Viruses

21 pages, 3920 KiB

Open AccessArticle

Intrafamilial Transmission of HTLV-1 and HTLV-2 in Indigenous Peoples of the Brazilian Amazon: Molecular Characterization and Phylogenetic Analysis

by Isabella Nogueira Abreu, Felipe Bonfim Freitas, Eliene Rodrigues Putira Sacuena, Gabriel dos Santos Pereira Neto, Bruno José Sarmento Botelho, Carlos Neandro Cordeiro Lima, Vanessa de Oliveira Freitas, Mike Barbosa dos Santos, Sandra Souza Lima, Ricardo Ishak, João Farias Guerreiro, Antonio Carlos Rosário Vallinoto and Izaura Maria Cayres Vallinoto

Viruses 2024, 16(10), 1525; https://doi.org/10.3390/v16101525 - 26 Sep 2024

Abstract

Human T-limphotropic virus 1 infection has a global distribution, with a high prevalence in some regions of Brazil and the world, while HTLV-2 infection is endemic mainly among indigenous people and drug users. To analyze intrafamilial transmission of HTLV-1/2 in five Kayapó indigenous [...] Read more.

Human T-limphotropic virus 1 infection has a global distribution, with a high prevalence in some regions of Brazil and the world, while HTLV-2 infection is endemic mainly among indigenous people and drug users. To analyze intrafamilial transmission of HTLV-1/2 in five Kayapó indigenous peoples (Gorotire, Kararaô, Kokraimoro, Kubenkokre, and Xikrin do Bacajá), we investigated 1452 individuals who underwent serological and molecular tests. Among the 276 indigenous people with positive results, we identified intrafamily transmission in 42.7% of cases, representing 38 families. It was possible to suggest horizontal and vertical transmissions in 15.8% (6/38) and 47.4% (18/38) of the family groups, respectively. In 15.8%, it was not possible to suggest the route, which indicated that the transmission may have occurred through both vertical and horizontal routes. Through phylogenetic analyses, 35 samples positive for HTLV-2 were sequenced and classified as subtype 2c, and the two samples that tested positive for HTLV-1 were shown to belong to the cosmopolitan subtype, transcontinental subgroup (HTLV-1aA). This study confirms the intrafamilial transmission of HTLV-1/2 infection in indigenous people of the Brazilian Amazon, highlighting the importance of the sexual and mother-to-child transmission routes in maintaining the virus in these people. Full article

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

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12 pages, 716 KiB

Open AccessArticle

Impact of Vaccination on Intra-Host Genetic Diversity of Patients Infected with SARS-CoV-2 Gamma Lineage

by Beatriz de Carvalho Marques, Cecília Artico Banho, Lívia Sacchetto, Andreia Negri, Nikos Vasilakis and Maurício Lacerda Nogueira

Viruses 2024, 16(10), 1524; https://doi.org/10.3390/v16101524 - 26 Sep 2024

Abstract

The high transmissibility, rapid evolution, and immune escape of SARS-CoV-2 variants can influence the course of infection and, in turn, morbidity and mortality in COVID-19, posing a challenge in controlling transmission rates and contributing to the emergence and spread of new variants. Understanding [...] Read more.

The high transmissibility, rapid evolution, and immune escape of SARS-CoV-2 variants can influence the course of infection and, in turn, morbidity and mortality in COVID-19, posing a challenge in controlling transmission rates and contributing to the emergence and spread of new variants. Understanding the factors that shape viral genetic variation is essential for comprehending the evolution and transmission of SARS-CoV-2, especially in vaccinated individuals where immune response plays a role in the progression and spread of this disease. In this context, we evaluated the impact of immunity induced by the CoronaVac vaccine (Butantan/Sinovac) on intra-host genetic diversity, analyzing 118 whole-genome sequences of SARS-CoV-2 from unvaccinated and vaccinated patients infected with the Gamma variant. Vaccination with CoronaVac favors negative selection at the intra-host level in different genomic regions. It prevents greater genetic diversity of SARS-CoV-2, reinforcing the importance of vaccination in reducing the emergence of new mutations and virus transmission. Full article

(This article belongs to the Section Coronaviruses)

16 pages, 1085 KiB

Open AccessReview

Ubiquitin-Mediated Effects on Oncogenesis during EBV and KSHV Infection

by Rachel Mund and Christopher B. Whitehurst

Viruses 2024, 16(10), 1523; https://doi.org/10.3390/v16101523 (registering DOI) - 26 Sep 2024

Abstract

The Herpesviridae include the Epstein–Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for [...] Read more.

