Search Results (658)

Background & Aims: Hepatitis C virus (HCV) infection remains one of the most significant and lethal infectious diseases worldwide. Since the approval of the first direct-acting antiviral agent in 2013, the therapeutic landscape has changed dramatically, with SVR rates exceeding 95%. The WHO set the ambitious goal of achieving global HCV elimination in 2030. High-risk populations remain among the most challenging yet essential groups to treat in order to reach this objective. The aim of this study is to describe two distinct approaches targeting high-risk populations to advance HCV elimination. Methods: An observational study was conducted from April 2017 to August 2025, including patients evaluated and treated at Porto’s correctional facility and Porto’s addiction centers. All patients received DAA therapy, and the primary outcome was sustained virological response at 12 weeks post-treatment. Results: A total of 124 patients from the prison setting were included. Their mean age was 43.0 ± 8.4 years, and all were males. Treatment with DAA resulted in an SVR of 99.2%. In addition, 43 patients from the addiction centers were included, with a mean age of 54.9 ± 5.9 years, and the majority were males (86%). These patients achieved an SVR 12 of 97.7%. Conclusions: In two distinct and difficult-to-reach high-risk populations, we demonstrated that a tailored approach involving on-site evaluation and treatment of HCV infection is highly effective and may be crucial to achieving HCV elimination. Full article

Host–virus relationships regulate every phase of viral infection and critically influence course of illness and the effectiveness of treatment. Viruses utilize host receptors, intracellular trafficking routes, metabolic programs, and immunological signaling networks to introduce infection, while host cells use innate and adaptive immune responses that both limit viral replication and, in certain situations, cause tissue damage. Given the fast viral evolution and drug resistance linked to virus-directed therapy, there is growing proof that these host-dependent mechanisms are appealing and underutilized targets for antiviral treatment. Recent developments in single-cell technology, proteomics, and functional genomics have made it possible to systematically identify host dependency and restriction factors shared by different viral families, exposing common molecular vulnerabilities that might be targeted therapeutically. This review integrates current knowledge of virus–host interplay via a translational lens, highlighting processes that directly guide the formation of host-directed antivirals and immune-regulating treatments. We emphasize host processes involved in viral entry, replication, and immune signaling that have shown therapeutic significance, while illustrating the difficulties of balancing antiviral effectiveness with immunopathology. By framing host–virus interactions through a therapeutic lens, this review attempts to offer a targeted and translationally relevant viewpoint for next-generation antiviral research. Full article

Ionic liquids (ILs) have emerged as multifunctional compounds with low volatility, high thermal stability, and tunable solvation capabilities, making them highly promising for biomedical applications. First explored in the late 1990s and early 2000s for enhancing the thermal stability of enzymes, antimicrobial agents, and controlled release systems, ILs have since gained significant attention in drug delivery, antimicrobial treatments, medical imaging, and biosensing. This review examines the diverse functions of ILs in contemporary therapeutics and diagnostics, highlighting their transformative capabilities in improving drug solubility, bioavailability, transdermal permeability, and pathogen inactivation. In drug delivery, ILs improve solubility of bioactive compounds, with several IL formulations achieving substantial solubility enhancements for poorly soluble drugs. Bio-ILs, in particular, show promise in enhancing drug delivery systems, such as improving transdermal permeability. ILs also exhibit significant antimicrobial and antiviral activity, offering new avenues for combating resistant pathogens. Despite their broad potential, challenges such as cytotoxicity, long-term metabolic effects, and the stability of ILs in physiological conditions persist. While much research has focused on their physicochemical properties, biological activity and in vivo studies are still underexplored. The future directions for ILs in biomedical applications include the development of bioengineered ILs and hybrid ILs, combining functional components like nanoparticles and polymers to create multifunctional materials. These ILs, derived from renewable resources, show great promise in personalized medicine and clinical applications. Further research is necessary to evaluate their pharmacokinetics, biodistribution, and long-term safety to fully realize their biomedical potential. This study emphasizes the potential of ILs to transform therapeutic and diagnostic technologies by highlighting present shortcomings and offering pathways for clinical translation, while also debating the need for continuous research to fully utilize their biomedical capabilities. Full article

