Viruses-Basel最新文献

Chikungunya virus (CHIKV) and other alphaviruses that primarily induce arthritogenic disease in humans, known as "Old World" alphaviruses, present an emerging public health concern as geographic ranges of mosquito vectors expand due to climate change. While a vaccine against CHIKV has recently been approved by several countries in North America and Europe, access to effective preventative countermeasures against disease induced by Old World alphaviruses remains elusive for the most vulnerable populations. Furthermore, treatment options continue to be limited to supportive care. Atypical neurological disease manifestations caused by Old World alphaviruses, which make up as many as 25% of the cases in some CHIKV outbreaks, present special challenges when considering strategies for developing effective countermeasures. This review focuses on Old World alphaviruses, specifically CHIKV, Ross River virus, O'nyoug-nyoug virus, and Mayaro virus, concentrating on the atypical neurological disease manifestations they may cause. Our current understanding of Old World alphavirus neuropathogenesis, gained from human cases and preclinical animal models, is discussed, including viral and host factors' roles in disease development. The current state of alphavirus preventatives and treatments, both virus-targeting and host-directed therapies, is then summarized and discussed in the context of addressing neurological disease induced by Old World alphaviruses.

Epstein-Barr virus (EBV) is strongly associated with the development of post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients. PTLD is one of the most common malignancies following liver transplantation and is associated with significant morbidity and mortality. Factors such as EBV-serostatus mismatch and prolonged or high levels of immunosuppression impact a patient's risk of developing PTLD. While pre-transplant EBV serological screening and post-transplant monitoring of EBV-DNA levels are strongly recommended, universal guidelines for its prevention and management are lacking. Due to a lack of robust prospective studies, current clinical practices vary widely. The treatment of PTLD typically involves reducing immunosuppression and using targeted therapies such as rituximab, or chemotherapy for refractory cases. This review aims to address our current understanding of EBV's relationship with PTLD, evaluate the available treatment modalities, and highlight evolving strategies for using EBV as a biomarker for PTLD screening and prevention.

Feline immunodeficiency virus (FIV) is the domestic cat analogue of HIV infection in humans. Both viruses induce oral disease in untreated individuals, with clinical signs that include gingivitis and periodontal lesions. Oral disease manifestations in HIV patients are abated by highly effective combination antiretroviral therapy (cART), though certain oral manifestations persist despite therapy. Microorganisms associated with oral cavity opportunistic infections in patients with HIV cause similar pathologies in cats. To further develop this model, we evaluated characteristics of feline oral health and the oral microbiome during experimental FIV infection over an 8-month period following cART. Using 16S rRNA sequencing, we evaluated gingival bacterial communities at four timepoints in uninfected and FIV-infected cats treated with either cART or placebo. Comprehensive oral examinations were also conducted by a veterinary dental specialist over the experimental period. Gingival inflammation was higher in FIV-infected cats treated with placebo compared to cART-treated cats and the controls at the study endpoint. Oral microbiome alpha diversity increased in all groups, while beta diversity differed among treatment groups, documenting a significant effect of cART therapy on microbiome community composition. This finding has not previously been reported, and indicates cART ameliorates immunodeficiency virus-associated oral disease via the preservation of oral mucosal microbiota. Further, this study illustrates the value of the FIV animal model for investigations of mechanistic associations and therapeutic interventions for HIV's oral manifestations.

The ongoing global outbreak of mpox caused by clade IIb viruses has led to more than 100,000 confirmed cases around the world, highlighting the urgent need for antiviral research to combat current and future mpox outbreaks. Reporter viruses expressing fluorescent proteins to monitor viral replication and virus spreading in cell culture provide a powerful tool for antiviral drug screening. In this work, we engineered two recombinant mpox clade IIb viruses by inserting, under the control of the vaccinia early/late promoter 7.5, the coding sequence of two different fluorescent proteins (EGFP and TurboFP635) in a previously unreported location within the viral genome. These recombinant viruses replicate in BSC-1 cells at rates similar to those of the parental virus. We show how these reporter mpox viruses allow the discrimination of infected cells by cell flow cytometry and facilitate the quantification of viral spread in cell culture. Finally, we validated these reporter viruses with two previously known inhibitors of poxvirus replication, cytosine arabinoside (AraC) and bisbenzimide.