The Herpesviridae include the Epstein–Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for degradation or alters their function, is manipulated by both EBV and KSHV to facilitate viral persistence and cancer development. EBV infects approximately 90% of the global population and is implicated in malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), and nasopharyngeal carcinoma. EBV latency proteins, notably LMP1 and EBNA3C, use ubiquitin-mediated mechanisms to inhibit apoptosis, promote cell proliferation, and interfere with DNA repair, contributing to tumorigenesis. EBV’s lytic proteins, including BZLF1 and BPLF1, further disrupt cellular processes to favor oncogenesis. Similarly, KSHV, a causative agent of Kaposi’s Sarcoma and lymphoproliferative disorders, has a latency-associated nuclear antigen (LANA) and other latency proteins that manipulate ubiquitin pathways to degrade tumor suppressors, stabilize oncogenic proteins, and evade immune responses. KSHV’s lytic cycle proteins, such as RTA and Orf64, also use ubiquitin-mediated strategies to impair immune functions and promote oncogenesis. This review explores the ubiquitin-mediated interactions of EBV and KSHV proteins, elucidating their roles in viral oncogenesis. Understanding these mechanisms offers insights into the similarities between the viruses, as well as provoking thought about potential therapeutic targets for herpesvirus-associated cancers. Full article

(This article belongs to the Special Issue Understanding the Oncogenesis of Human Herpesviruses through Their Critical Comparisons)

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17 pages, 4228 KiB

Open AccessBrief Report

Full-Length ASFV B646L Gene Sequencing by Nanopore Offers a Simple and Rapid Approach for Identifying ASFV Genotypes

by Vivian O’Donnell, Edward Spinard, Lizhe Xu, Amy Berninger, Roger W. Barrette, Douglas P. Gladue and Bonto Faburay

Viruses 2024, 16(10), 1522; https://doi.org/10.3390/v16101522 - 26 Sep 2024

Abstract

African swine fever (ASF) is an acute, highly hemorrhagic viral disease in domestic pigs and wild boars. The disease is caused by African swine fever virus, a double stranded DNA virus of the Asfarviridae family. ASF can be classified into 25 different genotypes, [...] Read more.

African swine fever (ASF) is an acute, highly hemorrhagic viral disease in domestic pigs and wild boars. The disease is caused by African swine fever virus, a double stranded DNA virus of the Asfarviridae family. ASF can be classified into 25 different genotypes, based on a 478 bp fragment corresponding to the C-terminal sequence of the B646L gene, which is highly conserved among strains and encodes the major capsid protein p72. The C-terminal end of p72 has been used as a PCR target for quick diagnosis of ASF, and its characterization remains the first approach for epidemiological tracking and identification of the origin of ASF in outbreak investigations. Recently, a new classification of ASF, based on the complete sequence of p72, reduced the 25 genotypes into only six genotypes; therefore, it is necessary to have the capability to sequence the full-length B646L gene (p72) in a rapid manner for quick genotype characterization. Here, we evaluate the use of an amplicon approach targeting the whole B646L gene, coupled with nanopore sequencing in a multiplex format using Flongle flow cells, as an easy, low cost, and rapid method for the characterization and genotyping of ASF in real-time. Full article

(This article belongs to the Special Issue Early Diagnosis and Surveillance of Transboundary and Emerging Viral Diseases of Animals)

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4 pages, 185 KiB

Open AccessEditorial

New Insights into Rabbit Viral Diseases

by Pedro J. Esteves, Joana Abrantes and Ana M. Lopes

Viruses 2024, 16(10), 1521; https://doi.org/10.3390/v16101521 - 26 Sep 2024

Viewed by 2

Abstract

Viruses are responsible for many devastating rabbit diseases that impact their health and welfare and put their conservation and economic revenue at risk [...] Full article

(This article belongs to the Special Issue Rabbit Viral Diseases)

8 pages, 504 KiB

Open AccessArticle

Impact of SARS-CoV-2 on Viral Respiratory Infections in Patients with Hematological Malignancies

by Antonio Giordano, Martina Quattrone, Marcello Viscovo, Barbara Fiori, Rosaria Santangelo, Maurizio Sanguinetti and Livio Pagano

Viruses 2024, 16(10), 1520; https://doi.org/10.3390/v16101520 - 26 Sep 2024

Viewed by 84

Abstract

Patients with hematological malignancies (HMs) are at high risk of respiratory viral infections due to the intrinsic deterioration of the immune system and chemotherapy treatments. In the recent past, SARS-CoV-2 respiratory viral infection has been responsible for most infectious complications in HMs. We [...] Read more.

