveillance data from Ecuador’s Ministry of Public Health. Statistical analyses included time series decomposition, change-point detection, correlation analysis, and climate association studies. Results: Ecuador reported 387,543 arboviral cases, with dengue comprising 91.3% (353,782 cases). Dengue exhibited endemic–epidemic cycles with major peaks during El Niño events (1994: 10,247 cases; 2000: 22,937 cases; 2015: 42,483 cases; 2024: 23,156 cases through week 26). CHIKV emerged explosively in 2015 (29,124 cases, incidence 181.10 per 100,000), followed by ZIKV in 2016 (2947 cases). Both showed rapid decline post-epidemic. Severe dengue cases paradoxically decreased from 2–4% of total cases in early 2000s to <0.1% post-2016, suggesting immunological modulation. Cross-correlation analysis revealed significant associations between climatic indices and epidemic timing (

r = 0.67

,

p < 0.001

), particularly for the El Niño-Southern Oscillation. Conclusions: Arboviral diseases in Ecuador function as an integrated epidemiological system with evidence of viral interactions, cross-protective immunity, and strong climate forcing. These findings emphasize the need for integrated surveillance and adaptive control strategies. Full article

(This article belongs to the Special Issue Preparation for the Next Potential Pandemic—Chikungunya, Dengue, Zika and Other Viruses)

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18 pages, 20579 KB

Open AccessArticle

Isolation and Characterization of a Novel Porcine Teschovirus 2 Strain: Incomplete PERK-Mediated Unfolded Protein Response Supports Viral Replication

by Xiaoying Feng, Yiyang Du, Yueqing Lv, Xiaofang Wei, Chang Cui, Yibin Qin, Bingxia Lu, Zhongwei Chen, Kang Ouyang, Ying Chen, Zuzhang Wei, Weijian Huang, Ying He and Yifeng Qin

Viruses 2025, 17(9), 1200; https://doi.org/10.3390/v17091200 - 31 Aug 2025

Abstract

Porcine Teschovirus (PTV) is a highly prevalent pathogen within swine populations, primarily associated with encephalitis, diarrhea, pneumonia, and reproductive disorders in pigs, thereby posing a significant threat to the sustainable development of the pig farming industry. In this study, a novel strain of [...] Read more.

Porcine Teschovirus (PTV) is a highly prevalent pathogen within swine populations, primarily associated with encephalitis, diarrhea, pneumonia, and reproductive disorders in pigs, thereby posing a significant threat to the sustainable development of the pig farming industry. In this study, a novel strain of PTV was isolated from the feces of a pig exhibiting symptoms of diarrhea, utilizing PK-15 cell lines. The structural integrity of the viral particles was confirmed via transmission electron microscopy, and the viral growth kinetics and characteristics were evaluated in PK-15 cells. High-throughput sequencing facilitated the acquisition of the complete viral genome, and subsequent phylogenetic analysis and full-genome alignment identified the strain as belonging to the PTV 2 genotype. Further investigation revealed that infection with the PTV-GXLZ2024 strain induces phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) in PK-15 cells, indicating activation of the unfolded protein response (UPR) through the PERK pathway, with minimal involvement of the IRE1 or ATF6 pathways. Notably, ATF4 protein expression was progressively downregulated throughout the infection, while downstream CHOP protein levels remained unchanged, indicating an incomplete UPR induced by PTV-GXLZ2024. Furthermore, PERK knockdown was found to enhance the replication of PTV-GXLZ2024. This study provides critical insights into the molecular mechanisms underlying PTV pathogenesis and establishes a foundation for future research into its evolutionary dynamics and interactions with host organisms. Full article

(This article belongs to the Section Animal Viruses)

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17 pages, 1782 KB

Open AccessArticle

Protein Language Models Expose Viral Immune Mimicry

by Dan Ofer and Michal Linial

Viruses 2025, 17(9), 1199; https://doi.org/10.3390/v17091199 - 31 Aug 2025

Abstract

Viruses have evolved sophisticated solutions to evade host immunity. One of the most pervasive strategies is molecular mimicry, whereby viruses imitate the molecular and biophysical features of their hosts. This mimicry poses significant challenges for immune recognition, therapeutic targeting, and vaccine development. In [...] Read more.