Mammarenaviruses (MaAv) cause persistent infection in their natural rodent hosts across the world and, via zoonotic events, can cause severe disease in humans. Thus, the MaAv Lassa virus (LASV) in Western Africa and the Junin virus (JUNV) in the Argentinean Pampas cause hemorrhagic fever diseases with significant case fatality rates in their endemic regions. In addition, the globally distributed MaAv lymphocytic choriomeningitis virus (LCMV) is an underrecognized human pathogen of clinical significance capable of causing devastating infections in neonates and immunocompromised individuals. Despite their impact on human health, there are currently no FDA-approved vaccines or specific antiviral treatments for MaAv infections. Existing anti-MaAv therapies are limited to the off-label use of ribavirin, whose efficacy remains controversial; hence, the development of novel therapeutics to combat human pathogenic MaAv is vital. We employed a high-throughput cell-based infection assay to screen the Pandemic Response Box, a collection of 400 diverse compounds with established antimicrobial activity, for MaAv inhibitors. We identified Ro-24-7429, an antagonist of the HIV-1 Tat protein and RUNX family transcription factor 1 inhibitor; WO 2006118607 A2, a dihydroorotate dehydrogenase inhibitor; and verdinexor, a novel selective inhibitor of nuclear export (SINE) targeting the XPO1/CRM1, as potent anti-MaAv compounds. Consistent with their distinct validated targets, verdinexor and WO 2006118607 A2 exhibited very strong synergistic antiviral activity when used in combination therapy. Our findings pave the way for the development of verdinexor as a potent host-directed antiviral against MaAv, which could be integrated into the development of combination therapy with direct- or host-acting antivirals to combat human pathogenic MaAv. Full article

Background/Objectives: Direct-acting antivirals (DAAs) have revolutionized the management of chronic hepatitis C virus (HCV) infection. However, real-world data on the effectiveness and safety of DAA therapy in patients with history orthotopic liver transplantation (OLTx) remain limited. This study aimed to evaluate the clinical characteristics, effectiveness, and safety of DAA therapy in liver transplant recipients with chronic hepatitis C in a nationwide, real-world cohort. Methods: A retrospective analysis was performed of all consecutive adult patients who underwent OLTx before starting DAA therapy between July 2015 and December 2024 within the EpiTer-2 project, which included 20,586 patients treated because of chronic hepatitis C. Results: A total of 141 patients participated in the study, with most of them being men (66%) and aged 50 years or older. Most patients (80%) had comorbidities, and nearly a quarter of the population had cirrhosis of the transplanted liver at the start of antiviral therapy. The median time from OLTx to initiation of antiviral therapy was 24 months. Overall, SVR was achieved in 96.4% of patients in the intention-to-treat analysis and in 98.6% after excluding patients lost to follow-up. The treatment was well tolerated. Serious adverse events were reported in five patients. During DAA treatment and 12 weeks of follow-up after treatment, two deaths were reported. Subgroup analysis by time from OLTx to antiviral therapy (≤24 vs. >24 months) revealed no differences in effectiveness and safety despite some baseline clinical variations. Conclusions: DAA therapy in liver transplant recipients with chronic HCV infection is highly effective and well-tolerated. Full article

Over the past decade, significant progress has been made in the treatment of chronic hepatitis C virus (HCV) infection. The introduction of direct-acting antivirals (DAAs) has revolutionized the treatment of HCV infection, offering nearly 100% efficacy. Furthermore, additional therapeutic regimens with pangenotypic efficacy have been registered. These drugs are also characterized by a few adverse events and good treatment tolerance. As DAA therapy is now accessible to virtually all patients, including those with multimorbidity who often take multiple medications, drug interactions (DDIs) have become a significant clinical challenge. One of the groups of patients who are frequently infected with HCV is those with mental disorders. Due to frequently overlapping metabolic pathways, DDIs can occur, affecting the effectiveness of both psychiatric and antiviral therapy. Knowledge of these interactions is crucial in these cases and influences patient management. This paper discusses the most significant interactions between pangenotypic DAA regimens and psychotropic medications. Full article

