Viruses

16 pages, 3112 KiB

Open AccessArticle

Persistent Type I Interferon Signaling Impairs Innate Lymphoid Cells During HIV-1 Infection Under Suppressive ART

by Runpeng Han, Haisheng Yu, Guangming Li, Lishan Su and Liang Cheng

Viruses 2025, 17(8), 1099; https://doi.org/10.3390/v17081099 - 8 Aug 2025

Persistent type I interferon (IFN-I) signaling compromises adaptive anti-HIV-1 T cell immunity and promotes viral reservoir persistence, yet its effects on innate lymphoid cells during chronic infection remain unclear. Through integrated single-cell RNA sequencing and functional validation in HIV-1-infected humanized mice with combination [...] Read more.

Persistent type I interferon (IFN-I) signaling compromises adaptive anti-HIV-1 T cell immunity and promotes viral reservoir persistence, yet its effects on innate lymphoid cells during chronic infection remain unclear. Through integrated single-cell RNA sequencing and functional validation in HIV-1-infected humanized mice with combination antiretroviral therapy (cART) and IFN-I signaling blockade, we reveal IFN-I-induced dysfunction of natural killer (NK) cells and group 3 innate lymphoid cells (ILC3s). Mechanistically, the IFN-I-CD9 axis drives NK cells toward a decidual NK cell-like phenotype, impairing their cytotoxic activity. Furthermore, IFNAR blockade rescues ILC3 functionality, which is critical for IL-17/IL-22-mediated antimicrobial defense and mucosal barrier maintenance. Our study delineates IFN-I-driven immunosuppression across innate lymphocyte compartments and proposes the targeted modulation of this pathway to enhance antiviral and mucosal immunity in HIV-1 management. Full article

(This article belongs to the Special Issue Interferon Signaling in Viral Pathogenesis)

15 pages, 2675 KiB

Open AccessArticle

Deficiency of IFNAR1 Increases the Production of Influenza Vaccine Viruses in MDCK Cells

by Qi Wang, Tuanjie Chen, Mengru Feng, Mei Zheng, Feixia Gao, Chenchen Qiu, Jian Luo and Xiuling Li

Viruses 2025, 17(8), 1097; https://doi.org/10.3390/v17081097 - 8 Aug 2025

Abstract

Cell culture-based influenza vaccines exhibit comparable safety and immunogenicity to traditional egg-based vaccines. However, improving viral yield remains a key challenge in optimizing cell culture-based production systems. Madin–Darby canine kidney (MDCK) cells, the predominant cell line for influenza vaccine production, inherently activate interferon [...] Read more.

Cell culture-based influenza vaccines exhibit comparable safety and immunogenicity to traditional egg-based vaccines. However, improving viral yield remains a key challenge in optimizing cell culture-based production systems. Madin–Darby canine kidney (MDCK) cells, the predominant cell line for influenza vaccine production, inherently activate interferon (IFN)-mediated antiviral defenses that restrict viral replication. To overcome this limitation, we employed CRISPR/Cas9 gene-editing technology to generate an IFN alpha/beta receptor subunit 1 (IFNAR1)-knockout (KO) adherent MDCK cell line. Viral titer analysis demonstrated significant enhancements in the yield of multiple vaccine strains (H1N1, H3N2, and type B) in IFNAR1-KO cells compared to wild-type (WT) cells. Transcriptomic profiling revealed marked downregulation of key interferon-stimulated genes (ISGs)—including OAS, MX2, and ISG15—within the IFNAR1-KO cells, indicating a persistent suppression of antiviral responses that established a more permissive microenvironment for influenza virus replication. Collectively, the engineered IFNAR1-KO cell line provides a valuable tool for influenza virus research and a promising strategy for optimizing large-scale MDCK cell cultures to enhance vaccine production efficiency. Full article

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

18 pages, 5221 KiB

Open AccessArticle

New Isolates of Betachloroviruses Shed Light on the Diversity and Biological Complexity of an Unexplored Group of Giant Algal Viruses

by Júlia W. Souza, Lethícia R. Henriques, Roger M. Carlson, Bruna B. F. Botelho, João Victor R. P. Carvalho, João Pedro N. Santos, Eric R. G. R. Aguiar, Irina V. Agarkova, James L. Van Etten, David D. Dunigan and Rodrigo A. L. Rodrigues

Viruses 2025, 17(8), 1096; https://doi.org/10.3390/v17081096 - 8 Aug 2025

Abstract

The majority of giant algal viruses belong to the family Phycodnaviridae, class Algavirales, phylum Nucleocytoviricota. Among them, the genus Chlorovirus is the most studied, with three recognized groups based on genomics and host range, although many fundamental questions remain to [...] Read more.