Viruses have evolved sophisticated solutions to evade host immunity. One of the most pervasive strategies is molecular mimicry, whereby viruses imitate the molecular and biophysical features of their hosts. This mimicry poses significant challenges for immune recognition, therapeutic targeting, and vaccine development. In this study, we leverage pretrained protein language models (PLMs) to distinguish between viral and human proteins. Our model enables the identification and interpretation of viral proteins that most frequently elude classification. We characterize these by integrating PLMs with explainable models. Our approach achieves state-of-the-art performance with ROC-AUC of 99.7%. The 3.9% of misclassified sequences are signified by viral proteins with low immunogenicity. These errors disproportionately involve human-specific viral families associated with chronic infections and immune evasion, suggesting that both the immune system and machine learning models are confounded by overlapping biophysical signals. By coupling PLMs with explainable AI techniques, our work advances computational virology and offers mechanistic insights into viral immune escape. These findings carry implications for the rational design of vaccines, and improved strategies to counteract viral persistence and pathogenicity. Full article

(This article belongs to the Special Issue Herpesviruses and Associated Diseases)

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26 pages, 1977 KB

Open AccessArticle

Whole-Exome Sequencing Reveals Rare Genetic Variants in Saudi COVID-19 Patients with Extreme Phenotypes

by Rashid Mir, Mohammad Fahad Ullah, Imadeldin Elfaki, Mohammad A. Alanazi, Naseh A. Algehainy, Faisal H. Altemani, Mamdoh S. Moawadh, Faris J. Tayeb, Badr A. Alsayed, Mohammad Muzaffar Mir, Jaber Alfaifi, Syed Khalid Mustafa, Jameel Barnawi and Salma Saleh Alrdahe

Viruses 2025, 17(9), 1198; https://doi.org/10.3390/v17091198 (registering DOI) - 30 Aug 2025

Abstract

The global impact of COVID-19 was staggering, with millions of cases and related mortality reported worldwide. Genetic variations play a significant role in determining an individual’s susceptibility to SARS-CoV-2 infection and progress to severe disease. This pilot study provides an experimental approach using [...] Read more.

The global impact of COVID-19 was staggering, with millions of cases and related mortality reported worldwide. Genetic variations play a significant role in determining an individual’s susceptibility to SARS-CoV-2 infection and progress to severe disease. This pilot study provides an experimental approach using WES to identify certain rare and novel genetic variants that might affect an individual’s susceptibility to the risk of SARS-CoV-2 infection, offering an initial exploration of these genetic variants. In the study cohort with 16 patients, the mortality rate was higher in male patients due to severe disease. There was a substantial burden of comorbidity, including hypertension, ischemic heart disease, and T2DM, conditions which independently increase the risk of adverse outcomes in COVID-19 patients. A total of 4478 variants were identified, distributed across 322 genes within the cohort. The majority of these variants were missense substitutions along with frameshift variants, inframe insertions/deletions (indels), and nonsense variants. The variants were further categorized by types to include single-nucleotide polymorphisms (SNPs), deletions (DEL), and insertions (INS). The gene with the highest number of variants was HLA-DRB1, followed by HLA-B, ABO, HPS4, and SP110 displaying both common polymorphisms and rare variants. Moreover, the HLA-B gene exhibited the highest number of rare candidate variants, followed by AK2, IRF7, KMT2D, TAP1, and HLA-DRB1. Several genes harbored multiple novel variants, including TAP1, AK2, G6PC3, HLA-B, IL12RB2, and ITGB2. The frequencies of the identified variants were found to be either zero or extremely low (below 1% threshold) in the Middle Eastern or in the overall combined population, suggesting that these are indeed rare and do not represent common indigenous polymorphisms. Functional enrichment analysis of the constructed protein–protein interaction network in our preliminary findings revealed that the identified genes are primarily enriched in pathways associated with immune deficiency and DNA repair. This initial exploration of genetic variants in COVID-19 susceptibility provides a foundation for future large-scale studies. Full article

(This article belongs to the Section Coronaviruses)

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15 pages, 2409 KB

Open AccessArticle

Genetic Diversity and Molecular Analysis of Human Parainfluenza Virus Type 3 in Saint Petersburg (Russia) in 2017–2023: Emergence of a New Phylogenetic Cluster

by Oula Mansour, Artem V. Fadeev, Alexander A. Perederiy, Marina I. Zadirienko, Daria M. Danilenko, Dmitry A. Lioznov and Andrey B. Komissarov

Viruses 2025, 17(9), 1197; https://doi.org/10.3390/v17091197 - 30 Aug 2025

Abstract

Human parainfluenza viruses 3 (hPIV3) are important pathogens, responsible for acute respiratory tract diseases, especially in young children. Information on hPIV3 circulation and their diversity pattern in Russia is limited. The aim of this study was to perform a molecular and genetic characterization [...] Read more.