Patients with hematological malignancies (HMs) are at high risk of respiratory viral infections due to the intrinsic deterioration of the immune system and chemotherapy treatments. In the recent past, SARS-CoV-2 respiratory viral infection has been responsible for most infectious complications in HMs. We analyzed 2950 samples from 505 patients admitted to the Hematology department from 2019 to 2023. The aim of this study was to determine the epidemiological trend of respiratory viruses in the SARS-CoV-2 era, the characteristics of the patients involved and their outcomes. In our analysis, we found a reduction in non-SARS-CoV-2 respiratory viral (NSRV) positivity during the pandemic period, although these data did not show statistical significance. Most of the HMs involved were Multiple Myeloma and Acute Myeloid Leukemia. Overall mortality rate was very low and characterized by the progression of the HMs as well as the worsening of respiratory failure. In conclusion, a reduction in non-COVID viral infections was highlighted, probably also thanks to the increase in prevention measures and environmental modifications of the viral background. Full article

(This article belongs to the Section Coronaviruses)

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14 pages, 1752 KiB

Open AccessArticle

Pediatric Respiratory Hospitalizations in the Pre-COVID-19 Era: The Contribution of Viral Pathogens and Comorbidities to Clinical Outcomes, Valencia, Spain

by Valérie Bosch Castells, Ainara Mira-Iglesias, Francisco Xavier López-Labrador, Beatriz Mengual-Chuliá, Mario Carballido-Fernández, Miguel Tortajada-Girbés, Joan Mollar-Maseres, Joan Puig-Barberà, Javier Díez-Domingo and Sandra S. Chaves

Viruses 2024, 16(10), 1519; https://doi.org/10.3390/v16101519 - 25 Sep 2024

Viewed by 324

Abstract

Viral respiratory diseases place a heavy burden on the healthcare system, with children making up a significant portion of related hospitalizations. While comorbidities increase the risk of complications and poor outcomes, many hospitalized children lack clear risk factors. As new vaccines for respiratory [...] Read more.

Viral respiratory diseases place a heavy burden on the healthcare system, with children making up a significant portion of related hospitalizations. While comorbidities increase the risk of complications and poor outcomes, many hospitalized children lack clear risk factors. As new vaccines for respiratory viral diseases emerge, this study examined pediatric respiratory hospitalizations, focusing on viral etiology, complication rates, and the impact of comorbidities to guide future policy. Data were analyzed from eight pre-COVID influenza seasons (2011/2012–2018/2019) involving patients under 18 years hospitalized with respiratory complaints across 4–10 hospitals in Valencia, Spain. Respiratory specimens were tested for eight viral targets using multiplex real-time reverse-transcription polymerase chain reaction. Demographics, clinical outcomes, discharge diagnoses, and laboratory results were examined. Among the hospitalized children, 26% had at least one comorbidity. These children had higher rates of pneumonia, asthma exacerbation, and pneumothorax, and were twice as likely to require ICU admission, though mechanical ventilation and length of stay were similar to those without comorbidities. Respiratory syncytial virus (RSV) was the most common virus detected (23.1%), followed by rhinovirus/enterovirus (9.5%) and influenza (7.2%). Viral codetection decreased with age, occurring in 4.6% of cases. Comorbidities increase the risk of complications in pediatric respiratory illnesses, however, healthcare utilization is driven largely by otherwise healthy children. Pediatric viral vaccines could reduce this burden and should be further evaluated. Full article

(This article belongs to the Special Issue Influenza and Other Respiratory Viruses: Prevention, Diagnosis, Treatment)

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17 pages, 2194 KiB

Open AccessArticle

Long Terminal Repeats of Gammaretroviruses Retain Stable Expression after Integration Retargeting

by Dalibor Miklík, Martina Slavková, Dana Kučerová, Chahrazed Mekadim, Jakub Mrázek and Jiří Hejnar

Viruses 2024, 16(10), 1518; https://doi.org/10.3390/v16101518 - 25 Sep 2024

Viewed by 184

Abstract

Retroviruses integrate into the genomes of infected host cells to form proviruses, a genetic platform for stable viral gene expression. Epigenetic silencing can, however, hamper proviral transcriptional activity. As gammaretroviruses (γRVs) preferentially integrate into active promoter and enhancer sites, the high transcriptional activity [...] Read more.