The majority of giant algal viruses belong to the family Phycodnaviridae, class Algavirales, phylum Nucleocytoviricota. Among them, the genus Chlorovirus is the most studied, with three recognized groups based on genomics and host range, although many fundamental questions remain to be elucidated, particularly regarding their diversity. In this study, we focus on betachloroviruses, a poorly explored subgroup that infects the alga Micractinium conductrix Pbi. Here, we describe the isolation and genomic analysis of 11 new betachloroviruses from water samples collected in Nebraska, USA. With 25 fully sequenced genomes now available, we assessed the genomic diversity of these viruses. They have double-stranded DNA genomes ranging from 295 to 374 kbp, encoding hundreds of ORFs, of which a large number (~40%) lack known function. Comparative genomics and phylogenetic analyses revealed three species of betachlorovirus, each with high intra-species genomic identity. Notably, some isolates with over 99.5% genomic identity display markedly different plaque phenotypes, which led us to propose the use of the term genomovar among giant algal viruses, a concept potentially applicable to other giant viral groups yet to be explored. Altogether, this work advances our understanding of betachloroviruses and highlights the importance of linking viral genotype to phenotype, opening new avenues for exploring the diversity of giant algal viruses. Full article

(This article belongs to the Special Issue Cyanophage and Algal Virus)

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28 pages, 3873 KiB

Open AccessArticle

Homologous and Heterologous Vaccination Regimens with mRNA and rVSV Platforms Induce Potent Immune Responses Against SFTSV Glycoprotein

by Tomaz B. Manzoni, Jonna B. Westover, Kendall A. Lundgreen, Philip D. Hicks, Raegan J. Petch, Jordan T. Ort, Drew Weissman, Steven H. Y. Fan, Scott E. Hensley, Norbert Pardi, Brian B. Gowen and Paul Bates

Viruses 2025, 17(8), 1095; https://doi.org/10.3390/v17081095 - 8 Aug 2025

Abstract

Background: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic bunyavirus with a high case-fatality ratio for which there is no approved vaccine. Studies have assessed different vaccine technologies. However, few studies have yet assessed the immunogenicity of heterologous prime-boost regimens. [...] Read more.

Background: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic bunyavirus with a high case-fatality ratio for which there is no approved vaccine. Studies have assessed different vaccine technologies. However, few studies have yet assessed the immunogenicity of heterologous prime-boost regimens. Methods: Here, we compare a lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA-based vaccine encoding the SFTSV glycoproteins, Gn and Gc, to our recently described recombinant VSV SFTSV (rVSV-SFTSV) vaccine in single dose, homologous, and heterologous prime-boost regimens in mice. Results: We show that all regimens protect from pathogenic SFTSV challenge and elicit strong long-lasting antibody responses. Furthermore, strong cellular immunity is elicited by mRNA-LNP immunizations and by heterologous immunization with an rVSV-SFTSV prime and mRNA-LNP boost. Cellular responses robustly polarized towards a type 1 response, characterized by high levels of IFNγ, TNFα, and IL-2. Immunization with mRNA led to a mixed type 1/type 2 immune response, as determined by antibody isotypes IgG1 and IgG2c. We found that homologous immunization leads to stronger antibody responses while heterologous immunization drives a slightly stronger cellular response. Conclusions: Taken together, the vaccine platforms described here represent strong vaccine candidates for further development. Full article

(This article belongs to the Special Issue Severe Fever with Thrombocytopenia Syndrome Virus 2025)

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37 pages, 3266 KiB

Open AccessReview

Phage Therapy: Combating Evolution of Bacterial Resistance to Phages

by Stephen T. Abedon

Viruses 2025, 17(8), 1094; https://doi.org/10.3390/v17081094 - 8 Aug 2025

Abstract

Treatments for bacterial infections can be less effective due to toxicities, bacterial tolerance, or genetic resistance to antibacterial agents. The emphasis here is on combating genetic bacterial resistance to bacteriophages. Commonly described simply as phages, bacteriophages are the viruses of bacteria. As phage [...] Read more.

Treatments for bacterial infections can be less effective due to toxicities, bacterial tolerance, or genetic resistance to antibacterial agents. The emphasis here is on combating genetic bacterial resistance to bacteriophages. Commonly described simply as phages, bacteriophages are the viruses of bacteria. As phage therapies, they are one of the oldest clinical treatments for bacterial infections. Thwarting bacterial evolution of resistance to phages, particularly during phage treatments, typically involves targeting more than one bacterial characteristic. This can be achieved serially, involving phage substitution after bacterial resistance has become problematic, something that is used especially during more personalized therapies. Substitution phages can be sourced in various ways. This includes as autophages, from phage banks, or via phage training—all as considered here—as well as through phage engineering. An alternative approach is preventing bacterial mutations from occurring at all. In addition, there is simultaneous targeting of multiple bacterial characteristics. These latter strategies include all of the following: using phages that target bacterial fitness or virulence determinants, employing individual phages that recognize multiple receptors, using phage cocktails, or applying phages in combination with antibiotics. This review discusses these different approaches for combating treatment resistance, highlighting various pros and cons. Full article

(This article belongs to the Collection Phage Therapy)

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15 pages, 959 KiB

Open AccessArticle

Hemophagocytic Lymphohistiocytosis Gene Variants in Severe COVID-19 Cytokine Storm Syndrome

by Abhishek Kamath, Mingce Zhang, Devin M. Absher, Lesley E. Jackson, Walter Winn Chatham and Randy Q. Cron

Viruses 2025, 17(8), 1093; https://doi.org/10.3390/v17081093 - 8 Aug 2025

Abstract

Severe COVID-19 infection resulting in hospitalization shares features with cytokine storm syndromes (CSSs) such as hemophagocytic lymphohistiocytosis (HLH). Various published criteria were explored to define CSS among patients (n = 32) enrolled in a COVID-19 clinical trial. None of the patients met HLH-04 [...] Read more.