Human parainfluenza viruses 3 (hPIV3) are important pathogens, responsible for acute respiratory tract diseases, especially in young children. Information on hPIV3 circulation and their diversity pattern in Russia is limited. The aim of this study was to perform a molecular and genetic characterization of hPIV3 circulating in Saint Petersburg, Russia. From October 2017 to September 2023, 14,704 swabs were screened using real-time reverse transcription-PCR. A phylogenetic analysis of the complete hemagglutinin–neuraminidase (HN) gene was performed. Out of 1,334 positive hPIV cases, hPIV3 was the most common subtype. Phylogenetic analysis of the studied and previously published HN sequences revealed four distinct genetic clusters, A, B, C, and D, with Cluster D being first delineated in this study. In addition, two newly subdivided genetic lineages, C5a and C5b, were documented. Phylogenetic analysis revealed that the analyzed Russian strains grouped into Cluster C and D; further subclusters C5a, C5b, C3b, C3e, and C3a. While three strains were classified within cluster D, the majority of isolates fell within subcluster C3a, followed by C5b. Taken together, these findings demonstrate the co-circulation of hPIV3 strains during the study period. This is the first study that describes the genetic and molecular aspects of hPIV3 circulating in Russia. Moreover, our results provide an up-to-date hPIV3 phylogenetic analysis. Full article

(This article belongs to the Special Issue Viral Genetic Variability and Its Role in Assessing Infectious Diseases)

23 pages, 1099 KB

Open AccessArticle

From Systemic Inflammation to Vascular Remodeling: Investigating Carotid IMT in COVID-19 Survivors

by Emilia Bielecka, Piotr Sielatycki, Paulina Pietraszko, Sara Anna Frankowska and Edyta Zbroch

Viruses 2025, 17(9), 1196; https://doi.org/10.3390/v17091196 - 30 Aug 2025

Abstract

Background: Atherosclerosis is a chronic inflammatory condition that underlies both cardiovascular and cerebrovascular complications. Emerging evidence suggests that COVID-19 may play a role in its progression. Purpose: The aim of the study was to evaluate the potential impact of SARS-CoV-2 infection on the [...] Read more.

Background: Atherosclerosis is a chronic inflammatory condition that underlies both cardiovascular and cerebrovascular complications. Emerging evidence suggests that COVID-19 may play a role in its progression. Purpose: The aim of the study was to evaluate the potential impact of SARS-CoV-2 infection on the development of atherosclerosis. Patients and Methods: Common carotid artery (CCA) intima media thickness (IMT) was measured by ultrasonography twice, 12–18 months apart, in a cohort of 92 patients (47 with COVID-19 and 45 controls). Clinical data were collected from medical histories, physical examinations, and laboratory findings. Results: Baseline IMT values were comparable between the study groups (0.85 mm vs. 0.78 mm). However, the COVID-19 group exhibited a significantly greater increase in IMT over time, with a median change of 0.13 mm compared to 0.05 mm in the controls (p = 0.018). Furthermore, 69.2% of COVID-19 patients exceeded the median IMT progression threshold compared to 36% in the control group (p = 0.017). An elevated level of C-reactive protein (CRP) and a higher triglyceride (Tg)-to-High-Density Lipoprotein Cholesterol (HDL) ratio were significantly associated with increased IMT in the COVID-19 group. Age and heart rate were identified as significant predictors of IMT progression across both groups. Conclusion: COVID-19 may accelerate the progression of subclinical atherosclerosis. The strong associations of CRP and the TG/HDL ratio with IMT highlight the potential roles of chronic inflammation and metabolic dysregulation in driving these vascular changes. Further large-scale, multicenter studies are needed to elucidate the underlying mechanisms, confirm these observations, and guide targeted preventive and therapeutic strategies for individuals with an increased cardiovascular and cerebrovascular risk. Full article

(This article belongs to the Special Issue COVID-19 Complications and Co-infections)

21 pages, 8620 KB

Open AccessReview

From Viral Infection to Malignancy: The Dual Threat of EBV and COVID-19 in Cancer Development

by Moyed Alsaadawe, Bakeel A. Radman, Longtai Hu, Jingyi Long, Qingshuang Luo, Chushu Tan, Hadji Sitti Amirat, Mohenned Alsaadawi and Xiaoming Lyu

Viruses 2025, 17(9), 1195; https://doi.org/10.3390/v17091195 - 30 Aug 2025

Abstract

This narrative review consolidates existing evidence about the interaction between Epstein-Barr virus (EBV) and SARS-CoV-2 in cancer development. EBV is a recognized oncogenic driver, whereas COVID-19 may heighten cancer risk by immunological dysregulation, persistent inflammation, and reactivation of latent viruses. We underscore molecular [...] Read more.

