Antiviral research最新文献_第3页

The phospho-dynamics of cytomegalovirus capsid interaction, with its protein kinase and nuclear egress complex, provide an antiviral targeting concept 巨细胞病毒衣壳相互作用的磷酸化动力学及其蛋白激酶和核出口复合体提供了抗病毒靶向概念。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2025-12-19 DOI: 10.1016/j.antiviral.2025.106335

Julia Tillmanns , Christina Wangen , Pia Geiger , Sigrun Häge , Tihana Lenac Roviš , Philipp Arnold , Heinrich Sticht , Manfred Marschall

Human cytomegalovirus (HCMV) is a major pathogen with worldwide distribution. Improved insight into antiviral targeting is urgently needed for drug development. Viral nuclear capsid egress is a validated target for new small molecules, including the approved viral kinase inhibitor maribavir (MBV). A detailed understanding of the regulatory interplay between HCMV kinase activity (pUL97), the nuclear egress complex (NEC), and viral capsids is pertinent in this regard. Specifically, the egress-based protein–protein interactions represent a virus rate-limiting determinant. The conserved process of nuclear capsid egress is defined by the interaction between the capsid and NEC, as well as an essential regulatory impact of pUL97 phosphorylation. Using recombinant virus analysis systems, we demonstrated the proteins responsible for NEC–capsid binding. The data indicated that the core NEC component pUL53 acts as the primary capsid interactor. Importantly, MBV revealed a dependence on phosphorylation for individual steps in these interactive processes. Of particular note, we used the highly selective mode of MBV in the study to identify pUL97 as a key factor in the regulation of NEC–capsid interaction. The findings also included the direct pUL97–capsid association, as supported by data from protein assembly assays, in vitro kinase reactions, comprehensive microscopy, and bioinformatic modeling of available structures. Finally, the determination of phosphorylated versus nonphosphorylated states of involved proteins led to a more refined understanding of the mechanistic concept of HCMV nuclear capsid egress. Combined, the study may improve our understanding of viral replication efficacy and mechanisms of antiviral drug activity.

人巨细胞病毒（HCMV）是一种世界性的主要病原体。药物开发迫切需要更好地了解抗病毒靶向性。病毒核衣壳出口是新小分子的有效靶标，包括已批准的病毒激酶抑制剂马里巴韦（MBV）。详细了解HCMV激酶活性（pUL97）、核出口复合体（NEC）和病毒衣壳之间的调节相互作用在这方面是相关的。具体来说，基于出口的蛋白质-蛋白质相互作用代表了病毒速率限制的决定因素。核衣壳出口的保守过程是由衣壳和NEC之间的相互作用以及pUL97磷酸化的重要调控作用所定义的。利用重组病毒分析系统，我们展示了负责nec衣壳结合的蛋白质。数据表明，核心NEC成分pUL53是主要的衣壳相互作用因子。重要的是，MBV揭示了这些相互作用过程中单个步骤的磷酸化依赖性。特别值得注意的是，我们在研究中使用了MBV的高选择性模式来确定pUL97是调节nec -衣壳相互作用的关键因子。这些发现还包括直接的pul97 -衣壳关联，这些数据得到了蛋白质组装分析、体外激酶反应、综合显微镜和可用结构的生物信息学建模的支持。最后，对相关蛋白磷酸化与非磷酸化状态的测定，使我们对HCMV核衣壳输出的机制概念有了更精确的理解。该研究有助于我们进一步了解病毒的复制效率和抗病毒药物的作用机制。

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引用次数: 0

Identification of claramine and anidulafungin as entry inhibitors of Crimean–Congo hemorrhagic fever virus 克里米亚-刚果出血热病毒入境抑制剂克拉拉胺和抗磺胺酮的鉴定

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2026-01-08 DOI: 10.1016/j.antiviral.2026.106343

Yasuteru Sakurai , Minato Hirano , Sayaka Okada , Yohei Kurosaki , Rokusuke Yoshikawa , John N. Barr , Roger Hewson , Kentaro Yoshii , Jiro Yasuda

