Antiviral research最新文献

{"title":"Tenofovir alafenamide promotes weight gain and impairs fatty acid metabolism-related signaling pathways in visceral fat tissue compared to tenofovir disoproxil fumarate","authors":"Bryan Dulion ,&nbsp;Arnold Z. Olali ,&nbsp;Niyati Patel ,&nbsp;Amber K. Virdi ,&nbsp;Ankur Naqib ,&nbsp;Jennillee Wallace ,&nbsp;Ryan D. Ross","doi":"10.1016/j.antiviral.2025.106151","DOIUrl":"10.1016/j.antiviral.2025.106151","url":null,"abstract":"<div><div>Modern antiretroviral therapy (ART) is associated with rapid weight gain, which appears to be antiretroviral-specific. Tenofovir is a nucleoside reverse transcriptase inhibitor commonly employed as a backbone in many ART formulations. Tenofovir alafenamide (TAF) has been associated with significant weight gain in people living with HIV (PLWH) initiating ART. Interestingly, tenofovir disoproxil fumarate (TDF), has no impact on weight or may even be weight suppressive. The current study compared the impact of two tenofovir-based ART formulations on weight and adipose tissue. We utilized a humanized mouse model of HIV-infection and administered two clinically relevant ART combinations TAF/dolutegravir (DTG)/emtricitabine (FTC) and TDF/DTG/FTC. As expected, female mice treated with TAF/DTG/FTC had the greatest weight gain and fat accumulation, as measured by dual energy x-ray absorptiometry (DXA). As ART-induced accumulation of visceral adipose tissue is linked to mortality, we isolated visceral adipose tissue for targeted (qPCR) and non-targeted (RNAseq) gene expression. Mice treated with TAF/DTG/FTC had increased expression of adipocyte differentiation related genes, leptin and PPAR-γ. RNAseq revealed that while the expression patterns for both TAF/DTG/FTC and TDF/DTG/FTC treated mice were similar, there were key differences. Specifically, KEGG pathway analysis indicated that TAF/DTG/FTC treated mice showed suppression of multiple fatty acid metabolism related pathways, while TDF/DTG/FTC treated mice showed evidence for increased thermogenesis. The results suggest that weight gain associated with TAF-based ART may be due to impaired adipocyte mediated lipid handling, while suppressed weight gain with TDF-based ART may be secondary to increased browning of visceral adipocytes, although independent validation is necessary.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106151"},"PeriodicalIF":4.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of influenza A virus proliferation in mice via universal RNA interference.","authors":"Yu-Shen Kuo, Pei-Chuan Chiang, Chieh-Ying Kuo, Chung-Guei Huang, Ming-Ling Kuo, Ya-Fang Chiu","doi":"10.1016/j.antiviral.2025.106149","DOIUrl":"https://doi.org/10.1016/j.antiviral.2025.106149","url":null,"abstract":"<p><p>Influenza A virus (IAV) is a respiratory pathogen that causes seasonal outbreaks and periodic pandemics. As frequent mutations in the IAV viral genome often render vaccines ineffective or inefficient in preventing the latest outbreak, there is a need to explore other preventive strategies to control the disease. This study sought to investigate the use of antiviral short hairpin RNA (shRNA), delivered by a recombinant adeno-associated virus (AAV), for the prevention of IAV infections. Conserved regions with less than 10% of variation were identified from IAV genome sequences deposited in the National Center for Biotechnology Information (NCBI) database between 2000 and 2023. The shRNA targeting these conserved sequences was transcribed from the human RNA polymerase III U6 promoter in an AAV system. This study demonstrates that AAV delivery of shRNA against IAV genes encoding two of the viral RNA-dependent RNA polymerase subunits, PB1 and PB2, inhibits the replication of IAV H1N1 and H3N2 viruses in Madin-Darby canine kidney (MDCK) cells. Delivered shPB1 to lung tissue in mice through AAV also provided effective protection against IAV infection. These results offer support for a shRNA-based strategy of influenza prevention.