This narrative review consolidates existing evidence about the interaction between Epstein-Barr virus (EBV) and SARS-CoV-2 in cancer development. EBV is a recognized oncogenic driver, whereas COVID-19 may heighten cancer risk by immunological dysregulation, persistent inflammation, and reactivation of latent viruses. We underscore molecular similarities (e.g., NF-κB activation, T-cell exhaustion) and clinical ramifications for high-risk individuals, stressing the necessity for interdisciplinary research to alleviate dual viral risks. EBV, a well-known oncogenic virus, has been linked to numerous malignancies, including lymphomas, nasopharyngeal carcinoma, and gastric cancer. Through the production of viral proteins that interfere with immune evasion, cellular signaling, and genomic integrity, it encourages malignant transformation and ultimately results in unchecked cell proliferation. Because of its capacity to induce tissue damage, immunological dysregulation, and chronic inflammation, COVID-19, which is brought on by the SARS-CoV-2 virus, has become a possible carcinogen. The virus’s influence on cellular pathways and its long-term effects on the immune system may raise the chance of malignancy, particularly in people with pre-existing vulnerabilities, even if direct correlations to cancer are still being investigated. When two viruses co-infect a host, the review highlights the possibility of synergistic effects that could hasten the development of cancer. It describes how overlapping mechanisms like inflammation, immune suppression, and viral reactivation may be used by a combined EBV and COVID-19 infection to exacerbate carcinogenic processes. Gaining an understanding of these relationships is essential for creating tailored treatment plans and enhancing cancer prevention in high-risk groups. Full article

(This article belongs to the Special Issue EBV and Disease: New Perspectives in the Post COVID-19 Era)

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22 pages, 1012 KB

Open AccessReview

Evolving Threats: Adaptive Mechanisms of Monkeypox Virus (MPXV) in the 2022 Global Outbreak and Their Implications for Vaccine Strategies

by Yuanwen Wang, Meimei Hai, Zijie Guo, Junbo Wang, Yong Li and Weifeng Gao

Viruses 2025, 17(9), 1194; https://doi.org/10.3390/v17091194 - 30 Aug 2025

Abstract

Monkeypox virus (MPXV) experienced an unprecedented global outbreak in 2022, characterized by a significant departure from historical patterns: a rapid spread of the epidemic to more than 110 non-traditional endemic countries, with more than 90,000 confirmed cases; a fundamental shift in the mode [...] Read more.

Monkeypox virus (MPXV) experienced an unprecedented global outbreak in 2022, characterized by a significant departure from historical patterns: a rapid spread of the epidemic to more than 110 non-traditional endemic countries, with more than 90,000 confirmed cases; a fundamental shift in the mode of transmission, with human-to-human transmission (especially among men who have sex with men (MSM)) becoming the dominant route (95.2%); and genetic sequencing revealing a key adaptive mutation in a novel evolutionary branch (Clade IIb) that triggered the outbreak. These features highlight the significant evolution of MPXV in terms of host adaptation, transmission efficiency, and immune escape ability. The aim of this paper is to provide insights into the viral adaptive evolutionary mechanisms driving this global outbreak, with a particular focus on the role of immune escape (e.g., novel mechanisms of M2 proteins targeting the T cell co-stimulatory pathway) in enhancing viral transmission and pathogenicity. At the same time, we systematically evaluate the cross-protective efficacy and limitations of existing vaccines (ACAM2000, JYNNEOS, and LC16), as well as recent advances in novel vaccine platforms, especially mRNA vaccines, in inducing superior immune responses. The study further reveals the constraints to outbreak control posed by grossly unequal global vaccine distribution (e.g., less than 10% coverage in high-burden regions such as Africa) and explores the urgency of optimizing stratified vaccination strategies and facilitating technology transfer to promote equitable access. The core of this paper is to elucidate the dynamic game between viral evolution and prevention and control strategies (especially vaccines). The key to addressing the long-term epidemiological challenges of MPXV in the future lies in continuously strengthening global surveillance of viral evolution (early warning of highly transmissible/pathogenic variants), accelerating the development of next-generation vaccines based on new mechanisms and platforms (e.g., multivalent mRNAs), and resolving the vaccine accessibility gap through global collaboration to build an integrated defense system of “Surveillance, Research and Development, and Equitable Vaccination,” through global collaboration to address the vaccine accessibility gap. Full article

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

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17 pages, 2037 KB

Open AccessArticle

First Detection and Identification of Southern Tomato Virus Infecting Tomatoes in Oklahoma with Complete Genome Characterization and Insights into Global Genetic Diversity

by Salil Jindal and Akhtar Ali

Viruses 2025, 17(9), 1193; https://doi.org/10.3390/v17091193 - 30 Aug 2025

Abstract

Southern tomato virus (STV) or Amalgavirus lycopersici is a persistent virus impacting tomato crops globally. This study identified new STV isolates from Oklahoma and analyzed their evolutionary relationship to global STV isolates. Phylogenetic analyses (complete genomes or individual genes) grouped STV isolates into [...] Read more.