Severe COVID-19 infection resulting in hospitalization shares features with cytokine storm syndromes (CSSs) such as hemophagocytic lymphohistiocytosis (HLH). Various published criteria were explored to define CSS among patients (n = 32) enrolled in a COVID-19 clinical trial. None of the patients met HLH-04 or HScore criteria, but the ferritin to erythrocyte sedimentation rate (ferritin–ESR) ratio and the COVID-19 cytokine storm score (CSs) identified 84% and 81% of patients, respectively. As 30–40% of patients in published secondary HLH cohorts possess rare heterozygous mutations in familial HLH (fHLH) genes, whole genome sequencing was undertaken to explore immunologic gene mutation associations among 20 patients enrolled in the trial. Rare mutations in fHLH genes were identified in 6 patients (30%), and 4 patients (20%) possessed rare mutations in DOCK8 (a novel CSS gene). Foamy viral transduction of the 3 DOCK8 missense mutations into NK-92 natural killer (NK) cells diminished NK cell cytolytic function, a feature of HLH. This severe COVID-19 cohort, like others, shares CSS features but is best identified by the ferritin–ESR ratio. Rare heterozygous CSS gene (fHLH genes and DOCK8) mutations were frequently (45%) identified in this severe COVID-19 cohort, and DOCK8 missense mutations may contribute to CSS via diminished lymphocyte cytolytic activity. Full article

(This article belongs to the Section Coronaviruses)

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15 pages, 3221 KiB

Open AccessArticle

Development of a Deer Tick Virus Infection Model in C3H/HeJ Mice to Mimic Human Clinical Outcomes

by Dakota N. Paine, Erin S. Reynolds, Charles E. Hart, Jessica Crooker and Saravanan Thangamani

Viruses 2025, 17(8), 1092; https://doi.org/10.3390/v17081092 - 7 Aug 2025

Abstract

Deer tick virus (DTV) is a Tick-Borne Orthoflavivirus endemic to the United States, transmitted to humans through bites from the deer tick, Ixodes scapularis, which is also the primary vector of Borrelia burgdorferi s.l., the causative agent of Lyme disease. Human [...] Read more.

Deer tick virus (DTV) is a Tick-Borne Orthoflavivirus endemic to the United States, transmitted to humans through bites from the deer tick, Ixodes scapularis, which is also the primary vector of Borrelia burgdorferi s.l., the causative agent of Lyme disease. Human infection with DTV can result in acute febrile illness followed by central nervous system complications, such as encephalitis and meningoencephalitis. Currently, there are mouse models established for investigating the pathogenesis and clinical outcomes of DTV that mimic human infections, but the strains of mice utilized are refractory to infection with B. burgdorferi s.l. Here, we describe the pathogenesis and clinical outcomes of DTV infection in C3H/HeJ mice. Neurological clinical signs, mortality, and weight loss were observed in all DTV-infected mice during the investigation. Infected animals demonstrated consistent viral infection in their organs. Additionally, neuropathology of brain sections indicated the presence of meningoencephalitis throughout the brain. This data, along with the clinical outcomes for the mice, indicates successful infection and showcases the neuroinvasive nature of the virus. This is the first study to identify C3H/HeJ mice as an appropriate model for DTV infection. As C3H/HeJ mice are already an established model for B. burgdorferi s.l. infection, this model could serve as an ideal system for investigating disease progression and pathogenesis of co-infections. Full article

(This article belongs to the Special Issue Tick-Borne Viruses 2026)

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18 pages, 1307 KiB

Open AccessArticle

Unveiling a Shift in the Rotavirus Strains in Benin: Emergence of Reassortment Intergenogroup and Equine-like G3P[8] Strains in the Post-Vaccination Era

by Jijoho M. Agbla, Milton T. Mogotsi, Alban G. Zohoun, Nkosazana D. Shange, Annick Capochichi, Ayodeji E. Ogunbayo, Rolande Assogba, Shainey Khakha, Aristide Sossou, Hlengiwe Sondlane, Jason M. Mwenda, Mathew D. Esona and Martin M. Nyaga

Viruses 2025, 17(8), 1091; https://doi.org/10.3390/v17081091 - 7 Aug 2025

Abstract

While a global downward trend in rotavirus diarrhea cases has been observed following vaccine introduction, reassortment, genetic drift, and vaccine-escaping strains remain a concern, particularly in Sub-Saharan Africa. Here, we provide genomic insights into three equine-like G3P[8] rotavirus strains detected in Benin during [...] Read more.