Crimean–Congo hemorrhagic fever virus (CCHFV) is a tick-borne enveloped virus that causes a severe disease in humans. Despite its wide geographic distribution, no approved vaccines or therapeutics exist. In this study, we achieved high-titer production of pseudotyped virus bearing CCHFV glycoproteins with a C-terminal truncation. Screening over 3,600 small compounds using this pseudotyped virus identified claramine and anidulafungin as CCHFV entry inhibitors. These hit compounds, as well as caspofungin, which is related to anidulafungin, inhibited pseudotyped viral infection in human liver cells and vascular endothelial cells. They inhibited infection of pseudotyped virus with glycoproteins from various CCHFV strains and Hazara virus, a nairovirus closely related to CCHFV. Using a quantitative fusion assay, the identified inhibitors were shown to block membrane fusion via CCHFV glycoproteins. Moreover, they inhibited infection of replication-competent Hazara virus. Therefore, the assays developed in this study were successful in identifying CCHFV entry inhibitors that target membrane fusion.

克里米亚-刚果出血热病毒（CCHFV）是一种蜱传包膜病毒，可引起人类严重疾病。尽管其地理分布广泛，但没有批准的疫苗或治疗方法。在这项研究中，我们实现了高滴度生产携带c端截断的CCHFV糖蛋白的假型病毒。利用该伪型病毒筛选了3600多种小化合物，确定了claramine和anidulafungin作为CCHFV进入抑制剂。这些hit化合物，以及与anidulafungin相关的caspofungin，抑制了人肝细胞和血管内皮细胞的假型病毒感染。它们用来自各种CCHFV毒株和哈扎拉病毒（一种与CCHFV密切相关的奈罗病毒）的糖蛋白抑制假型病毒的感染。通过定量融合实验，鉴定出的抑制剂可以通过CCHFV糖蛋白阻断膜融合。此外，它们还能抑制具有复制能力的哈扎拉病毒的感染。因此，本研究中开发的检测方法成功地鉴定了靶向膜融合的CCHFV进入抑制剂。

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引用次数: 0

An orally available peptidomimetic with broad-spectrum antiviral activity targeting the enterovirus 2C helicase 具有广谱抗病毒活性的口服拟肽，靶向肠病毒2C解旋酶

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2026-01-02 DOI: 10.1016/j.antiviral.2025.106341

Chang Wang , Huoyan Tong , Xi Zhou , Yuan Fang

Enteroviruses (EVs) are significant human pathogens, and the development of orally available, broad-spectrum antiviral agents remains an urgent need. The viral protein 2C, a conserved nonstructural protein with helicase activity, is a promising target for antiviral intervention. Although the peptide 2CL was previously identified as a 2C inhibitor, its cell-penetrating peptide motif and extended core sequence may limit its binding efficiency and pharmacological properties. Here, we report the optimization of 2CL to develop a novel peptidomimetic, 2CA-1, with a more compact structure and absence of a cell-penetrating motif. Besides its potent cellular antiviral activity, achieved by precise docking into the 2C binding pocket to inhibit helicase function, 2CA-1 exhibited excellent oral bioavailability in a murine model, significantly reducing viral loads and showing broad efficacy against multiple enteroviruses including CV-A6, CV-A16, CV-B3, Echo11, EV-D68 and rhinovirus. This study not only presents 2CA-1 as an optimized 2C-targeted antiviral candidate but also highlights its potential as an orally available and broad-spectrum therapeutic against EVs.

肠病毒（ev）是重要的人类病原体，迫切需要开发可口服的广谱抗病毒药物。病毒蛋白2C是一种具有解旋酶活性的保守非结构蛋白，是抗病毒干预的一个有希望的靶点。虽然肽2CL先前被确定为2C抑制剂，但其细胞穿透肽基序和延长的核心序列可能限制了其结合效率和药理学性质。在这里，我们报道了2CL的优化，以开发一种新的拟肽，2CA-1，具有更紧凑的结构和缺乏细胞穿透基序。除了通过精确对接2C结合口袋抑制解旋酶功能而获得的有效细胞抗病毒活性外，2CA-1在小鼠模型中表现出优异的口服生物利用度，显著降低病毒载量，并对多种肠道病毒（包括CV-A6、CV-A16、CV-B3、Echo11、EV-D68和鼻病毒）显示出广泛的功效。这项研究不仅表明2CA-1是一种优化的2c靶向抗病毒候选药物，而且还强调了它作为一种口服的广谱治疗ev的潜力。