In human and non-human primates, filoviruses, e.g., Ebolaviruses, cause severe hemorrhagic fever for which there are few therapeutic options. While there are licensed vaccines and therapeutics for Ebola virus disease, there is no approved vaccine or treatment for other Ebola diseases. There is a need for broad-spectrum antivirals to treat Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV). We have previously demonstrated that probenecid, an FDA-approved drug with a safety profile spanning over 7 decades, is safe and effective in preventing the replication of influenza A viruses, SARS-CoV-2, and other RNA respiratory viruses, such as HMPV and RSV, both in vitro and in vivo. In this study, probenecid was shown to inhibit the replication of infectious EBOV, SUDV, and MARV in Vero E6 cells, with IC50 Values of 3 μM, 8 μM, and 13 μM, respectively. It also reduced plaque size in infected Vero cell lawns, suggesting reduced virus spread. These studies show that probenecid is an effective, broad-spectrum, host-directed antiviral drug. Full article

Conventional ultrasound (US) has long been central to hepatocellular carcinoma (HCC) surveillance in cirrhotic patients, due to its low cost, wide availability, non-invasiveness, and adequate sensitivity for detecting small nodules. However, its specificity in distinguishing HCC from other lesions is limited. Contrast-enhanced ultrasound (CEUS) has significantly improved the characterization of nodules first identified on conventional US. Yet, when CEUS is performed using sulfur hexafluoride (SonoVue)—the only contrast agent available in Western countries—assessment remains restricted to a single nodule per examination, and enhanced CT or MRI is still required for full characterization and staging. In clinical settings, such as hepatology, internal medicine, infectious diseases, and surgery, CEUS offers the advantage of immediate availability, enabling rapid characterization of suspicious nodules in cirrhotic livers and facilitating timely therapeutic decisions. Although the introduction of direct-acting antivirals (DAAs) has substantially reduced HCV-related HCC, HCC incidence is increasingly driven by metabolic dysfunction-associated steatohepatitis (MASH). Evidence on surveillance strategies for MASH patients remains limited, and current EASL guidelines recommend monitoring only patients with >F2 fibrosis. Additionally, the effectiveness of US in obese or diabetic/obese populations is under ongoing investigation; abbreviated non-contrast MRI has been proposed as an alternative surveillance tool, but its adoption would entail significant economic implications for healthcare systems. HCC arising from MASH—sometimes even without cirrhosis—exhibits different sonographic and pathological features. Instead of small, hypoechoic nodules, typically seen in HCV-related cirrhosis, clinicians increasingly encounter larger or multiple lesions, often accompanied by macrovascular invasion, limiting access to curative treatments. Furthermore, typical CEUS LI-RADS patterns are less frequently observed. This review summarizes the evolving US findings in the era of MASH-related HCC and underscores the continued importance of US as the primary imaging tool in routine clinical practice. Full article

People who use crack cocaine (PWUCC) constitute a key population due to vulnerability and marginalization, especially in a socio-ecologically diverse, relatively isolated region with limited public health infrastructure. This study aimed to perform a genetic characterization of circulating HCV among PWUCC in the municipality of Bragança, situated on the Brazilian Amazon coast, identifying viral genotypes, subtypes, resistance-associated substitutions (RAS)—naturally occurring mutations in the viral genome that can reduce the efficacy of direct-acting antiviral (DAA) agents—and predictions of phenotypic resistance. Methods: Between 2016 and 2018, biological samples and epidemiological data were obtained from 165 PWUCC. Viral detection was performed using RT-PCR, while genotyping, subtyping, and RAS profiling were conducted through nucleotide sequencing and fragment analysis. Results: In 165 PWUCC, 22 (13.3%) tested positive for HCV RNA. Most of them had not had access to public health services (91.5%), and more than half (57.0%) reported living in unstable housing conditions. HCV subtypes 1a (27.3%), 1b (40.9%), and 3a (31.8%) were detected. Evidence of resistance associated with DAAs, such as daclatasvir and dasabuvir, was detected in five PWUCC with HCV (22.7%). Conclusions: The high prevalence of HCV infection, predominantly subtype 1b, and significant levels of resistance are very concerning. This demonstrates the urgent need for targeted public health interventions to expand access to testing, treatment, and effective antiviral therapy in this vulnerable population of the Brazilian Amazon. Full article