While a global downward trend in rotavirus diarrhea cases has been observed following vaccine introduction, reassortment, genetic drift, and vaccine-escaping strains remain a concern, particularly in Sub-Saharan Africa. Here, we provide genomic insights into three equine-like G3P[8] rotavirus strains detected in Benin during the post-vaccine era. Whole-genome sequencing was performed using the Illumina MiSeq platform, and genomic analysis was conducted using bioinformatics tools. The G3 of the study strains clustered within the recently described lineage IX, alongside the human-derived equine-like strain D388. The P[8] is grouped within the lineage III, along with cognate strains from the GenBank database. Both the structural and non-structural gene segments of these study strains exhibited genetic diversity, highlighting the ongoing evolution of circulating strains. Notably, we identified a novel NSP2 lineage, designated NSP2-lineage VI. Amino acid comparisons of the G3 gene showed two conservative substitutions at positions 156 (A156V) and 260 (I260V) and one radical substitution at position 250 (K250E) relative to the prototype equine-like strain D388, the equine strain Erv105, and other non-equine-like strains. In the P[8] gene, three conservative (N195G, N195D, N113D) and one radical (D133N) substitutions were observed when compared with vaccine strains Rotarix and RotaTeq. These findings suggest continuous viral evolution, potentially driven by vaccine pressure. Ongoing genomic surveillance is essential to monitor genotype shifts as part of the efforts to evaluate the impact of emerging strains and to assess vaccine effectiveness in Sub-Saharan Africa. Full article

(This article belongs to the Section General Virology)

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19 pages, 2642 KiB

Open AccessArticle

Lipid Nanoparticle-Encapsulated TALEN-Encoding mRNA Inactivates Hepatitis B Virus Replication in Cultured Cells and Transgenic Mice

by Tiffany Smith, Prashika Singh, Ridhwaanah Bhana, Dylan Kairuz, Kristie Bloom, Mohube Betty Maepa, Abdullah Ely and Patrick Arbuthnot

Viruses 2025, 17(8), 1090; https://doi.org/10.3390/v17081090 - 7 Aug 2025

Abstract

Chronic infection with the hepatitis B virus (HBV) results in over 1 million deaths annually. Although currently licensed treatments, including pegylated interferon-α and nucleoside/nucleotide analogs, can inhibit viral replication, they rarely eradicate covalently closed circular DNA (cccDNA) reservoirs. Moreover, vaccination does not offer [...] Read more.

Chronic infection with the hepatitis B virus (HBV) results in over 1 million deaths annually. Although currently licensed treatments, including pegylated interferon-α and nucleoside/nucleotide analogs, can inhibit viral replication, they rarely eradicate covalently closed circular DNA (cccDNA) reservoirs. Moreover, vaccination does not offer therapeutic benefit to already infected individuals or non-responders. Consequently, chronic infection is maintained by the persistence of cccDNA in infected hepatocytes. For this reason, novel therapeutic strategies that permanently inactivate cccDNA are a priority. Obligate heterodimeric transcription activator-like effector nucleases (TALENs) provide the precise gene-editing needed to disable cccDNA. To develop this strategy using a therapeutically relevant approach, TALEN-encoding mRNA targeting viral core and surface genes was synthesized using in vitro transcription with co-transcriptional capping. TALENs reduced hepatitis B surface antigen (HBsAg) by 80% in a liver-derived mammalian cell culture model of infection. In a stringent HBV transgenic murine model, a single dose of hepatotropic lipid nanoparticle-encapsulated TALEN mRNA lowered HBsAg by 63% and reduced viral particle equivalents by more than 99%, without evidence of toxicity. A surveyor assay demonstrated mean in vivo HBV DNA mutation rates of approximately 16% and 15% for Core and Surface TALENs, respectively. This study presents the first evidence of the therapeutic potential of TALEN-encoding mRNA to inactivate HBV replication permanently. Full article

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

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24 pages, 3149 KiB

Open AccessArticle

Evaluation of Aggregate Oral Fluid Sampling for Early Detection of African Swine Fever Virus Infection

by Bonto Faburay, Kathleen O’Hara, Marta Remmenga, Theophilus Odoom, Sherry Johnson, William Tasiame, Matilda Ayim-Akonor, Benita Anderson, Kingsley Kwabena Amoako, Diane Holder, Wu Ping, Michelle Zajac, Vivian O’Donnell, Lizhe Xu, Robin Holland, Corrie Brown, Randall Levings and Suelee Robbe-Austerman

Viruses 2025, 17(8), 1089; https://doi.org/10.3390/v17081089 - 6 Aug 2025

Abstract

African swine fever (ASF) needs to be controlled, and prevention of the spread of African swine fever virus (ASFV) is dependent on enhanced surveillance and early disease detection. Commercial swine operations, especially in North America, Europe, and Asia, are characterized by comparatively large [...] Read more.