Southern tomato virus (STV) or Amalgavirus lycopersici is a persistent virus impacting tomato crops globally. This study identified new STV isolates from Oklahoma and analyzed their evolutionary relationship to global STV isolates. Phylogenetic analyses (complete genomes or individual genes) grouped STV isolates into two distinct clades, independent of geographic origin or host. Notably, Oklahoma isolates formed a separate cluster from previously reported isolates in the United States of America (USA). Coalescent analysis suggested the most recent common ancestor of STV fusion protein emerged around 135 years ago. Genetic diversity among STV isolates was low, with slightly more variability in the RNA-dependent RNA polymerase (RdRp) gene than the p42 gene. Both genes showed strong purifying selection. No recombination events were detected across complete genomes. Structure analysis revealed that the p42 protein, particularly its C-terminal region, displayed higher disorder, indicating a possible role in host interactions and viral adaptability. These findings deepen our understanding of STV’s evolution and highlight the need for ongoing surveillance and broader genomic sampling. Full article

(This article belongs to the Special Issue Plant Viral Pathogens: Innovations in Detection, Genetic Diversity, and Evolutionary Dynamics)

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23 pages, 315 KB

Open AccessReview

The Use of Nonhuman Primate Models for Advancing HIV PrEP

by Elena Bekerman and Christian Callebaut

Viruses 2025, 17(9), 1192; https://doi.org/10.3390/v17091192 - 30 Aug 2025

Abstract

The global fight against HIV/AIDS has been significantly bolstered by the development and implementation of pre-exposure prophylaxis (PrEP), yet innovation in PrEP interventions, improved adherence and greater access are still needed to maximize its benefit. Nonhuman primate (NHP) infection with simian immunodeficiency virus [...] Read more.

The global fight against HIV/AIDS has been significantly bolstered by the development and implementation of pre-exposure prophylaxis (PrEP), yet innovation in PrEP interventions, improved adherence and greater access are still needed to maximize its benefit. Nonhuman primate (NHP) infection with simian immunodeficiency virus (SIV) has served as an instrumental animal model in advancing HIV PrEP research. This review comprehensively examines the utility of NHP models in evaluating the efficacy, pharmacokinetics, and safety of diverse PrEP strategies, including oral, injectable, implantable, and topical formulations. It discusses the development of diverse challenge models that simulate human transmission routes and the advantages of NHPs in enabling controlled and mechanistically informative studies. It also highlights the successful translation of pivotal NHP studies evaluating tenofovir-based regimens as well the long-acting agents, cabotegravir and lenacapavir, into the clinical settings, emphasizing the consistently high predictive power of the NHP models for the HIV PrEP clinical efficacy. Finally, it underscores the importance of species-specific pharmacologic considerations and the value of NHP data in informing clinical trial design. As the global community strives to end the HIV epidemic as a public health threat in the absence of an efficacious prophylactic vaccine, NHP models make a critical contribution in the development of next-generation HIV prevention tools. Full article

(This article belongs to the Special Issue Simian Immunodeficiency Virus Models of HIV/AIDS in Nonhuman Primates, 2nd Edition)

19 pages, 2263 KB

Open AccessArticle

T-Cell Epitope-Based SARS-CoV-2 DNA Vaccine Encoding an Antigen Fused with Type 1 Herpes Simplex Virus Glycoprotein D (gD)

by Luana Raposo de Melo Moraes Aps, Aléxia Adrianne Venceslau-Carvalho, Carla Longo de Freitas, Bruna Felício Milazzotto Maldonado Porchia, Mariângela de Oliveira Silva, Lennon Ramos Pereira, Natiely Silva Sales, Guilherme Formoso Pelegrin, Ethiane Segabinazi, Karine Bitencourt Rodrigues, Jamile Ramos da Silva, Bianca da Silva Almeida, Jéssica Pires Farias, Maria Fernanda Castro-Amarante, Paola Marcella Camargo Minoprio, Luís Carlos de Souza Ferreira and Rúbens Prince dos Santos Alves

Viruses 2025, 17(9), 1191; https://doi.org/10.3390/v17091191 - 30 Aug 2025

Abstract

Authorized SARS-CoV-2 vaccines elicit both antibody and T-cell responses; however, benchmark correlates and update decisions have largely emphasized neutralizing antibodies. Motivated by the complementary role of cellular immunity, we designed a prototype polyepitope DNA vaccine encoding conserved human and mouse T-cell epitopes from [...] Read more.