Retroviruses integrate into the genomes of infected host cells to form proviruses, a genetic platform for stable viral gene expression. Epigenetic silencing can, however, hamper proviral transcriptional activity. As gammaretroviruses (γRVs) preferentially integrate into active promoter and enhancer sites, the high transcriptional activity of γRVs can be attributed to this integration preference. In addition, long terminal repeats (LTRs) of some γRVs were shown to act as potent promoters by themselves. Here, we investigate the capacity of different γRV LTRs to drive stable expression within a non-preferred epigenomic environment in the context of diverse retroviral vectors. We demonstrate that different γRV LTRs are either rapidly silenced or remain active for long periods of time with a predominantly active proviral population under normal and retargeted integration. As an alternative to the established γRV systems, the feline leukemia virus and koala retrovirus LTRs are able to drive stable, albeit intensity-diverse, transgene expression. Overall, we show that despite the occurrence of rapid silencing events, most γRV LTRs can drive stable expression outside of their preferred chromatin landscape after retrovirus integrations. Full article

(This article belongs to the Section General Virology)

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10 pages, 4023 KiB

Open AccessArticle

Kinetic Studies on the Interaction of HIV-1 Gag Protein with the HIV-1 RNA Packaging Signal

by Constance Rink, Tomas Kroupa, Siddhartha A. K. Datta and Alan Rein

Viruses 2024, 16(10), 1517; https://doi.org/10.3390/v16101517 - 25 Sep 2024

Viewed by 198

Abstract

During HIV-1 virus assembly, the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag–Psi interactions, there is almost no information on the kinetic aspects [...] Read more.

During HIV-1 virus assembly, the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag–Psi interactions, there is almost no information on the kinetic aspects of this interaction. We investigated the kinetics of Gag binding to different RNAs using switchSENSE DRX² technology. We measured the association rate of Gag binding to monomeric Psi, to a “Multiple Binding Site Mutant” Psi that is inactive for genome packaging in vivo, and to a scrambled Psi. We discovered that Gag binds more rapidly to Psi RNA than to the mutant or scrambled RNAs. Furthermore, rapid Gag association kinetics are retained within sub-regions of Psi: Gag associates more rapidly with RNA containing only the 3′ two of the three Psi stem-loops than with monomeric RNA containing the 5′ two stem-loops or a scrambled RNA. No differences were detectable with individual Psi stem-loops. Interestingly, the rate of binding of Gag molecules to Psi increases with increasing Gag concentration, suggesting cooperativity in binding. The results are consistent with the hypothesis that selectivity in packaging derives from kinetic differences in initiation of particle assembly. Full article

(This article belongs to the Special Issue 12th International Retroviral Symposium: Assembly, Maturation and Uncoating)

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18 pages, 1531 KiB

Open AccessSystematic Review

Gastrointestinal Sequelae of COVID-19: Investigating Post-Infection Complications—A Systematic Review

by Ibrahim Mohammed, Sudharsan Podhala, Fariha Zamir, Shamha Shiyam, Abdel Rahman Salameh, Zoya Salahuddin, Huda Salameh, Chaehyun Kim, Zena Sinan, Jeongyeon Kim, Deema Al-Abdulla, Sa’ad Laws, Malik Mushannen and Dalia Zakaria

Viruses 2024, 16(10), 1516; https://doi.org/10.3390/v16101516 - 25 Sep 2024

Viewed by 280

Abstract

Gastrointestinal (GI) complications are significant manifestations of COVID-19 and are increasingly being recognized. These complications range from severe acute pancreatitis to colitis, adding complexity to diagnosis and management. A comprehensive database search was conducted using several databases. Our inclusion criteria encompassed studies reporting [...] Read more.