African swine fever (ASF) needs to be controlled, and prevention of the spread of African swine fever virus (ASFV) is dependent on enhanced surveillance and early disease detection. Commercial swine operations, especially in North America, Europe, and Asia, are characterized by comparatively large numbers of pigs, and sampling individual pigs, which represents the main strategy for current ASF surveillance, can be both costly and labor intensive. A study performed in Ghana was designed to estimate the diagnostic sensitivity of pen-based aggregate oral fluid testing for ASFV in infected pigs in a pen of 30 animals and to evaluate its utility as a tool to support surveillance of ASF in the US. This study was performed in three phases: (i) virus (Ghana ASFV24) amplification in a target host species to generate the challenge inoculum; (ii) titration of the inoculum (10% spleen homogenate) in target host species to determine the minimum dose inducing acute ASF in pigs with survival up to 5–6 days post-inoculation (dpi); and (iii) the main study, involving 186 pigs, consisting of 6 replicates of 30 pigs per pen and one seeder pig inoculated with wildtype ASFV (highly virulent genotype II) per pen. Daily sampling of aggregate oral fluids, uncoagulated blood, oropharyngeal swabs, fecal and water nipple swabs, and recording of rectal temperatures and clinical observations was carried out. The seeder pigs were each inoculated intramuscularly with 0.5 mL of the 10% spleen homogenate, which induced the desired clinical course of ASF in the pigs, with survival of up to 6 dpi. ASFV DNA was detected in the seeder pigs as early as 1 dpi and 2 dpi in the blood and oropharyngeal swabs, respectively. Transmission of ASFV from the seeder pigs to the contact pig population was detected via positive amplification of ASFV DNA in aggregate oral fluid samples at 3 days post-contact (dpc) in 4 out of 6 pens, and in all 6 pens, at 4 dpc. Testing of oropharyngeal swabs and blood samples from individual pigs revealed a variable number of ASFV-positive pigs between 3 and 5 dpc, with detection of 100% positivity between 6 and 18 dpc, the study endpoint. These findings demonstrate the potential utility of aggregate oral fluid sampling for sensitive and early detection of ASFV incursion into naïve swine herds. It also demonstrates that testing of environmental samples from the premises could further enhance overall ASF early detection and surveillance strategies. Full article

(This article belongs to the Collection African Swine Fever Virus (ASFV))

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24 pages, 10760 KiB

Open AccessArticle

Pseudomonas Phage Banzai: Genomic and Functional Analysis of Novel Pbunavirus with Lytic Activity Against Pseudomonas aeruginosa

by Andrei V. Chaplin, Nina N. Sykilinda, George A. Skvortsov, Konstantin S. Troshin, Anna A. Vasilyeva, Sofia A. Shuraleva, Artem A. Malkov, Vladislav S. Simonov, Boris A. Efimov, Lyudmila I. Kafarskaia, Konstantin A. Miroshnikov, Anna A. Kuznetsova and Peter V. Evseev

Viruses 2025, 17(8), 1088; https://doi.org/10.3390/v17081088 - 6 Aug 2025

Abstract

Antibiotic-resistant Pseudomonas aeruginosa presents a critical global health challenge, particularly in hospital-acquired infections. Bacteriophages offer a promising therapeutic avenue due to their ability to target and lyse resistant strains. This study characterizes Pseudomonas phage Banzai, a newly isolated Pbunavirus (family Lindbergviridae) with [...] Read more.

Antibiotic-resistant Pseudomonas aeruginosa presents a critical global health challenge, particularly in hospital-acquired infections. Bacteriophages offer a promising therapeutic avenue due to their ability to target and lyse resistant strains. This study characterizes Pseudomonas phage Banzai, a newly isolated Pbunavirus (family Lindbergviridae) with lytic activity against multiple P. aeruginosa isolates, including multidrug-resistant strains. Genomic analysis revealed a 66,189 bp genome, lacking antibiotic resistance or virulence factors, and suggested a headful packaging mechanism and the presence of a bidirectional component in the replication. In vivo experiments using Galleria mellonella showed therapeutic potential, significantly improving larval survival (87% at 24 h). Host range analysis revealed activity against 13 of 30 P. aeruginosa isolates, including members of O1, O3, O5 and O6 in silico predicted serogroups. Phylogenomic analyses place phage Banzai within the genus Pbunavirus, sharing 94.8% intergenomic similarity with its closest relatives, supporting its classification as a novel species. These findings highlight phage Banzai as a potential candidate for phage therapy, demonstrating genomic stability, a strictly lytic lifestyle, and in vivo efficacy. Full article

(This article belongs to the Section Bacterial Viruses)

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22 pages, 1582 KiB

Open AccessSystematic Review

The Magnitude and Patterns of Acquired Drug Resistance Mutations and Circulating HIV-1 Subtypes in HIV Patients in Tanzania, a Systematic Review and Meta-Analysis

by Shimba Henerico, Christa Kasang, Benson R. Kidenya, Deodatus Sabas, Violet D. Kajogoo, Gert Van Zyl, Wolfgang Preiser, Stephen E. Mshana and Samuel E. Kalluvya

Viruses 2025, 17(8), 1087; https://doi.org/10.3390/v17081087 - 6 Aug 2025

Abstract

The emergence and spread of HIV drug resistance mutations (DRMs) pose a threat to current and future treatment options. To inform policy, this review aimed to determine the magnitude and patterns of DRMs in patients on ART in Tanzania. A systematic literature search [...] Read more.

