Viruses

15 pages, 453 KiB

Open AccessReview

Safety, Tolerability, and Metabolic Effects of Long-Acting Cabotegravir and Rilpivirine in HIV Care: A Comprehensive Review

by Martina Bottanelli, Antonella Castagna and Camilla Muccini

Viruses 2025, 17(8), 1108; https://doi.org/10.3390/v17081108 - 12 Aug 2025

Abstract

The use of long-acting cabotegravir and rilpivirine (LA CAB/RPV) is a novel approach to manage human immunodeficiency virus (HIV). This injectable regimen offers benefits such as an improved quality of life, reduced stigma and enhanced treatment satisfaction by minimising the need for daily [...] Read more.

The use of long-acting cabotegravir and rilpivirine (LA CAB/RPV) is a novel approach to manage human immunodeficiency virus (HIV). This injectable regimen offers benefits such as an improved quality of life, reduced stigma and enhanced treatment satisfaction by minimising the need for daily medication adherence. This review summarises the findings of clinical trials and real-world studies on the safety, tolerability and metabolic effects of LA CAB/RPV, which are areas that have received less extensive coverage in previous reviews. Clinical trial data suggest that LA CAB/RPV is generally safe and well tolerated. The most common side effects were injection site reactions, affecting 70–97% of participants. However, these were typically mild and short lived, rarely leading to treatment discontinuation in fewer than 2–3% of cases. Systemic side effects were minimal and comparable to those observed with traditional oral antiretroviral therapy. Real-world studies corroborated these findings, reporting low discontinuation rates due to adverse events. Regarding metabolic impact, clinical trials showed minimal weight gain (an average increase of 1–2 kg over 48–96 weeks) with no significant differences or impact on lipid and glucose levels. Although real-world data are still emerging, they suggest similar trends, including a possible improvement in lipid profiles. Overall, LA CAB/RPV appears to be a safe, well-tolerated and effective treatment option, although longer-term follow-up is needed. Full article

(This article belongs to the Special Issue Long-Acting Antiretrovirals)

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11 pages, 328 KiB

Open AccessArticle

Seroprevalence of Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) Among Blood Donors in Borgou, Benin in 2023: A Cross-Sectional Study

by Kamel-Dine Djaliri, Brice Boris Legba, Victorien Dougnon, Abdelsalam Tidjani and Lamine Baba-Moussa

Viruses 2025, 17(8), 1107; https://doi.org/10.3390/v17081107 - 12 Aug 2025

Abstract

Blood transfusion remains vital in healthcare but poses risks, particularly from transfusion-transmissible viral infections (TTVIs). This study aims to determine the seroprevalence of HIV, HBV, and HCV among blood donors in Borgou (Benin) in 2023. This prospective, cross-sectional study involved voluntary, non-remunerated blood [...] Read more.

Blood transfusion remains vital in healthcare but poses risks, particularly from transfusion-transmissible viral infections (TTVIs). This study aims to determine the seroprevalence of HIV, HBV, and HCV among blood donors in Borgou (Benin) in 2023. This prospective, cross-sectional study involved voluntary, non-remunerated blood donors recruited via mobile campaigns and at a fixed site from January to December 2023. Screening for HIV, HBV, and HCV was performed using fourth-generation ELISA (Biorad^®). Data analysis used SPSS with Chi-square test of independence (p < 0.05), and multiple logistic regression identified independent risk factors. Among 9646 donors, 87.80% were male (sex ratio 7.19), mostly aged 18–24 (55.93%), with students forming the largest group (58.67%). Mobile units collected 70.80% of donations; 52.60% were repeat donors. Overall TTVI seroprevalence was 9.35%, with HBV (6.29%) most common, followed by HCV (1.78%) and HIV (1.28%). Chi-square tests revealed significant associations between serostatus and donor status, donation site, and occupation, but not sex. Logistic regression identified independent risk factors: age, donor status, and donation site were significantly associated with HIV infection; male sex, older age, occupation, and donor status predicted HBV infection; and only donor status was significantly associated with HCV infection. These findings highlight the need for targeted recruitment and awareness strategies to improve transfusion safety. Full article

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

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14 pages, 1584 KiB

Open AccessArticle

Murine Cytomegalovirus and Human Cytomegalovirus Differ in Pyroptosis Induction in Different Cell Types During Productive Replication

by Jessica J. Carter, Daniel H. Schneider, Arshaan M. Hisamuddin and Richard D. Dix

Viruses 2025, 17(8), 1106; https://doi.org/10.3390/v17081106 - 12 Aug 2025

Abstract

Pyroptosis is a proinflammatory programmed cell death (PCD) that protects the host against invading viruses. We previously reported that pyroptosis plays a prominent role in the pathogenesis of murine cytomegalovirus (MCMV) retinal necrosis using mice with MAIDS as a mouse model for AIDS-related [...] Read more.