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106149"},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the host transcription factor HSF1 prevents human cytomegalovirus replication in vitro and in vivo","authors":"Dilruba Akter ,&nbsp;Juthi Biswas ,&nbsp;Shima Moradpour ,&nbsp;Meghan F. Carter ,&nbsp;Michael J. Miller ,&nbsp;Dennis J. Thiele ,&nbsp;Eain A. Murphy ,&nbsp;Christine M. O'Connor ,&nbsp;Jennifer F. Moffat ,&nbsp;Gary C. Chan","doi":"10.1016/j.antiviral.2025.106150","DOIUrl":"10.1016/j.antiviral.2025.106150","url":null,"abstract":"<div><div>FDA-approved antivirals against HCMV have several limitations, including only targeting the later stages of the viral replication cycle, adverse side effects, and the emergence of drug-resistant strains. Antivirals targeting host factors specifically activated within infected cells and necessary for viral replication could address the current drawbacks of anti-HCMV standard-of-care drugs. In this study, we found HCMV infection stimulated the activation of the stress response transcription factor heat shock transcription factor 1 (HSF1). HCMV entry into fibroblasts rapidly increased HSF1 activity and subsequent relocalization from the cytoplasm to the nucleus, which was maintained throughout viral replication and in contrast to the transient burst of activity induced by canonical heat shock. Prophylactic pharmacological inhibition or genetic depletion of HSF1 prior to HCMV infection attenuated the expression of all classes of viral genes, including immediate early (IE) genes, and virus production, suggesting HSF1 promotes the earliest stages of the viral replication cycle. Therapeutic treatment with SISU-102, an HSF1 inhibitor tool compound, after IE expression also reduced the levels of L proteins and progeny production, suggesting HSF1 regulates multiple steps along the HCMV replication cycle. Leveraging a newly developed human skin xenograft transplant murine model, we found prophylactic treatment with SISU-102 significantly attenuated viral replication in transplanted human skin xenografts as well as viral dissemination to distal sites. These data demonstrate HCMV infection rapidly activates and relocalizes HSF1 to the nucleus to promote viral replication, which can be exploited as a host-directed antiviral strategy.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106150"},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“Insights in the RSV L polymerase function and structure”","authors":"Brecht Bonneux ,&nbsp;Martina Ceconi ,&nbsp;Kim Stobbelaar ,&nbsp;Florence Herschke ,&nbsp;Peter Delputte","doi":"10.1016/j.antiviral.2025.106148","DOIUrl":"10.1016/j.antiviral.2025.106148","url":null,"abstract":"<div><div>Respiratory syncytial virus (RSV) continues to have a large medical and economic impact worldwide, mainly in infants, elderly, and immunocompromised patients. While several vaccines and prophylactic antibodies are now available, effective treatment options are still needed. A highly interesting target for treatment is the replication process of the virus, in which the viral polymerase complex is critical. A critical protein of this complex is the RSV large (L) protein, which harbors multiple enzymatic functions that are all interesting targets for antiviral drug discovery. Unfortunately, not all structural parts of this L protein are currently resolved, which makes antiviral drug design and optimization challenging. In this review, an overview is given of current knowledge on the RSV L structure. Furthermore, a comparison is made between the L proteins of RSV and human metapneumovirus (hMPV), which, based on their sequence similarity, could shed light on missing structural gaps. New insights into the RSV and hMPV L protein structures are given, by modeling unresolved domains with AlphaFold2 and Alphafold3. While more structural studies are needed to confirm the modeling data, there is clearly potential for development of treatments targeting the L protein, for RSV and closely related viruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106148"},"PeriodicalIF":4.