Authorized SARS-CoV-2 vaccines elicit both antibody and T-cell responses; however, benchmark correlates and update decisions have largely emphasized neutralizing antibodies. Motivated by the complementary role of cellular immunity, we designed a prototype polyepitope DNA vaccine encoding conserved human and mouse T-cell epitopes from non-structural proteins of the original strain SARS-CoV-2 lineage. Epitope selection was guided by in silico predictions for common HLA class I alleles in the Brazilian population and the mouse H-2Kb haplotype. To enhance immunogenicity, the polyepitope sequences were fused to glycoprotein D (gD) from Herpes Simplex Virus 1 (HSV-1), an immune activator of dendritic cells (DCs), leading to enhanced activation of antigen-specific T-cell responses. Mice were immunized with two doses of the electroporated DNA vaccine encoding the gD-fused polyepitope, which induced robust interferon-gamma– and tumor necrosis factor-alpha–producing T cell responses compared to control mice. In addition, K18-hACE2 transgenic mice showed protection against intranasal challenge with the original SARS-CoV-2 strain, with reduced clinical symptoms, less weight loss, and decreased viral burden in both lung and brain tissues. The results experimentally confirm the protective role of T cells in vaccine-induced protection against SARS-CoV-2 and open perspectives for the development of universal anti-coronavirus vaccines. Full article

(This article belongs to the Special Issue SARS-CoV-2, COVID-19 Pathologies, Long COVID, and Anti-COVID Vaccines)

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17 pages, 1464 KB

Open AccessArticle

Use of the Slow-Delivery Platform, VacSIM, Shapes the Host Immune Response to Increase Protection Against Influenza Infection

by Anna L. McCormick, Ted M. Ross, Donald A. Harn and Jarrod J. Mousa

Viruses 2025, 17(9), 1190; https://doi.org/10.3390/v17091190 - 30 Aug 2025

Abstract

Influenza virus is a leading cause of global morbidity and mortality due to acute lower respiratory infection, even with the widespread use of multiple licensed influenza vaccines. However, antigenic drift during influenza replication can cause vaccine-induced antibodies to poorly neutralize influenza virus, thereby [...] Read more.

Influenza virus is a leading cause of global morbidity and mortality due to acute lower respiratory infection, even with the widespread use of multiple licensed influenza vaccines. However, antigenic drift during influenza replication can cause vaccine-induced antibodies to poorly neutralize influenza virus, thereby reducing vaccine effectiveness. To help overcome this problem, we leveraged a hydrogel platform with influenza hemagglutinin (HA) protein to induce prolonged antigen exposure. The hydrogel platform, Vaccine Self-Assembling Immune Matrix (VacSIM^®), in combination with recombinant influenza H1 or H3 HA protein antigens, increased antigen-specific antibody titers in vaccinated mice, which led to decreased disease severity after H1N1 infection for H1 HA-vaccinated mice and decreased lung viral titers after H3N2 challenge for H3 HA-vaccinated mice. Sera collected from mice immunized with VacSIM and HA also showed broader HAI activity, increasing by 1–3 log against a panel of influenza viruses. These results were consistent with the use of cocktail immunization, containing both an H1 and H3 HA, where mice immunized with VacSIM had an increase in antigen-specific antibody titers and decreased disease severity and lung viral titers against H1N1 and H3N2 influenza challenges, respectively. Finally, it was determined that a single immunization with VacSIM and H1 HA could provide protection against lethal H1N1 challenge compared to a group without VacSIM. In summary, we demonstrate that use of the slow-release platform VacSIM can improve the host immune response to vaccination and increase protection against influenza infection. Full article

(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)

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17 pages, 1862 KB

Open AccessArticle

Molecular Epidemiology of SARS-CoV-2 Detected from Different Areas of the Kandy District of Sri Lanka from November 2020–March 2022

by Bushran N. Iqbal, Sibra R. M. Shihab, Tao Zhang, Aadhil Ahamed, Shiyamalee Arunasalam, Samanthika Jagoda, Leo L. M. Poon, Malik Peiris and Faseeha Noordeen

Viruses 2025, 17(9), 1189; https://doi.org/10.3390/v17091189 - 29 Aug 2025

Abstract

A comprehensive analysis of the molecular epidemiology of SARS-CoV-2 in the Kandy District of Sri Lanka from November 2020 to March 2022 was conducted to address the limited genomic surveillance data available across the country. The study investigated the circulating SARS-CoV-2 lineages, their [...] Read more.

A comprehensive analysis of the molecular epidemiology of SARS-CoV-2 in the Kandy District of Sri Lanka from November 2020 to March 2022 was conducted to address the limited genomic surveillance data available across the country. The study investigated the circulating SARS-CoV-2 lineages, their temporal dynamics, and the associated mutational profiles in the study area. A total of 280 SARS-CoV-2-positive samples were selected, and 252 complete genomes were successfully sequenced using Oxford Nanopore Technology. Lineage classification was performed using the EPI2ME tool, while phylogenetic relationships were inferred through maximum likelihood and time-scaled phylogenetic trees using IQ-TREE2 and BEAST, respectively. Amino acid substitutions were analyzed to understand lineage-specific mutation patterns. Fifteen SARS-CoV-2 lineages were identified, and of those B.1.411 (36%) was the most prevalent, followed by Q.8 (21%), AY.28 (9.5%), and the Delta and Omicron variants. The lineage distribution showed a temporal shift from B.1.411 to Alpha, Delta, and finally the Omicron, mirroring the global trends. Time to the most recent common ancestor analyses provided estimates for the introduction of major variants, while mutation analysis revealed the widespread occurrence of D614G in the spike protein and lineage-specific mutations across structural, non-structural, and accessory proteins.Detection of the Epsilon variant (absent in other national-level studies) in November 2020, highlighted the regional heterogeneity viral spread. This study emphasizes the importance of localized genomic surveillance to capture the true diversity and evolution of SARS-CoV-2, to facilitate containment strategies in resource-limited settings. Full article