In an epidemiologic investigation of Enterovirus (EV) infections in a Verona hospital, September 2022-September 2024, we detected EV-C105 in six pediatric patients with upper respiratory symptoms between March and May 2023. The primary objective was to describe the local incidence of EV cases. The secondary objective was to perform Sanger's genomic characterization and the whole-genome sequencing (WGS) of EV-C105. The proportion of positive EV results was calculated based on routine molecular method testing. An available cohort of 114 underwent Sanger sequencing, and the six EV-C105 were characterized with WGS. Overall, 96% EV results were from the upper respiratory tract. The total proportion of positives in children was 83%. Out of the typed 114, 90% were Rhinoviruses and 9%, EVs. Notably, six pediatric cases were EV-C105, placing together in a unique cluster with 99% of nucleotides belonging to the European lineage with the highest Average Nucleotide Identity, including EV-C104, EV-C109, and EV-C118. Our data describes the first cluster indicating that EV-C105 incidence may be higher than previously estimated. However, a limitation for affirming this hypothesis is the lack of a more in-depth epidemiological investigation on a larger case series with the possibility of including data from coordinated laboratories.

In 2021, at the height of the COVID-19 pandemic, coronavirus research spiked, with over 83,000 original research articles related to the word "coronavirus" added to the online resource PubMed. Just 2 years later, in 2023, only 30,900 original research articles related to the word "coronavirus" were added. While, irrefutably, the funding of coronavirus research drastically decreased, a possible explanation for the decrease in interest in coronavirus research is that projects on SARS-CoV-2, the causative agent of COVID-19, halted due to the challenge of establishing a good cellular or animal model system. Most laboratories do not have the capabilities to culture SARS-CoV-2 'in house' as this requires a Biosafety Level (BSL) 3 laboratory. Until recently, BSL 2 laboratory research on endemic coronaviruses was arduous due to the low cytopathic effect in isolated cell culture infection models and the lack of means to quantify viral loads. The purpose of this review article is to compare the human coronaviruses and provide an assessment of the latest techniques that use the endemic coronaviruses-HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1-as lower-biosafety-risk models for the more pathogenic coronaviruses-SARS-CoV-2, SARS-CoV, and MERS-CoV.

Herpes simplex viruses (HSV-1 and HSV-2), which can be transmitted both orally and sexually, cause lifelong morbidity and in some cases, meningitis and encephalitis. While both the passive transfer of neutralizing antibodies and placental transfer of anti-HSV monoclonal antibodies (Mabs) have shown therapeutic promise in animal models, clinical trials have yet to identify approved immunotherapeutics for herpes infection. Here, we present strategies for the generation of recombinant bispecific antibodies (BsAbs) that target different domains of glycoprotein D (gD), crucial for HSV entry, that have the potential to outperform the effect of individual Mabs to curb herpes infection. Specifically, we selected three pairs of Mabs from our extensive panel for BsAb design and production based on their binding site and ability to block virus entry. Actual binding of BsAbs to gD and epitope availability on gD after BsAb binding were characterized using surface plasmon resonance (SPR) and inhibition by IgG Fab fragments generated from selected Mabs. While one BsAb exhibited an additive effect similar to that observed using a combination of the Mabs utilized for its generation, two showed antagonistic effects, suggesting that the simultaneous engagement of two epitopes or selective binding to one affected their activity against HSV. One BsAb (DL11/1D3) targeting the binding site for both nectin-1 and HVEM receptors demonstrated synergistic inhibitory activity against HSV, outperforming the effect of the individual antibodies. Recombinant DL11/1D3 antibody variants, in which the size of one or both paratopes was decreased to single chains (scFv-Fc), highlighted differences in potency depending on antibody size and format. We propose that BsAbs to individual glycoproteins offer a potential avenue for herpes therapeutics, but their design, mechanism of action, antibody format, and epitope engagement require careful consideration of structure for optimal efficacy.