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Glucosidase Inhibitors as Broad-Spectrum Antivirals: Current Knowledge and Future Prospects.","authors":"James Wj Kang, Kitti Wing Ki Chan, Subhash G Vasudevan, Jenny G Low","doi":"10.1016/j.antiviral.2025.106147","DOIUrl":"https://doi.org/10.1016/j.antiviral.2025.106147","url":null,"abstract":"","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106147"},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility\" [Antiv. Res. (2025) 106082].","authors":"Mengxin Xu, Zhaoyong Zhang, Yuzhu Sun, Haoting Mai, Siqi Liu, Shuning Liu, Kexin Lv, Feiyang Yu, Yuanyuan Wang, Xinyu Yue, Jiayi Zhang, Xiaoyu Cai, Ruixin Zhao, Hongjie Lu, Lin Liu, Huanle Luo, Haiyan Zhao, Yanqun Wang, Peng Gong, Shoudeng Chen, Xuping Jing, Jincun Zhao, Yao-Qing Chen","doi":"10.1016/j.antiviral.2025.106146","DOIUrl":"https://doi.org/10.1016/j.antiviral.2025.106146","url":null,"abstract":"","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106146"},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepato-selective dihydroquinolizinones active against hepatitis A virus in vitro and in vivo","authors":"Ichiro Misumi ,&nbsp;Zhizhou Yue ,&nbsp;Zhengyuan Jiang ,&nbsp;Anilkumar Karampoori ,&nbsp;Jason K. Whitmire ,&nbsp;John M. Cullen ,&nbsp;Timothy Block ,&nbsp;Stanley M. Lemon ,&nbsp;Yanming Du ,&nbsp;You Li","doi":"10.1016/j.antiviral.2025.106145","DOIUrl":"10.1016/j.antiviral.2025.106145","url":null,"abstract":"<div><div>Despite the considerable clinical and economic burden imposed by hepatitis A virus (HAV) infection, both globally and in U.S., there are currently no available antiviral therapies for the treatment of type A hepatitis. Here we describe novel third-generation hepato-selective dihydroquinolizinones (HS-DHQs) with cellular uptake mediated by transport via hepatocyte-specific solute organic anion transporter family members 1B1 and 1B3 (OATP1B1-B3). The lead HS-DHQ compound, HS83128, demonstrates robust inhibition of the host cell TENT4A/B terminal nucleotidyltransferases required for efficient HAV RNA synthesis (IC₅₀ 6–25nM), and potent antiviral activity against HAV in cell culture (EC₅₀ 0.6 nM). Pharmacokinetic studies in CD-1 mice receiving comparable oral doses of HS83128 and a first-generation dihydroquinolizinone, RG7834, revealed a 5-fold increase in intrahepatic drug concentration and more than 10-fold improvement in liver versus nervous system tissue selectivity. Twice-daily oral administration of HS83128 rapidly arrested viral replication in HAV-infected <em>Ifnar1</em>^{<em>−/−</em>} mice, reducing fecal virus shedding and cytokine markers of hepatic inflammation and reversing virus-induced liver injury. The hepato-selective nature of HS83128 may reduce the risk of neurologic and reproductive track toxicities observed with long-term administration of other dihydroquinolizinones, making it a candidate for the first antiviral therapy of hepatitis A.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106145"},"PeriodicalIF":4.5,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fusion peptide of the spike protein S2 domain may be a mimetic analog of β-coronaviruses and serve as a novel virus-host membrane fusion inhibitor","authors":"Abass Alao Safiriyu ,&nbsp;Afaq Hussain ,&nbsp;Nikesh Dewangan ,&nbsp;Grishma Kasle ,&nbsp;Kenneth Shindler ,&nbsp;Debnath Pal ,&nbsp;Jayasri Das Sarma","doi":"10.1016/j.antiviral.2025.106144","DOIUrl":"10.1016/j.antiviral.2025.106144","url":null,"abstract":"<div><div>Coronavirus has garnered more attention recently, particularly in the aftermath of the 2019 pandemic. The β genus of the coronavirus family has demonstrated a significant threat to humanity. Current mitigation strategies involve the development of vaccines and repurposing drugs for symptomatic management of coronavirus infection, specifically SARS-Cov 2. Fusion inhibitors that are available as antiviral drugs for coronavirus have targeted the heptad repeat (HR) 1 and 2 in the S2 domain of the spike protein. The current study identified a fusion peptide (FP) upstream of HR1 as a potential target for developing membrane fusion inhibitors, and mimetic peptides analogous to the FP segment were tested for antiviral activity. Four mimetic fusion peptides (MFPs) (RSA59PP (MFP633), RSA59P (MFP634), RSMHV2P (MFP635), and RSMHV2PP (MFP636)) that are analogous to the FP of murine β coronavirus mouse hepatitis virus (MHV), MHV-A59/RSA59 (PP) and MHV-2/RSMHV2 (P) with central proline mutations, were tested. Results show the ability of MFPs to reduce cell-to-cell fusion and viral replication <em>in vitro</em>. MFP633, which contains a central double proline, exhibited the most potent inhibitory effect in