Gastrointestinal (GI) complications are significant manifestations of COVID-19 and are increasingly being recognized. These complications range from severe acute pancreatitis to colitis, adding complexity to diagnosis and management. A comprehensive database search was conducted using several databases. Our inclusion criteria encompassed studies reporting severe and long-term GI complications of COVID-19. Digestive disorders were categorized into infections, inflammatory conditions, vascular disorders, structural abnormalities, other diagnoses, and undiagnosed conditions. Of the 73 studies that were selected for full-text review, only 24 met our inclusion criteria. The study highlights a broad range of gastrointestinal complications following COVID-19 infection (excluding liver complications, which are examined separately), including inflammatory conditions, such as ulcerative colitis (UC), acute pancreatitis, and multisystem inflammatory syndrome in children (MIS-C). Other GI complications were reported such as vascular disorders, including diverse thrombotic events and structural abnormalities, which ranged from bowel perforations to adhesions. Additionally, undiagnosed conditions like nausea and abdominal pain were prevalent across different studies involving 561 patients. The findings emphasize the substantial impact of COVID-19 on the GI tract. Ongoing research and monitoring are crucial to understanding the long-term effects and developing effective management strategies for these complications. Full article

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

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12 pages, 1736 KiB

Open AccessArticle

Evolutionary Insights from Association Rule Mining of Co-Occurring Mutations in Influenza Hemagglutinin and Neuraminidase

by Valentina Galeone, Carol Lee, Michael T. Monaghan, Denis C. Bauer and Laurence O. W. Wilson

Viruses 2024, 16(10), 1515; https://doi.org/10.3390/v16101515 - 25 Sep 2024

Viewed by 219

Abstract

Seasonal influenza viruses continuously evolve via antigenic drift. This leads to recurring epidemics, globally significant mortality rates, and the need for annually updated vaccines. Co-occurring mutations in hemagglutinin (HA) and neuraminidase (NA) are suggested to have synergistic interactions where mutations can increase the [...] Read more.

Seasonal influenza viruses continuously evolve via antigenic drift. This leads to recurring epidemics, globally significant mortality rates, and the need for annually updated vaccines. Co-occurring mutations in hemagglutinin (HA) and neuraminidase (NA) are suggested to have synergistic interactions where mutations can increase the chances of immune escape and viral fitness. Association rule mining was used to identify temporal relationships of co-occurring HA–NA mutations of influenza virus A/H3N2 and its role in antigenic evolution. A total of 64 clusters were found. These included well-known mutations responsible for antigenic drift, as well as previously undiscovered groups. A majority (41/64) were associated with known antigenic sites, and 38/64 involved mutations across both HA and NA. The emergence and disappearance of N-glycosylation sites in the pattern of N-X-[S/T] were also identified, which are crucial post-translational processes to maintain protein stability and functional balance (e.g., emergence of NA:339ASP and disappearance of HA:187ASP). Our study offers an alternative approach to the existing mutual-information and phylogenetic methods used to identify co-occurring mutations, enabling faster processing of large amounts of data. Our approach can facilitate the prediction of critical mutations given their occurrence in a previous season, facilitating vaccine development for the next flu season and leading to better preparation for future pandemics. Full article

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

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19 pages, 2675 KiB

Open AccessArticle

Characterization of Nasal Mucosal T Cells in Horses and Their Response to Equine Herpesvirus Type 1

by Camille M. Holmes and Bettina Wagner

Viruses 2024, 16(10), 1514; https://doi.org/10.3390/v16101514 - 25 Sep 2024

Viewed by 276

Abstract

Equine herpesvirus type 1 (EHV-1) enters through the upper respiratory tract (URT). Mucosal immunity at the URT is crucial in limiting viral infection and morbidity. Here, intranasal immune cells were collected from horses (n = 15) during an experimental EHV-1 infection. CD4 [...] Read more.

Equine herpesvirus type 1 (EHV-1) enters through the upper respiratory tract (URT). Mucosal immunity at the URT is crucial in limiting viral infection and morbidity. Here, intranasal immune cells were collected from horses (n = 15) during an experimental EHV-1 infection. CD4⁺ and CD8⁺ T cells were the major intranasal cell populations before infection and increased significantly by day six and fourteen post-infection, respectively. Nasal mucosal T cells were further characterized in healthy horses. Compared to peripheral blood mononuclear cells (PBMC), mucosal CD8⁺ T-cell percentages were elevated, while CD4⁺ T-cell percentages were similar. A small population of CD4⁺CD8⁺ T cells was also recovered from mucosal samples. Within the URT tissue, CD4⁺ cells predominantly accumulated in the epithelial layer, while most CD8⁺ cells resided deeper in the mucosa or the submucosa below the basement membrane. In vitro stimulation of mucosal cells from healthy horses with (n = 5) or without (n = 5) peripheral T-cell immunity against EHV-1 induced IFN-γ production in nasal T cells upon polyclonal stimulation. However, after EHV-1 re-stimulation, mucosal T cells failed to respond with IFN-γ. This work provided the first characterization of mucosal T-cell phenotypes and functions in the URT of healthy horses and during EHV-1 infection. Full article