(This article belongs to the Section Coronaviruses)

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20 pages, 3751 KB

Open AccessArticle

Application of Bovine Nasal Epithelial Cells as an In Vitro Model for Studying Viral Infection in the Upper Respiratory Tract

by Malte Pitters, Henrik Fritsch, Ang Su, Klaus Jung and Paul Becher

Viruses 2025, 17(9), 1188; https://doi.org/10.3390/v17091188 - 29 Aug 2025

Abstract

Bovine respiratory disease complex (BRDC) is a multifactorial and globally prevalent condition involving a combination of viral and bacterial pathogens, as well as environmental stressors. Viral agents often initiate infections in the upper respiratory tract (URT), predisposing animals to secondary bacterial infections and [...] Read more.

Bovine respiratory disease complex (BRDC) is a multifactorial and globally prevalent condition involving a combination of viral and bacterial pathogens, as well as environmental stressors. Viral agents often initiate infections in the upper respiratory tract (URT), predisposing animals to secondary bacterial infections and severe clinical manifestations. Among the key viral contributors to BRDC are bovine viral diarrhea virus (BVDV) and bovine herpesvirus 1 (BHV-1). In this study, submerged liquid cultures of undifferentiated bovine nasal epithelial cells (BNECs) were employed to investigate mono- and co-infections with BVDV and BHV-1. Epithelial barrier integrity was assessed to evaluate the cytopathic effects of BHV-1, while viral replication and release were quantified. Both viruses demonstrated polarized release, and BHV-1 infection exhibited a pronounced cytopathic effect. Notably, a preceding BVDV infection did not alter the progression or outcome of BHV-1 infection in this in vitro model. These findings suggest that primary BNEC cultures represent a valuable and physiologically relevant tool for studying viral dynamics and interactions associated with BRDC. Full article

(This article belongs to the Special Issue Bovine Viral Diarrhea Viruses and Other Pestiviruses)

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17 pages, 639 KB

Open AccessReview

Gastrointestinal Infiltration in Influenza Virus Infection: Mechanisms and Clinical Insights

by Aakriti Dua, Bhavna Trehan, Shymaa E. Bilasy, Catherine Yang and Ahmed ElShamy

Viruses 2025, 17(9), 1187; https://doi.org/10.3390/v17091187 - 29 Aug 2025

Abstract

Background: Influenza, a primarily respiratory illness, frequently manifests with gastrointestinal (GI) symptoms including nausea, vomiting, diarrhea, and abdominal pain. In this review, we analyze mechanisms describing GI infiltration and subsequent involvement of the GI system during influenza infection. Direct mechanisms involve the [...] Read more.

Background: Influenza, a primarily respiratory illness, frequently manifests with gastrointestinal (GI) symptoms including nausea, vomiting, diarrhea, and abdominal pain. In this review, we analyze mechanisms describing GI infiltration and subsequent involvement of the GI system during influenza infection. Direct mechanisms involve the presence of viral particles in the GI tract and binding to sialic acid receptor, α2,3 and α2,6 linkages. The influenza virus may gain access to gut tissue via swallowing of respiratory secretions, hematogenous spread, or lymphocytic migration via the lung–gut axis. Indirect mechanisms involve immune system dysregulation via cytokine, interferon, and leukotriene flux, upregulation of consequential apoptotic pathways, or gut microbiome dysbiosis. Together, they promote secondary GI opportunistic infections. These findings improve our knowledge of GI infiltration during influenza infection which may aid in effective clinical diagnosis and treatment, ultimately improving patient outcomes. Full article

(This article belongs to the Special Issue Evolutionary Challenges of RNA Viruses: Insights from SARS-CoV-2 Variants and Emerging Respiratory Diseases)

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23 pages, 1289 KB

Open AccessArticle

Development and Clinical Validation of a Skin Test for In Vivo Assessment of SARS-CoV-2 Specific T-Cell Immunity

by Tikhon V. Savin, Vladimir V. Kopat, Elena D. Danilenko, Alexey A. Churin, Anzhelika M. Milichkina, Edward S. Ramsay, Ilya V. Dukhovlinov, Andrey S. Simbirtsev and Areg A. Totolian

Viruses 2025, 17(9), 1186; https://doi.org/10.3390/v17091186 - 29 Aug 2025

Abstract

A novel skin test for an in vivo assessment of SARS-CoV-2-specific T-cell immunity was developed using CoronaDermPS, a multiepitope recombinant polypeptide encompassing MHC II–binding CD4+ T-cell epitopes of the SARS-CoV-2 structural proteins (S, E, M) and full length nucleocapsid (N). In silico epitope [...] Read more.