spike protein-mediated membrane fusion assays. Biophysical experiments also demonstrated the strongest interactions between double-proline containing MFPs (MFP633 and MFP636) with biomimetic liposomes. <em>In vivo</em> studies using a liposome-mediated delivery system in mice confirmed the antiviral activity of MFP633. These findings suggest that targeting FPs could develop effective fusion inhibitors against coronaviruses. MFPs act on the host cell membrane by competing with the viral FP during the early stage of host-viral membrane fusion events. MFP633 is a promising peptide drug candidate that warrants future examination to assess whether this and other dual-proline containing peptides may exert similar anti-viral effects in other coronaviruses with conserved FP structures.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106144"},"PeriodicalIF":4.5,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A hepatitis B virus-free cccDNA-producing stable cell for antiviral screening","authors":"Chengqian Feng ,&nbsp;Jingrong Shi ,&nbsp;Yunfu Chen ,&nbsp;Sisi Chen ,&nbsp;Jianping Cui ,&nbsp;Jun Zhang ,&nbsp;Xiaowen Zheng ,&nbsp;Yaping Wang ,&nbsp;Feng Li","doi":"10.1016/j.antiviral.2025.106143","DOIUrl":"10.1016/j.antiviral.2025.106143","url":null,"abstract":"<div><div>The covalently closed circular DNA (cccDNA) of the Hepatitis B virus (HBV) serves as a template for producing progeny viruses in virally infected hepatocytes. Promising cccDNA-targeting antiviral agents remain unavailable and unpredictable in the research and development pipelines, making sterile HBV elimination challenging at the current stage. The major challenge of discriminating trace amounts of cccDNA from the abundant HBV relaxed circular DNA (rcDNA), which is nearly identical to cccDNA in sequence, substantially discourages efforts to discover and directly screen cccDNA-targeting drugs. Therefore, an easy cccDNA cell culture system is required for high-throughput drug screening. In this study, we designed an HBV cccDNA self-generating stable cell culture system using a functional complementary concept and successfully generated an HBV cccDNA Gaussia luciferase reporter cell line in HepG2 and Huh7 cells. This design ensures that the Gluc signal is exclusively expressed upon cccDNA formation, allowing for the accurate and easy measurement of cccDNA levels via luminescent signals. Using this system, in conjunction with a firefly luciferase reporter to monitor cell activity, we screened 2074 drugs in the HepG2-HBV-cccDNA/Firefly cell line. Four compounds were selected for further experimentation and their anti-HBV effects were confirmed. Thus, this virus-free hepatitis B cccDNA cell culture system provides a valuable and convenient platform for the high-throughput screening of anti-HBV drugs.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106143"},"PeriodicalIF":4.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host RNA-binding proteins and specialized viral RNA translation mechanisms: Potential antiviral targets","authors":"Leandro Fernández-García ,&nbsp;Mariano A. Garcia-Blanco","doi":"10.1016/j.antiviral.2025.106142","DOIUrl":"10.1016/j.antiviral.2025.106142","url":null,"abstract":"<div><div>RNA-binding proteins (RBPs) are the key regulators of the metabolism of RNA, from its genesis to its degradation. Qualitative and quantitative alterations of RBPs, including their post-translational modifications, impact cellular physiology and are associated with disease processes. Many cellular RBPs also play essential roles in the replication of viruses, especially RNA viruses, which, as obligatory parasites, rely on the host cell's biosynthetic and structural machinery. Viral protein synthesis is a key step in viral lifecycles and critically depends on host RBPs. In many cases, the translation of viral mRNAs employs specialized mechanisms that give viral mRNAs advantages over cellular RNAs. Host RBPs regulate these specialized mechanisms. In this work, we review the role of RBPs in specialized viral RNA translation, focusing on these RBPs as potential antiviral drug targets.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"237 ","pages":"Article 106142"},"PeriodicalIF":4.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}