(This article belongs to the Special Issue Animal Herpesvirus)

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11 pages, 6820 KiB

Open AccessArticle

Isolation, Identification and Genomic Analysis of Orange-Spotted Grouper Iridovirus Hainan Strain in China

by Helong Cao, Dongzhuo Zhang, Guanghui Mu, Siting Wu, Yurong Tu, Qiwei Qin and Jingguang Wei

Viruses 2024, 16(10), 1513; https://doi.org/10.3390/v16101513 - 24 Sep 2024

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Abstract

The orange-spotted grouper (Epinephelus coioides) is an important mariculture fish in China. However, in recent years, with the rapid development of aquaculture activities, outbreaks of viral diseases have affected the grouper aquaculture industry, causing severe economic losses. In the present study, [...] Read more.

The orange-spotted grouper (Epinephelus coioides) is an important mariculture fish in China. However, in recent years, with the rapid development of aquaculture activities, outbreaks of viral diseases have affected the grouper aquaculture industry, causing severe economic losses. In the present study, we isolated and identified a virus from diseased, orange-spotted groupers from an aquaculture farm in Hainan Province, China. The isolated virus was identified as orange-spotted grouper iridovirus, hence named the orange-spotted grouper iridovirus Hainan strain (OSGIV-HN-2018-001). OSGIV-HN-2018-001 induces a cytopathic effect after the infection of mandarin fish (Siniperca chuatsi) brain clonal passage (SBC) cells. In addition, the cytoplasm of the OSGIV-HN-2018-001-infected SBC cells was found to contain a large number of hexagonal virus particles with a diameter of approximately 134 nm. Using the Illumina NovaSeq system, we assembled the sequence data and annotated the complete genome of OSGIV-HN-2018-001 (GenBank accession number: PP974677), which consisted of 110,699 bp and contained 122 open reading frames (ORFs). Phylogenetic tree analysis showed that OSGIV-HN-2018-001 was most closely related to ISKNV-ASB-23. The cumulative mortality rate of groupers infected with OSGIV-HN-2018-001 reached 100% on day 8. The spleens were enlarged and blackened after the dissection of the dying groupers. These results contribute to the understanding of the molecular regulatory mechanism of the iridovirus infection and provide a basis for iridovirus prevention. Full article

(This article belongs to the Special Issue Iridoviruses, 2nd Edition)

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14 pages, 1216 KiB

Open AccessArticle

Methodological Validation and Inter-Laboratory Comparison of Microneutralization Assay for Detecting Anti-AAV9 Neutralizing Antibody in Human

by Shuangqing Yu, Qian Zhao, Cengceng Zhang, Diyi Fu, Xueyang Zhu, Jianfang Zhou, Wenhao Ma, Zheyue Dong, Xiaoliang Zhai, Lijie Jiang, Xiaohong Han, Shuyang Zhang, Xiaobing Wu and Xiaoyan Dong

Viruses 2024, 16(10), 1512; https://doi.org/10.3390/v16101512 - 24 Sep 2024

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Abstract

Anti-AAV neutralizing Abs (NAbs) titer is usually measured by cell-based microneutralization (MN) assay and is crucial for patient screening in AAV-based gene therapy clinical trials. However, achieving uniform operation and comparable results among different laboratories remains challenging. Here, we established a standardized MN [...] Read more.