A novel skin test for an in vivo assessment of SARS-CoV-2-specific T-cell immunity was developed using CoronaDermPS, a multiepitope recombinant polypeptide encompassing MHC II–binding CD4+ T-cell epitopes of the SARS-CoV-2 structural proteins (S, E, M) and full length nucleocapsid (N). In silico epitope prediction and modeling guided antigen design, which was expressed in Escherichia coli, was purified (>95% purity) and formulated for intradermal administration. Preclinical evaluation in guinea pigs, mice, and rhesus macaques demonstrated a robust delayed type hypersensitivity (DTH) response at optimal doses (10–75 µg), with no acute or chronic toxicity, mutagenicity, or adverse effects on reproductive organs. An integrated clinical analysis included 374 volunteers stratified by vaccination status (EpiVacCorona, Gam-COVID-Vac, CoviVac) prior to COVID-19 infection (Wuhan/Alpha, Delta, Omicron variants), and SARS-CoV-2–naïve controls. Safety assessments across phase I–II trials recorded 477 adverse events, of which >88% were mild and self-limiting; no severe or anaphylactic reactions occurred. DTH responses were measured at 24 h, 72 h, and 144 h post-injection by papule and hyperemia measurements. Overall, 282/374 participants (75.4%) exhibited a positive skin test. Receiver operating characteristic analysis yielded an overall AUC of 0.825 (95% CI: 0.726–0.924), sensitivity 79.5% (95% CI: 75.1–83.3%), and specificity 85.5% (95% CI: 81.8–88.7%), with comparable diagnostic accuracy across vaccine, and variant subgroups (AUC range 0.782–0.870). CoronaDerm-PS–based skin testing offers a simple, reproducible, and low-cost method for qualitative evaluation of T-cell–mediated immunity to SARS-CoV-2, independent of specialized laboratory equipment (Eurasian Patent No. 047119). Its high safety profile and consistent performance across diverse cohorts support its utility for mass screening and monitoring of cellular immune protection following infection or vaccination. Full article

(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)

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15 pages, 1263 KB

Open AccessArticle

Connecting the Evolution and Spread of Turkey Reovirus Across the United States: A Genomic Perspective

by Nakarin Pamornchainavakul, Jonathan T. Vannatta, Vikash K. Singh, Robert Porter, Sagar M. Goyal, Sunil K. Mor and Kimberly VanderWaal

Viruses 2025, 17(9), 1185; https://doi.org/10.3390/v17091185 - 29 Aug 2025

Abstract

A major cause of lameness in turkeys is reoviral arthritis, driven by turkey reovirus (TRV) infection. In the U.S., TRV was first isolated in the 1980s but re-emerged as a significant pathogen causing arthritis in 2011. Since then, TRV outbreaks have spread nationwide [...] Read more.

A major cause of lameness in turkeys is reoviral arthritis, driven by turkey reovirus (TRV) infection. In the U.S., TRV was first isolated in the 1980s but re-emerged as a significant pathogen causing arthritis in 2011. Since then, TRV outbreaks have spread nationwide across turkey-producing regions and have occasionally resulted in hepatitis-associated pathotypes. The absence of a consistently effective commercial vaccine continues to hinder disease control efforts. To better understand TRV’s evolutionary trajectory and transmission dynamics, we analyzed 211 complete TRV genome sequences collected across the U.S. from 2007 to 2021. Bayesian time-scaled phylogenetic and phylogeographic analyses were conducted for all ten genome segments to estimate gene flow among geographic regions, client groups, and pathotypes. The results reconstructed a coherent, decades-long history of TRV evolution, which revealed segment-specific differences in the evolutionary rates—particularly in S1c (σC protein coding region of S1) and M2—suggesting reassortment with other avian reoviruses during the 2011 emergence. Nationwide spread patterns indicated dominant transmission routes from the Eastern U.S. to Minnesota and from breeder to smallholder flocks, likely driven by inter-regional animal or feed movement via the multi-stage turkey production cycle. Pathotype transitions were more frequently observed from arthritis-associated strains to those causing hepatitis or cardiac lesions. These findings provide crucial insights to support national TRV control strategies and long-term monitoring by industry stakeholders. Full article

(This article belongs to the Special Issue Avian Reovirus)

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