Pyroptosis is a proinflammatory programmed cell death (PCD) that protects the host against invading viruses. We previously reported that pyroptosis plays a prominent role in the pathogenesis of murine cytomegalovirus (MCMV) retinal necrosis using mice with MAIDS as a mouse model for AIDS-related human cytomegalovirus (HCMV) retinal necrosis. Because MCMV and HCMV exhibit species specificity, we sought to determine if pyroptosis induction extends to different cell types of murine or human origin. In vitro studies were therefore performed in which MCMV-infected mouse fibroblasts and mouse macrophages were compared with HCMV-infected human fibroblasts and human ARPE-19 cells for stimulation of caspase-1, gasdermin G (GSDMD), and interleukin (IL)-18 and/or IL-1β transcripts as markers for canonical pyroptosis operation. Whereas MCMV stimulated significant stimulation of pyroptosis-associated transcripts during productive replication of mouse fibroblasts and mouse macrophages, significant stimulation of these transcripts was not detected during HCMV productive replication of human fibroblasts or ARPE-19 cells. Additional studies using UV-inactivated MCMV suggested that virion tegument proteins are not involved in the induction of pyroptosis in MCMV-infected mouse fibroblasts. We conclude that pyroptosis induction during productive replication of MCMV or HCMV is host cell type-dependent and may extend to species specificity, although virus-encoded PCD suppressors must be considered. Full article

(This article belongs to the Special Issue Viruses and Eye Diseases)

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15 pages, 1201 KiB

Open AccessArticle

Immune Responses and Replication of Rescued Torque Teno Virus (TTSuV1) in Mice

by Md-Tariqul Islam, Brett Webb and Sheela Ramamoorthy

Viruses 2025, 17(8), 1105; https://doi.org/10.3390/v17081105 - 12 Aug 2025

Abstract

Although Torque Teno Viruses (TTVs) were initially considered to be ubiquitous members of the mammalian virome, the finding that swine TTVs (TTSuV) can act as primary pathogens elevates the possible status of swine TTVs (TTSuVs) to an emerging swine pathogen. Since their discovery, [...] Read more.

Although Torque Teno Viruses (TTVs) were initially considered to be ubiquitous members of the mammalian virome, the finding that swine TTVs (TTSuV) can act as primary pathogens elevates the possible status of swine TTVs (TTSuVs) to an emerging swine pathogen. Since their discovery, the molecular mechanisms of TTV–host interactions remain largely unknown as robust in vitro culture systems and in vivo animal models have not been available. This study was undertaken to address some of these long-standing gaps. Recombinant TTSuV1 rescued from an infectious clone was used to infect C57BL/J6 mice. Infected mice seroconverted within 15 days post-infection and mounted virus neutralizing antibody responses. Viral DNA was detected in blood and lung tissue for the duration of the study. TTSuV1 isolated from the lung tissue of infected mice productively and serially infected PK-15 cells in vitro, indicating that the treatment produced viable, replicative viral particles in the host. TTSuV1 antigen was also detected by flow cytometry in lymphocytes, including the T and B lymphocyte subsets. Infected mice exhibited mild splenic hyperplasia and lymphopenia. The ability to respond to mitogenic stimuli was highly diminished in infected mice and a striking lack of virus-specific recall responses was observed for the 30-day duration of the study. Therefore, this study is the first to provide experimental evidence that recombinant TTSuV1 rescued from an infectious clone is infective and induces immune responses in laboratory mice. This model provides a critical tool for advancing research on TTV immunopathogenesis. Full article

(This article belongs to the Special Issue Viral Infections and Immune Dysregulation 2024–2025)