The COVID-19 pandemic has demonstrated that its effects go far beyond the initial respiratory illness, with many survivors experiencing lasting neurological problems. Some patients develop a condition known as Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), which includes current issues such as reduced cognitive function, chronic headaches, depression, neuropathic pain, and sensory disturbances. These symptoms can severely disrupt daily life and overall well-being. In this narrative review, we provide an overview of current understanding regarding the neurological effects of COVID-19, with a focus on Long COVID. We discuss possible underlying mechanisms, including direct viral invasion of the nervous system, immune-related damage, and vascular complications. We also summarize findings from cohort studies and meta-analyses that explore the causes, symptom patterns, and frequency of these neurological issues. Approximately one-third of people who have had COVID-19 report neurological symptoms, especially those who experienced severe illness or were infected with pre-Omicron variants. Emerging research has identified potential biomarkers such as neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) that may help in diagnosis. Treatment approaches under investigation include antiviral medications, nutraceuticals, and comprehensive rehabilitation programs. Factors like older age, existing health conditions, and genetic differences in ACE2 and TMPRSS2 genes may affect an individual’s risk. To effectively address these challenges, current research is essential to improve diagnostic methods, develop targeted treatments, and enhance rehabilitation strategies. Ultimately, a coordinated, multidisciplinary effort is crucial to reduce the neurological impact of Long COVID and support better recovery for patients. Full article

Lipids provide essential membrane components and energy sources for viral replication, playing multiple roles in viral infection. However, the mutual influence between lipid metabolism and PRRSV proliferation remains unclear. Using transcriptomics, lipidomics, BODIPY staining, and Western blot (WB) analysis, our findings revealed that PRRSV infection significantly altered the abundance of lipid-metabolism-associated genes and lipid metabolites in cells. qRT-PCR confirmed that PRRSV infection dose-dependently upregulated SREBP2 expression (p < 0.01), while BODIPY staining demonstrated a significant increase in intracellular lipid droplets post-infection (p < 0.01). Let-7f-5p significantly reduced lipid droplet accumulation and suppressed PRRSV N protein expression. Notably, 15 lipid species that were upregulated during PRRSV infection were downregulated by let-7f-5p overexpression. These lipids were enriched in pathways related to phosphatidylcholines, monounsaturated fatty acids, and C16-C18 fatty acid metabolism. Exogenous palmitic acid (C16:0) treatment reversed the inhibitory effects of let-7f-5p on SREBP2 expression and viral replication, demonstrating that viral proliferation can be regulated by modulating host lipid metabolism. This study reveals that PRRSV hijacks host lipid metabolism to facilitate viral replication, whereas let-7f-5p exerts antiviral effects through dual mechanisms. These findings provide new insights into host-directed antiviral strategies against PRRSV infection. Full article

Chimeric antigen receptor (CAR)-modified natural killer (NK) cells represent a promising immunotherapeutic approach for the treatment of oncological malignancies such as hepatocellular carcinoma (HCC). In this work, we have engineered primary human NK cells, re-directing them so they can specifically recognize Glypican-3 (GPC3), an immunotherapeutic target for HCC. In previous studies, we have demonstrated that IFN-α significantly enhances NK cells’ anti-tumor and anti-viral cytotoxicity. Fourth-generation self-inactivating lentiviral vectors were used to deliver a transgenic expression of IFN-α or its co-expression with IL-15 (which induces NK cells expansion, survival, and function), aiming to enhance CAR-GPC3 NK cells’ anti-tumor response against HCC. We optimized a protocol for efficient transduction of primary NK cells, demonstrating that CAR expression is maintained at high levels over time. Exposure of HCC ectopically expressing GPC3+ to CAR-GPC3-IL15 and CAR-GPC3-IL15-IFNα NK cells demonstrated significant in vitro cytotoxicity and cytokine production, dependent on GPC3 expression. To prevent undesired side effects of CAR-NK cell immunotherapy, co-delivery with a suicide gene is advised as a safety measure. Thus, a truncated epidermal growth factor receptor (tEGFR) was co-delivered with the anti-GPC3 CAR, which efficiently promoted the suicide of the CAR-NK used in this work. Our study demonstrates the efficacy of re-directed CAR-GPC3 primary NK cells, encouraging further preclinical and clinical translation studies and strengthening the potential of these cells as a novel treatment option for patients with HCC. Full article