The emergence and spread of HIV drug resistance mutations (DRMs) pose a threat to current and future treatment options. To inform policy, this review aimed to determine the magnitude and patterns of DRMs in patients on ART in Tanzania. A systematic literature search was conducted in MEDLINE through PubMed, Embase, and CINAHL up to December 2024. A total of 9685 HIV patients from 23 eligible studies were analyzed. The prevalence of virological failure in studies that used a threshold of >1000 and >400 copies/mL was 24.83% (95% CI: 17.85–32.53%) and 36.94% (95% CI: 24.79–50.00%), respectively. Major DRMs were observed at 87.61% (95% CI: 76.25–95.91%). A decrease in prevalence was observed in studies conducted from 2019, with a pooled prevalence of 62.15% (95% CI: 31.57–88.33%). The most frequently observed HIV-1 subtypes were subtype C at 36.20% (95% CI: 30.71–41.85%), A1 at 33.13% (95% CI: 28.23–38.20%), and subtype D at 16.00% (95% CI: 11.41–21.12%), while recombinant forms of the virus were observed at 13.29% (95% CI: 9.79–17.17%). The prevalence of DRMs against NRTIs and NNRTIs was significantly high, while that against INSTIs and PIs was low, supporting the continued use of PI- and INSTI-based regimens in Tanzania and the need for continued surveillance of DRMs. Full article

(This article belongs to the Special Issue Antiviral Resistance Mutations)

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15 pages, 1302 KiB

Open AccessArticle

Screening of Medicinal Herbs Identifies Cimicifuga foetida and Its Bioactive Component Caffeic Acid as SARS-CoV-2 Entry Inhibitors

by Ching-Hsuan Liu, Yu-Ting Kuo, Chien-Ju Lin, Feng-Lin Yen, Shu-Jing Wu and Liang-Tzung Lin

Viruses 2025, 17(8), 1086; https://doi.org/10.3390/v17081086 - 5 Aug 2025

Abstract

The emergence of SARS-CoV-2 variants highlights the urgent need for novel therapeutic strategies, particularly entry inhibitors that could efficiently prevent viral infection. Medicinal herbs and herbal combination formulas have long been recognized for their effects in treating infectious diseases and their antiviral properties, [...] Read more.

The emergence of SARS-CoV-2 variants highlights the urgent need for novel therapeutic strategies, particularly entry inhibitors that could efficiently prevent viral infection. Medicinal herbs and herbal combination formulas have long been recognized for their effects in treating infectious diseases and their antiviral properties, thus providing abundant resources for the discovery of antiviral candidates. While many candidates have been suggested to have antiviral activity against SARS-CoV-2 infection, few have been validated for their mechanisms, including possible effects on viral entry. This study aimed to identify SARS-CoV-2 entry inhibitors from medicinal herbs and herbal formulas that are known for heat-clearing and detoxifying properties and/or antiviral activities. A SARS-CoV-2 pseudoparticle (SARS-CoV-2pp) system was used to assess mechanism-specific entry inhibition. Our results showed that the methanol extract of Anemarrhena asphodeloides rhizome, as well as the water extracts of Cimicifuga foetida rhizome, Xiao Chai Hu Tang (XCHT), and Sheng Ma Ge Gen Tang (SMGGT), have substantial inhibitory effects on the entry of SARS-CoV-2pps into host cells. Given the observation that Cimicifuga foetida exhibited the most potent inhibition and is a constituent of SMGGT, we further investigated the major compounds of the herb and identified caffeic acid as a bioactive component for blocking SARS-CoV-2pp entry. Entry inhibition of Cimicifuga foetida and caffeic acid was validated on both wild-type and the currently dominant JN.1 strain SARS-CoV-2pp systems. Moreover, caffeic acid was able to both inactivate the pseudoparticles and prevent their entry into pretreated host cells. The results support the traditional use of these herbal medicines and underscore their potential as valuable resources for identifying active compounds and developing therapeutic entry inhibitors for the management of COVID-19. Full article

(This article belongs to the Section Coronaviruses)

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17 pages, 1472 KiB

Open AccessArticle

Single-Dose Intranasal or Intramuscular Administration of Simian Adenovirus-Based H1N1 Vaccine Induces a Robust Humoral Response and Complete Protection in Mice

by Daria V. Voronina, Irina V. Vavilova, Olga V. Zubkova, Tatiana A. Ozharovskaia, Olga Popova, Anastasia S. Chugunova, Polina P. Goldovskaya, Denis I. Zrelkin, Daria M. Savina, Irina A. Favorskaya, Dmitry V. Shcheblyakov, Denis Y. Logunov and Alexandr L. Gintsburg

Viruses 2025, 17(8), 1085; https://doi.org/10.3390/v17081085 - 5 Aug 2025

Abstract

Despite the widespread accessibility of vaccines and antivirals, seasonal influenza virus epidemics continue to pose a threat to public health. In this study, we constructed a recombinant replication-deficient simian adenovirus type 25 vector carrying the full-length hemagglutinin (HA) of the H1N1 influenza virus, [...] Read more.