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10 pages, 1901 KiB

Open AccessArticle

Bovine Viral Diarrhea Virus-1 (Pestivirus bovis) Associated with Stillborn and Mummified Fetuses in Farmed White-Tailed Deer (Odocoileus virginianus) in Florida

by An-Chi Cheng, Emily DeRuyter, Pedro H. de Oliveira Viadanna, Zoe S. White, John A. Lednicky, Samantha M. Wisely, Kuttichantran Subramaniam and Juan M. Campos Krauer

Viruses 2025, 17(8), 1104; https://doi.org/10.3390/v17081104 - 12 Aug 2025

Abstract

Bovine viral diarrhea virus (BVDV) is a globally significant pathogen affecting both domestic livestock and wildlife, including white-tailed deer (WTD; Odocoileus virginianus). While experimental infections have demonstrated WTD susceptibility to BVDV, natural infections and associated reproductive outcomes remain scarcely documented. Here, we [...] Read more.

Bovine viral diarrhea virus (BVDV) is a globally significant pathogen affecting both domestic livestock and wildlife, including white-tailed deer (WTD; Odocoileus virginianus). While experimental infections have demonstrated WTD susceptibility to BVDV, natural infections and associated reproductive outcomes remain scarcely documented. Here, we report the first confirmed case of naturally occurring BVDV-1 infection associated with fetal mummification in farmed WTD in Florida. A two-year-old doe experienced a stillbirth involving two mummified fetuses, which were submitted for necropsy and laboratory diagnostics. Gross findings included diarrhea and underdeveloped eyes in the fetuses, along with small white nodules indicative of amnion nodosum. While not harmful, this condition suggests underlying fetal compromise or intrauterine stress. Virus isolation using Vero E6 and bovine turbinate cell lines, along with a reverse transcription PCR (RT-PCR) assay specifically developed in this study, confirmed the presence of BVDV-1 (Pestivirus bovis) RNA in both maternal and fetal samples, suggesting vertical transmission. Sanger sequencing of RT-PCR amplicons further verified the virus species as BVDV-1. Differential diagnostics for other pathogens, including bluetongue virus, epizootic hemorrhagic disease virus, Mycobacterium spp., and Toxoplasma gondii, were negative. These findings underscore the importance of using biosecurity measures and including BVDV in the differential diagnosis of abortions to reduce the risk of BVDV transmission and potential outbreaks on deer farms, particularly those close to cattle operations. The molecular tools developed in this study provide a robust framework for improved detection and monitoring of BVDV in both wildlife and livestock populations. Full article

(This article belongs to the Section Animal Viruses)

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29 pages, 6741 KiB

Open AccessArticle

Unveiling the Genomic Landscape of G2P[6] Rotavirus a Strains in Brazil: Evolutionary and Epidemiological Perspectives

by Vanessa Cristina Martins Silva, Yasmin França, Lais Sampaio de Azevedo, Raquel Guiducci, Edlaine Faria de Moura Villela and Adriana Luchs

Viruses 2025, 17(8), 1103; https://doi.org/10.3390/v17081103 - 11 Aug 2025

Abstract

In Brazil, molecular surveillance expanded after Rotarix™ vaccine introduction, alongside G2P[4] dominance. The G2P[6] genotype, despite sharing the same DS-1-like constellation as G2P[4] strains, remains rare. This retrospective study analyzed eight Brazilian G2P[6] strains (2012–2014) through RT-PCR and 11-segments sequencing, followed by phylogenetic [...] Read more.

In Brazil, molecular surveillance expanded after Rotarix™ vaccine introduction, alongside G2P[4] dominance. The G2P[6] genotype, despite sharing the same DS-1-like constellation as G2P[4] strains, remains rare. This retrospective study analyzed eight Brazilian G2P[6] strains (2012–2014) through RT-PCR and 11-segments sequencing, followed by phylogenetic analysis. Two distinct groups were identified: 2012–2013 strains (six) carried a DS-1-like backbone with the rare NSP4 E6 genotype, while 2014 strains (two) exhibited the classical DS-1-like constellation with E2. Phylogenetic analysis confirmed the two main clusters: 2012–2013 strains related to classical G2P[4] and uncommon global genotypes, and 2014 strains resembling emerging DS-1-like G1/G3/G8P[8] reassortants. The 2012–2013 strains clustered within G2-VP7 Lineage IVa, while the 2014 strains belonged to Lineage V, reflecting the global distribution of these variants. All VP4 genes were classified within the P[6]-Ia lineage, with phylogenetic analyses suggesting separate introductions from Asia and Africa. The E6 NSP4 gene segment identified in these strains has an undetermined origin and was not previously associated with G2P[6] strains in Brazil. Despite similarities to G2P[4], G2P[6] strains remain rare, with no genomic features explaining their limited spread. Phylogenetic data indicate multiple reassortment events and international viral exchange, highlighting Brazil’s role in RVA diversity. Ongoing full-genome surveillance is crucial to track rare variants and assess their public health relevance. Full article