More than 3 million children are infected with hepatitis C virus (HCV) worldwide. Therapies with direct-acting antivirals (DAAs) are characterized by high efficiency and acceptable tolerability. Rare cases of autoimmune hepatitis (AIH) following HCV elimination have been reported in adults. Here, we present the first pediatric case of AIH after successful treatment with DAAs. A girl, born in 2012, was diagnosed with vertical HCV infection in 2013. In 2023, she was treated with the DAA glecaprevir/pibrentasvir. HCV RNA was undetectable after 4 weeks of treatment and at the end of treatment (EOT). However, at the EOT, the aminotransferase concentration elevated with further increase, despite a confirmed sustained viral response (SVR) 12 weeks after the EOT. Gamma-globulins were elevated, with positive anti-nuclear antibodies (ANA) and anti-liver kidney microsome (LKM) antibodies. Other causes were excluded. Elastography revealed no fibrosis. Aminotransferase levels decreased but did not normalize. A liver biopsy was performed, confirming a diagnosis of AIH. Immunosuppressive therapy with prednisone and azathioprine resulted in normalization of aminotransferase levels, and the titers of both ANA and LKM antibodies decreased. Monitoring aminotransferase levels should not be omitted in patients after successful DAA treatment of HCV infection. Full article

COVID-19 has resulted in over 777 million confirmed cases and more than 7 million deaths globally. While vaccination offers protection for individuals with a functional immune system, immunocompromised populations will not generate sufficient responses, highlighting the critical need for new antiviral treatments. Here we evaluated four highly conserved anti-COVID siRNAs targeting the ORF1a-Nsp1, Membrane, and Nucleocapsid regions by identifying their antiviral efficacy in vitro and investigated the direct delivery of naked siRNAs to the respiratory tract of mice via intranasal instillation to provide proof-of-concept evidence of their in vivo antiviral activity. Dose-response analysis of siRNAs revealed a range of IC50 0.02 nM to 0.9 nM. Intranasal administration of naked anti-COVID siRNA-18 in a K18-hACE2 transgenic SARS-CoV-2 mouse model was capable of reducing viral mRNA levels and disease severity. While anti-COVID siRNA-30 induced modest interferon-stimulated gene expression in vitro and immune cell infiltration in vivo, these effects were markedly reduced by 2′-O-methyl-AS456 chemical modification, which preserved antiviral efficacy against SARS-CoV-2 while minimizing off-target immune activation. These results demonstrate the feasibility of direct respiratory siRNA administration for in vivo viral suppression and highlight the benefit of using conserved target sequences and chemical modification to enhance therapeutic safety and efficacy. Full article

Background/Objectives: Chronic hepatitis C virus (HCV) remains a major public health concern in Taiwan, particularly in southern regions with high endemicity. While HCV elimination is a national priority, resources are often limited. Relying solely on broad, township-level prevalence rates is inefficient, as the true disease burden can vary dramatically at the village level. Therefore, identifying local hotspots through fine-scale mapping is critical for efficient resource allocation and targeted intervention. This study aimed to validate village-level prevalence estimates and evaluate the efficiency of a community-based, targeted screening approach utilizing this detailed prevalence data in Chiayi County. Methods: We integrated data from the Chiayi Health Bureau and Chiayi Chang Gung Memorial Hospital (2000–2015) to generate village-level risk maps for five townships: Lioujiao (LJ), Yijhu (YH), Dongshih (DS), Taibao (TB), and Lucao (LC). Between 2018 and 2021, we conducted door-to-door community screening using anti-HCV testing with reflex HCV antigen (Ag) testing. Anti-HCV/HCV Ag prevalence, number needed to test (NNT), and linkage-to-care rates were calculated to validate prevalence estimates and assess screening efficiency. Results: Among 3910 participants, anti-HCV prevalence ranged from 5.4% (TB) to 8.7% (DS). Estimated and observed village-level prevalence showed moderate-to-strong correlation (r = 0.696–0.830, p < 0.001). Screening efficiency was highest in DS (NNT = 21) and lowest in TB (NNT = 42). Of 132 antigen-positive individuals, 131 (99.2%) initiated direct-acting antiviral therapy. Conclusions: The village-level risk maps accurately predicted local HCV burden, enabling targeted screening with high diagnostic yield and near-complete treatment uptake. This approach maximizes resource efficiency and may serve as a scalable model for advancing Taiwan and the WHO’s 2030 HCV elimination goals. Full article