Despite the widespread accessibility of vaccines and antivirals, seasonal influenza virus epidemics continue to pose a threat to public health. In this study, we constructed a recombinant replication-deficient simian adenovirus type 25 vector carrying the full-length hemagglutinin (HA) of the H1N1 influenza virus, named rSAd25-H1. Both systemic and mucosal humoral immune responses, as well as the protective efficacy, were assessed in mice immunized via the intramuscular (IM) or intranasal (IN) route. A single-dose IM or IN administration of rSAd25-H1 elicited a robust systemic IgG antibody response, including hemagglutination inhibition antibodies. As expected, only IN immunization was able to induce IgA production in serum and respiratory mucosa. Notably, a single dose of rSAd25-H1 at the highest dose (10¹⁰ viral particles) conferred complete protection against lethal homologous H1N1 challenge in mice despite the route of administration. These findings demonstrate the potential of simian adenovirus type 25-based vectors as a promising candidate for intranasal vaccine development targeting respiratory pathogens. Full article

(This article belongs to the Special Issue Influenza, SARS-CoV-2, RSV and Other Vaccines: Immunogenicity Parameters and Protection, 3rd Edition)

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14 pages, 1669 KiB

Open AccessArticle

Guinea Pig X Virus Is a Gammaherpesvirus

by Vy Ngoc Yen Truong, Robert Ellis and Brent A. Stanfield

Viruses 2025, 17(8), 1084; https://doi.org/10.3390/v17081084 - 5 Aug 2025

Abstract

The Guinea Pig X Virus (GPXV), a newly identified gammaherpesvirus, provides an opportunity to study viral evolution and host–virus dynamics. This study characterizes the GPXV genome and investigates its phylogenetic relationships and divergence from related viruses through comparative genomic and phylogenetic analyses. Virus [...] Read more.

The Guinea Pig X Virus (GPXV), a newly identified gammaherpesvirus, provides an opportunity to study viral evolution and host–virus dynamics. This study characterizes the GPXV genome and investigates its phylogenetic relationships and divergence from related viruses through comparative genomic and phylogenetic analyses. Virus propagation was conducted in Vero cells, followed by genomic DNA extraction and pan-herpesvirus nested PCR. Sanger sequencing filled gaps in the initial genome assembly, and whole-genome sequencing was performed using the Illumina MiSeq platform. Phylogenetic analyses focused on ORF8 (glycoprotein B), ORF9 (DNA polymerase catalytic subunit), ORF50 (RTA: replication and transcription activator), and ORF73 (LANA: latency-associated nuclear antigen). Results showed that GPXV ORFs showed variable evolutionary relationships with other gammaherpesviruses, including divergence from primate-associated viruses and clustering with bovine and rodent viruses. In addition to phylogenetics, a comprehensive comparative analysis of protein-coding genes between GPXV and the previously described Guinea Pig Herpes-Like Virus (GPHLV) revealed divergence. Twenty-four non-ORF genomic features were unique to GPXV, while 62 shared ORFs exhibited low to high sequence divergence. These findings highlight GPXV’s distinct evolutionary trajectory and its potential role as a model for studying host-specific adaptations and gammaherpesvirus diversity. Full article

(This article belongs to the Special Issue Animal Herpesvirus 2025)

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16 pages, 4746 KiB

Open AccessArticle

SARS-CoV-2 Nsp1 Is a Major Suppressor of HLA Class I and Class II Expression

by Ivo Schirmeister, Nicolas Eckert, Sebastian Weigang, Jonas Fuchs, Lisa Kern, Georg Kochs and Anne Halenius

Viruses 2025, 17(8), 1083; https://doi.org/10.3390/v17081083 - 5 Aug 2025

Abstract

Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 [...] Read more.

Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition. Full article

(This article belongs to the Section Coronaviruses)

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18 pages, 3120 KiB

Open AccessArticle

Měnglà Virus VP40 Localizes to the Nucleus and Impedes the RIG-I Signaling Pathway

by Joyce Sweeney Gibbons, Naveen Thakur, Emma Komers, Olivia A. Vogel, Poushali Chakraborty, JoAnn M. Tufariello and Christopher F. Basler

Viruses 2025, 17(8), 1082; https://doi.org/10.3390/v17081082 - 5 Aug 2025

Abstract

Měnglà virus (MLAV) is a member of the genus Dianlovirus in the family Filoviridae, which also includes Ebola virus (EBOV) and Marburg virus (MARV). Whether MLAV poses a threat to human health is uncertain. However, the MLAV VP35 and VP40 proteins can impair [...] Read more.

Měnglà virus (MLAV) is a member of the genus Dianlovirus in the family Filoviridae, which also includes Ebola virus (EBOV) and Marburg virus (MARV). Whether MLAV poses a threat to human health is uncertain. However, the MLAV VP35 and VP40 proteins can impair IFNα/β gene expression and block IFNα/β-induced Jak-STAT signaling, respectively, suggesting the capacity to counteract human innate immune defenses. In this study, MLAV VP40 is demonstrated to impair the Sendai virus (SeV)-induced activation of the IFNβ promoter. Inhibition is independent of the MLAV VP40 PPPY late-domain motif that interacts with host proteins possessing WW-domains to promote viral budding. Similar IFNβ promoter inhibition was not detected for EBOV or MARV VP40. MLAV VP40 exhibited lesser capacity to inhibit TNFα activation of an NF-κB reporter gene. MLAV VP40 impaired IFNβ promoter activation by an over-expressed, constitutively active form of RIG-I and by the over-expressed IRF3 kinases TBK1 and IKKε. However, MLAV VP40 did not inhibit IFNβ promoter activation by constitutively active IRF3 5D. Consistent with these findings, MLAV VP40 inhibited SeV-induced IRF3 phosphorylation. Although IRF3 phosphorylation occurs in the cytoplasm, MLAV VP40 exhibits substantial nuclear localization, accumulating in foci in HeLa cell nuclei. In contrast, the VP40 of EBOV and MARV exhibited lower degrees of nuclear localization and did not accumulate in foci. MLAV VP40 interacts with importin alpha-1 (IMPα1), suggesting entry via the IMPα/IMPβ nuclear import pathway. Cumulatively, these data identify novel features that distinguish MLAV VP40 from its homologues in EBOV and MARV. Full article