Anti-AAV neutralizing Abs (NAbs) titer is usually measured by cell-based microneutralization (MN) assay and is crucial for patient screening in AAV-based gene therapy clinical trials. However, achieving uniform operation and comparable results among different laboratories remains challenging. Here, we established a standardized MN assay for anti-AAV9 NAbs in human sera or plasma and transferred the method to the other two research teams. Then, we validated its parameters and tested a set of eight human samples in blind across all laboratories. The end-point titer, defined by a transduction inhibition of 50% (IC₅₀), was calculated using curve-fit modelling. A mouse neutralizing monoclonal antibody in human negative serum was used for system quality control (QC), requiring inter-assay titer variation of <4-fold difference or geometric coefficient of variation (%GCV) of <50%. The assay demonstrated a sensitivity of 54 ng/mL and no cross-reactivity to 20 μg/mL anti-AAV8 MoAb. The intra-assay and inter-assay variation for the low positive QC were 7–35% and 22–41%, respectively. The titers of the blind samples showed excellent reproducibility within and among laboratories, with a %GCV of 18–59% and 23–46%, respectively. This study provides a commonly transferrable MN assay for evaluating anti-AAV9 NAbs in humans, supporting its application in clinical trials. Full article

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

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14 pages, 877 KiB

Open AccessArticle

Limited Short-Term Evolution of SARS-CoV-2 RNA-Dependent RNA Polymerase under Remdesivir Exposure in Upper Respiratory Compartments

by Vladimir Novitsky, Curt G. Beckwith, Kristin Carpenter-Azevedo, Jimin Shin, Joel Hague, Soya Sam, Jon Steingrimsson, Richard C. Huard, Kevin Lethbridge, Sujata Sahu, Kim Rapoza, Karen Chandran, Lauri Bazerman, Evelyn Hipolito, Isabella Diaz, Daniella Carnevale, August Guang, Fizza Gillani, Angela M. Caliendo and Rami Kantor

Viruses 2024, 16(10), 1511; https://doi.org/10.3390/v16101511 - 24 Sep 2024

Viewed by 292

Abstract

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood. Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, [...] Read more.

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood. Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region—the RDV target gene—were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset. The statistical analysis used a generalized linear mixed-effects model. Results: A total of 139 sequences were obtained from 37 out of the 44 (84%) enrolled participants. The genotyping success varied across respiratory compartments, which ranged from 42% with oropharyngeal specimens to 67% with nasopharyngeal specimens and showed improvement with higher viral loads. No RdRp mutations known to be associated with RDV resistance were identified, and for 34 detected mutations at 32 amino acid positions that are not known as RDV-associated, there was no evidence of any associations with the RDV exposure, respiratory compartment, or time. At least 1 of these 34 mutations were detected in all participants, and some differed from the larger sequence dataset. Conclusions: This study highlighted the SARS-CoV-2 short-term genomic stability within hosts and across upper respiratory compartments, which suggests a lack of evolution of RDV resistance over time. This contributes to our understanding of SARS-CoV-2 genomic dynamics. Full article

(This article belongs to the Section Coronaviruses)

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21 pages, 7715 KiB

Open AccessArticle

Chlorine Dioxide: Antiviral That Reduces the Spread of ToBRFV in Tomato (Solanum lycopersicum L.) Plants

by Ubilfrido Vásquez Gutiérrez, Gustavo Alberto Frías Treviño, Juan Carlos Delgado Ortiz, Luis Alberto Aguirre Uribe, Alberto Flores Olivas, Mariana Beltrán Beache and Francisco Daniel Hernández Castillo

Viruses 2024, 16(10), 1510; https://doi.org/10.3390/v16101510 - 24 Sep 2024

Viewed by 325

Abstract

Tomato brown rugose fruit virus (ToBRFV), being a mechanically transmitted disease, is usually difficult to control; therefore, an effective alternative to reduce transmission and replication in the crop is by spraying with chlorine dioxide (ClO₂) during routine crop management. In this [...] Read more.

Tomato brown rugose fruit virus (ToBRFV), being a mechanically transmitted disease, is usually difficult to control; therefore, an effective alternative to reduce transmission and replication in the crop is by spraying with chlorine dioxide (ClO₂) during routine crop management. In this research, the efficacy of chlorine dioxide (ClO₂) for ToBRFV management in a greenhouse and open field was determined. The phytotoxicity of ClO₂ and its effective concentration against ToBRFV in Nicotiana longiflora plants were evaluated. Subsequently, the effect of ClO₂ on ToBRFV was evaluated in tomato plants grown in an open field. Finally, the effectiveness of ClO₂ on plants inoculated with ToBRFV under greenhouse conditions was evaluated and the number of necrotic local lesions (NLLs) was quantified. The results revealed that ClO₂ at 760 mg L⁻¹ did not show phytotoxicity and reduced the number of NLLs in N. longiflora plants. It also decreased ToBRFV transmission and replication in field- and greenhouse-grown tomato plants, improving agronomic parameters. ClO₂ reduced replication in plants inoculated with different amounts of ToBRFV inoculum in a greenhouse. N. longiflora leaves expressed lower numbers of NLLs when inoculated with ClO₂-treated tomato plant extracts. Finally, the results demonstrate that ClO₂ represents an effective management alternative when used by direct application to plants. To our knowledge, this is the first study where the use of an antiviral compound is carried out under field and greenhouse conditions. Full article