Introduction: Hepatitis D virus (HDV) infection remains a significant global health challenge due to its severity and high risk of progression to cirrhosis and hepatocellular carcinoma (HCC). Bulevirtide, a novel HDV entry inhibitor, has shown promise in managing chronic hepatitis D by blocking viral entry into hepatocytes. This study evaluated the efficacy and safety of bulevirtide in reducing HDV RNA levels and improving liver function in a real-life cohort of Italian patients with HDV infection.

Methods: This multicenter prospective trial enrolled 108 consecutive patients with chronic HDV infection, from June 2023 to June 2024, who received 2 mg/day of bulevirtide in combination with a nucleoside/nucleotide analogue for hepatitis B virus (HBV) infection. Patients with any stage of liver fibrosis or compensated cirrhosis were included. Data collected included demographic and clinical characteristics, liver function tests, HDV RNA levels, and adverse events at baseline and 6 months.

Results: The virological response was achieved in 54.6% of patients (n = 59), with 36 demonstrating undetectable HDV RNA levels. Among responders, ALT levels decreased significantly from 67.0 U/mL [IQR 44.0-116.3] to 31.5 U/mL [IQR 24.0-36.5, p = 0.001], and AST levels from 66.0 U/mL [IQR 46.5-91.0] to 32.5 U/mL [IQR 28.0-38.0, p = 0.021]. Median HDV RNA dropped from 29,800 IU/mL [IQR 3100-375,000] to 0 IU/mL [IQR 0-291, p < 0.001]. No significant predictors of response emerged. Mild adverse events, including pruritus (5.6%) and injection-site reactions (1.9%) and flu-like syndrome (0.9) were reported, with no treatment discontinuation.

Conclusions: Bulevirtide effectively reduces HDV RNA levels and improves liver function with a favorable safety profile, offering a promising therapeutic option for chronic hepatitis D. Further large-scale studies are needed to confirm these findings and explore long-term outcomes.

A nuclear export signal (NES) is a cluster of hydrophobic amino acids that can maintain the dynamic shuttling of target proteins between the nucleus and cytoplasm. Bioinformatics analysis showed that the hydrophobic region of ⁹²PLLLHKFLLA in Bm65 is very likely to be an NES and may be involved in the production of infectious virions. In this study, we generated several mutations in ⁹²PLLLHKFLLA of Bm65, which were further used to generate recombinant viruses to study their roles in viral propagation. Subcellular analysis revealed that the ⁹²PLLLHKFLLA sequence was an NES involved in the dynamic transport of Bm65. Mutations in the hydrophobic region could block the formation and accumulation of Bm65 aggregates, resulting in a uniform distribution of Bm65 in BmN cells. The ribosomal protein L13 (RPL13) of silkworms was previously reported to interact with Bm65. Here, intracellular co-localization analysis showed that the interaction between Bm65 and RPL13 was regulated by the ⁹²PLLLHKFLLA of Bm65. In summary, the interaction between Bm65 and RPL13 is essential for the production and accumulation of Bm65 aggregates and may play an important role in the regulation of viral propagation.

Inhaled dry powder formulations of antiviral agents represent a novel and potentially transformative approach to managing respiratory viral infections. Traditional antiviral therapies in the form of tablets or capsules often face limitations in terms of therapeutic activity, systemic side effects, and delayed onset of action. Dry powder inhalers (DPIs) provide a targeted delivery system, ensuring the direct administration of antivirals to the infection site, the respiratory tract, which potentially enhance therapeutic efficacy and minimize systemic exposure. This review explores the current state of inhaled dry powder antiviral agents, their advantages over traditional routes, and specific formulations under development. We discuss the benefits of targeted delivery, such as improved drug deposition in the lungs and reduced side effects, alongside considerations related to the formulation preparation. In addition, we summarize the developed (published and marketed) inhaled dry powders of antiviral agents.