(This article belongs to the Section Animal Viruses)

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14 pages, 2266 KiB

Open AccessArticle

PCV2 Infection Upregulates SOCS3 Expression to Facilitate Viral Replication in PK-15 Cells

by Yiting Li, Hongmei Liu, Yi Wu, Xiaomei Zhang, Juan Geng, Xin Wu, Wengui Li, Zhenxing Zhang, Jianling Song, Yifang Zhang and Jun Chai

Viruses 2025, 17(8), 1081; https://doi.org/10.3390/v17081081 - 5 Aug 2025

Abstract

Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests [...] Read more.

Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests that certain viruses exploit Suppressor of Cytokine Signaling 3 (SOCS3), a key immune checkpoint protein, to subvert host innate immunity by suppressing cytokine signaling. While SOCS3 has been implicated in various viral infections, its regulatory role in PCV2 replication remains undefined. This study aims to elucidate the mechanisms underlying the interplay between SOCS3 and PCV2 during viral pathogenesis. Porcine SOCS3 was amplified using RT-PCR and stably overexpressed in PK-15 cells through lentiviral delivery. Bioinformatics analysis facilitated the design of three siRNA candidates targeting SOCS3. We systematically investigated the effects of SOCS3 overexpression and knockdown on PCV2 replication kinetics and host antiviral responses by quantifying the viral DNA load and the mRNA levels of cytokines. PCV2 infection upregulated SOCS3 expression at both transcriptional and translational levels in PK-15 cells. Functional studies revealed that SOCS3 overexpression markedly enhanced viral replication, whereas its knockdown suppressed viral proliferation. Intriguingly, SOCS3-mediated immune modulation exhibited a divergent regulation of antiviral cytokines: PCV2-infected SOCS3-overexpressing cells showed elevated IFN-β but suppressed TNF-α expressions, whereas SOCS3 silencing conversely downregulated IFN-β while amplifying TNF-α responses. This study unveils a dual role of SOCS3 during subclinical porcine circovirus type 2 (PCV2) infection: it functions as a host-derived pro-viral factor that facilitates viral replication while simultaneously reshaping the cytokine milieu to suppress overt inflammatory responses. These findings provide novel insights into the mechanisms underlying PCV2 immune evasion and persistence and establish a theoretical framework for the development of host-targeted control strategies. Although our results identify SOCS3 as a key host determinant of PCV2 persistence, the precise molecular pathways involved require rigorous experimental validation. Full article

(This article belongs to the Section Animal Viruses)

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24 pages, 1028 KiB

Open AccessReview

Biocontrol of Phage Resistance in Pseudomonas Infections: Insights into Directed Breaking of Spontaneous Evolutionary Selection in Phage Therapy

by Jumpei Fujiki, Daigo Yokoyama, Haruka Yamamoto, Nana Kimura, Manaho Shimizu, Hinatsu Kobayashi, Keisuke Nakamura and Hidetomo Iwano

Viruses 2025, 17(8), 1080; https://doi.org/10.3390/v17081080 - 4 Aug 2025

Abstract

Phage therapy, long overshadowed by antibiotics in Western medicine, has a well-established history in some Eastern European countries and is now being revitalized as a promising strategy against antimicrobial resistance (AMR). This resurgence of phage therapy is driven by the urgent need for [...] Read more.

Phage therapy, long overshadowed by antibiotics in Western medicine, has a well-established history in some Eastern European countries and is now being revitalized as a promising strategy against antimicrobial resistance (AMR). This resurgence of phage therapy is driven by the urgent need for innovative countermeasures to AMR, which will cause an estimated 10 million deaths annually by 2050. However, the emergence of phage-resistant variants presents challenges similar to AMR, thus necessitating a deeper understanding of phage resistance mechanisms and control strategies. The highest priority must be to prevent the emergence of phage resistance. Although phage cocktails targeting multiple receptors have demonstrated a certain level of phage resistance suppression, they cannot completely suppress resistance in clinical settings. This highlights the need for strategies beyond simple resistance suppression. Notably, recent studies examining fitness trade-offs associated with phage resistance have opened new avenues in phage therapy that offer the potential of restoring antibiotic susceptibility and attenuating pathogen virulence despite phage resistance. Thus, controlling phage resistance may rely on both its suppression and strategic redirection. This review summarizes key concepts in the control of phage resistance and explores evolutionary engineering as a means of optimizing phage therapy, with a particular focus on Pseudomonas infections. Harnessing evolutionary dynamics by intentionally breaking the spontaneous evolutionary trajectories of target bacterial pathogens could potentially reshape bacterial adaptation by acquisition of phage resistance, unlocking potential in the application of phage therapy. Full article

(This article belongs to the Section Bacterial Viruses)

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