(This article belongs to the Special Issue Plant Virus Interactions with Hosts: Mechanisms and Applications)

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27 pages, 7717 KiB

Open AccessArticle

Cannabis Use and Cannabidiol Modulate HIV-Induced Alterations in TREM2 Expression: Implications for Age-Related Neuropathogenesis

by Bryant Avalos, Jacqueline R. Kulbe, Mary K. Ford, Anna Elizabeth Laird, Kyle Walter, Michael Mante, Jazmin B. Florio, Ali Boustani, Antoine Chaillon, Johannes C. M. Schlachetzki, Erin E. Sundermann, David J. Volsky, Robert A. Rissman, Ronald J. Ellis, Scott L. Letendre, Jennifer Iudicello and Jerel Adam Fields

Viruses 2024, 16(10), 1509; https://doi.org/10.3390/v16101509 - 24 Sep 2024

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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. [...] Read more.

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2^R47H mutant mice were used to study HIV’s impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2^R47H mice, with increased IBA1 protein in TREM2^R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse, 3rd Edition)

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Open AccessArticle

Preclinical Profile of the HIV-1 Maturation Inhibitor VH3739937

by Brian McAuliffe, Paul Falk, Jie Chen, Yan Chen, Sing-Yuen Sit, Jacob Swidorski, Richard A. Hartz, Li Xu, Brian Venables, Ny Sin, Nicholas A. Meanwell, Alicia Regueiro-Ren, David Wensel, Umesh Hanumegowda and Mark Krystal

Viruses 2024, 16(10), 1508; https://doi.org/10.3390/v16101508 - 24 Sep 2024

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Abstract

The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory [...] Read more.

The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory strains, clinical isolates, and recombinant viruses examined, with half-maximal effective concentration (EC₅₀) values ≤ 5.0 nM. In multiple-cycle assays, viruses less susceptible to other MIs, including A364V, were inhibited at EC₅₀ values ≤ 8.0 nM and maximal percent inhibition (MPI) values ≥ 92%. However, VH-937 was less potent against A364V in single-cycle assays (EC₅₀, 32.0 nM; MPI, 57%) and A364V emerged in one of four resistance selection cultures. Other substitutions were selected by VH-937, although re-engineered viruses with these sequences were non-functional in multiple-cycle assays. Measured dissociation rates from wild-type and A364V-containing VLPs help explain resistance to the A364V mutation. Overall, the in vitro antiviral activity of VH-937 supports its continued development as a treatment for HIV-1. Full article

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

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20 pages, 4613 KiB

Open AccessArticle

Redundancy in Innate Immune Pathways That Promote CD8⁺ T-Cell Responses in AAV1 Muscle Gene Transfer

by Ning Li, Sandeep R. P. Kumar, Di Cao, Maite Munoz-Melero, Sreevani Arisa, Bridget A. Brian, Calista M. Greenwood, Kentaro Yamada, Dongsheng Duan and Roland W. Herzog

Viruses 2024, 16(10), 1507; https://doi.org/10.3390/v16101507 - 24 Sep 2024

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Abstract

While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8⁺ T-cell responses against [...] Read more.

While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8⁺ T-cell responses against the transgene product upon AAV1 vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8⁺ T-cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1 > MyD88 and TLR9 > MyD88 > type I IFN > IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. Further, even low-frequency CD8⁺ T-cell responses could eliminate transgene expression, even in MyD88- or IL-1R1-deficient animals that received a low vector dose. However, we provide evidence that CpG depletion of vector genomes and including TLR9 inhibitory sequences can synergize. When this construct was combined with the use of a muscle-specific promoter, transgene expression in muscle was sustained with minimal local or systemic CD8⁺ T-cell response. Thus, innate immune avoidance/blockade strategies by themselves, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of the redundancy of immune-activating pathways. Full article

(This article belongs to the Special Issue Virology and Immunology of Gene Therapy)

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Viruses, Volume 16, Issue 10 (October 2024) – 19 articles

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