(This article belongs to the Special Issue Viruses Associated with Gastroenteritis)

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11 pages, 416 KiB

Open AccessArticle

Hepatitis B Virus PreS-Mutated Strains in People Living with HIV: Long-Term Hepatic Outcomes Following ART Initiation

by Xianglong Lan, Yurou Wang, Min Liao, Linghua Li and Fengyu Hu

Viruses 2025, 17(8), 1102; https://doi.org/10.3390/v17081102 - 11 Aug 2025

Abstract

In the modern era of HIV treatment, people co-infected with HIV and HBV still face poor liver outcomes, including liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. We investigated baseline characteristics and long-term liver function outcomes in 435 people living with HIV and HBV [...] Read more.

In the modern era of HIV treatment, people co-infected with HIV and HBV still face poor liver outcomes, including liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. We investigated baseline characteristics and long-term liver function outcomes in 435 people living with HIV and HBV co-infection, focusing on HCC-associated point mutations (PMs) and PreS region deletion mutations. PMs were present in 72.9% of participants and were associated with male predominance, lower HBV genotype C prevalence, reduced HBV DNA and HBeAg levels, and higher HBsAg and HBeAb positivity. However, PMs did not significantly impact liver function or fibrosis progression over six years of ART follow-up. In contrast, PreS deletions were found in 21.8% of cases and stratified into PreS1, PreS2, and PreS1+2 deletions. PreS2 and PreS1+2 deletions were linked to older age, higher HBsAg and AFP levels, elevated liver enzymes, and lower platelet counts. These groups also exhibited significantly worse liver fibrosis markers (APRI and FIB-4), with PreS2 deletions consistently showing the highest values throughout the follow-up. Despite the initial improvement with ART, patients with PreS2 and PreS1+2 deletions maintained higher fibrosis and cirrhosis risks over six years. In summary, while PMs were not predictive of liver disease progression, PreS deletion mutations (especially in the PreS2 region) were associated with poorer liver outcomes, indicating their potential as biomarkers for fibrosis risk in co-infected individuals with long-term ART. Full article

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18 pages, 2780 KiB

Open AccessArticle

Evolutionary Insights of Hepatitis B Virus Genotypes and Profiles of Mutations in Surface and Basal Core Promoter/Pre-Core Genes Among HBsAg-Positive Patients in North-Central and Southwestern Nigeria

by Priscilla Abechi, Uwem E. George, Olawale A. Adejumobi, Umar Ahmad, Olamide Y. Aborisade, Arthur O. Oragwa, Oluremi I. Ajayi, Oluwasemilogo O. Akinlo, Christian Happi and Onikepe A. Folarin

Viruses 2025, 17(8), 1101; https://doi.org/10.3390/v17081101 - 10 Aug 2025

Abstract

In Nigeria, hepatitis B virus (HBV) infection remains a significant public health issue. The emergence of immune escape mutants (IEMs), basal core promoters, and precore (BCP/PC) mutants among asymptomatic individuals has enabled the continuous evolution of the virus in the country. In this [...] Read more.

In Nigeria, hepatitis B virus (HBV) infection remains a significant public health issue. The emergence of immune escape mutants (IEMs), basal core promoters, and precore (BCP/PC) mutants among asymptomatic individuals has enabled the continuous evolution of the virus in the country. In this study, we used Sanger sequencing of the S gene and the BCP/PC region to investigate the genetic diversity, phylogenetic relationships, and mutational profiles of HBV strains detected in two regions in Nigeria. A total of 178 HBsAg-positive samples confirmed by ELISA underwent viral DNA extraction and PCR amplification of the surface and BCP/PC genes, and 76 and 60 sequences were found to be exploitable for S and BCP/PC genes, respectively, which were used for HBV genotyping and mutational analysis. We detected various mutations in the major hydrophilic loop (target of neutralizing antibodies), including vaccine escape mutants (VEMs) (L127P/R, S140T/L, and G145A), HBV immunoglobulin resistance mutants (T131N, S143T, and W156R), and mutations previously reported in patients with reactivated infections (T115N, G159A/R, and F161Y). We also identified a high proportion of C1741T in 34/42 (81%) along with A1762T or G1764A mutation in 14/42 (33%) and 18/42 (43%) as the dominant variants in the BCP region. The predominant classical PC G1896A and G1899A variants were identified in 26/42 (62%) and 17/42 (40%) participants in this study. Two HBV genotypes were identified (A and E). However, HBV genotype E was the most frequently identified genotype, and is still the dominant strain circulating in Nigeria. We report the circulation of HBV IEMs and the preponderance of BCP and classical PC variants among asymptomatic carriers. Our findings suggest that the spread of these HBV mutant variants among asymptomatic carriers may have an impact on the effectiveness of diagnostic immunoassays and the success of HBsAg-based vaccinations. This highlights the need for robust surveillance. Full article

(This article belongs to the Special Issue Hepatitis Viral Infections, Pathogenesis and Therapeutics (2nd Edition))

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28 pages, 858 KiB

Open AccessReview

Updates on Recent Advancements in Hepatitis D Virus Treatment

by Ali Emre Bardak, Nazli Begum Ozturk, Merve Gurakar, Lynette Sequeira, Eda Yildiz, Enis Hikmet Ozmert, Ramazan Idilman and Ahmet Gurakar

Viruses 2025, 17(8), 1100; https://doi.org/10.3390/v17081100 - 10 Aug 2025

Abstract

Hepatitis D virus (HDV) infection remains a major cause of severe liver disease among hepatitis B virus (HBV)-infected patients, contributing to accelerated progression to cirrhosis and hepatocellular carcinoma. Pegylated interferon-α remains the first-line therapy for chronic HDV infection in most cases. However, despite [...] Read more.

Hepatitis D virus (HDV) infection remains a major cause of severe liver disease among hepatitis B virus (HBV)-infected patients, contributing to accelerated progression to cirrhosis and hepatocellular carcinoma. Pegylated interferon-α remains the first-line therapy for chronic HDV infection in most cases. However, despite its approval for HBV and hepatitis C virus (HCV) infections, its use in HDV is largely driven by a lack of other options and is constrained by its limited efficacy, suboptimal durability of response, and a substantial side effect profile. Meanwhile, bulevirtide, an entry inhibitor, became the first agent to be approved for use in chronic HDV infections by the European Medicines Agency (EMA), and several other therapies are currently being investigated as well. In this review, we provide updates on recent advancements in HDV treatment and novel therapies. Full article

(This article belongs to the Special Issue Hepatitis Viral Infections, Pathogenesis and Therapeutics (2nd Edition))

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29 pages, 2765 KiB

Open AccessReview

Breathless Aftermath: Post-COVID-19 Pulmonary Fibrosis

by Dharanya Muthiah, Kishore Vaddadi and Lin Liu

Viruses 2025, 17(8), 1098; https://doi.org/10.3390/v17081098 - 9 Aug 2025

Abstract

A significant number of individuals recovering from COVID-19 continue to experience persistent symptoms, collectively referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC), or long COVID. Among these complications, post-COVID-19 pulmonary fibrosis (PC19-PF) is one of the most severe long-term outcomes, characterized by [...] Read more.

A significant number of individuals recovering from COVID-19 continue to experience persistent symptoms, collectively referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC), or long COVID. Among these complications, post-COVID-19 pulmonary fibrosis (PC19-PF) is one of the most severe long-term outcomes, characterized by progressive lung scarring, chronic respiratory impairment, and reduced quality of life. Despite the increasing prevalence of PC19-PF, its underlying mechanisms remain poorly understood. In this review, we provide a comprehensive overview of PC19-PF, including its epidemiology, clinical manifestations, diagnostic strategies, and mechanistic insights. Additionally, we highlight the shared pathways between PC19-PF and other fibrotic lung diseases and discuss emerging therapeutic strategies. This review consolidates emerging insights from both clinical and experimental studies to advance our understanding of PC19-PF pathogenesis and guide the development of mechanism-based therapeutic approaches. Full article

(This article belongs to the Special Issue Lung Immunity to Viral Infections)

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16 pages, 2761 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

Abstract

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)

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15 pages, 2746 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)

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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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Graphical abstract

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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