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引用次数: 0

Low-level viremia increases the risk of adverse long-term outcomes in entecavir-treated patients with chronic hepatitis B 低水平病毒血症增加恩替卡韦治疗的慢性乙型肝炎患者不良长期结局的风险。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2025-12-16 DOI: 10.1016/j.antiviral.2025.106334

Dong Ji , Meng-Wen He , Wen-Chang Wang , Wei Han , Yan Chen , Yan Liu , Le Li , Xu-Yang Li , Yi-Fan Guo , Wu-Cai Yang , Zheng Dong , Chun-Yan Wang , Jing Xu , Lin Tan , George Lau , Yongping Yang

Low-level viremia (LLV) still occurs in some patients with chronic hepatitis B (CHB) after entecavir (ETV) treatment. We aimed to evaluate the effects of LLV on the adverse long-term outcomes. A secondary analysis of a multicenter prospective cohort study, consisting patients who underwent liver biopsy and received entecavir treatment, was conducted. LLV was defined as detectable HBV DNA levels (20–2000 IU/mL) at week 48 after the imitation of ETV treatment, maintained complete virological response (CVR) was defined as HBV DNA <20 IU/mL. The zero time was defined as the date of LLV diagnosis, the primary endpoint was the occurrence of HCC. The time-to-event analyses were performed using log-rank analysis, and multivariable COX regression. The inverse probability of treatment weighting and propensity score matching were used in the sensitivity analyses. In total, 766 patients were enrolled in the final analysis, and LLV was found in 182 patients (23.8 %). Patients with LLV had a significantly higher 7-year cumulative incidence of HCC (18.7 % vs. 8.1 %, p < 0.001) and fibrosis progression rate (17.5 % vs. 8.7 %, p = 0.017) than those with CVR. Multivariate analysis identified LLV as an independent risk factor associated with HCC (adjusted HR: 3.935; 95 % CI: 2.218–6.979, p < 0.001) and fibrosis progression (adjusted OR 5.342; 95 % CI: 1.630–17.480, p = 0.006). A nomogram incorporating LLV, age, PLT and liver cirrhosis was developed and validated for HCC risk prediction, demonstrating excellent performance with a C-index of 0.778. In conclusion, LLV significantly promoted HCC occurrence and fibrosis progression in CHB patients receiving anti-HBV treatment.

一些慢性乙型肝炎（CHB）患者在恩替卡韦（ETV）治疗后仍会发生低水平病毒血症（LLV）。我们的目的是评估LLV对不良长期预后的影响。对一项多中心前瞻性队列研究进行了二次分析，该研究包括接受肝活检并接受恩替卡韦治疗的患者。LLV定义为在模拟ETV治疗后第48周可检测到的HBV DNA水平（20-2000 IU/mL），维持完全病毒学应答（CVR）定义为HBV DNA

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引用次数: 0

Single-shot design of a cyclic peptide inhibitor of HIV membrane fusion HIV膜融合环肽抑制剂的单次设计。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2025-12-20 DOI: 10.1016/j.antiviral.2025.106336

Diandra Daumiller , Federica Giammarino , Qiuzhen Li , Anders Sönnerborg , Rafael Ceña Diez , Patrick Bryant

HIV evades immune detection through rapid mutation of its surface proteins, yet essential steps in viral entry, such as CD4 and co-receptor engagement, remain highly conserved. While therapies like Lenacapavir represent major advances, the emergence of resistant strains highlights the urgent need for adaptable, rapid-response antivirals. This challenge extends beyond HIV, demanding scalable design strategies for diverse viral threats. Here, we demonstrate that AI-driven design can address this need by generating cyclic peptide binders targeting a previously unexploited interface on the HIV-1 fusion protein gp41. Using only sequence information, without prior structural or binding site data, we designed and experimentally validated a single candidate. This inhibitor potently blocked infection by two HIV-1 strains in cell-based assays with no detectable cytotoxicity. Affinity analysis with SPR confirms the interaction with gp41 as designed. Our findings illustrate how AI-guided peptide design, coupled with rapid in-vitro validation, can accelerate early-stage therapeutic discovery and enable timely intervention against emerging viral threats.

HIV通过其表面蛋白的快速突变来逃避免疫检测，但病毒进入的关键步骤，如CD4和共受体结合，仍然高度保守。虽然Lenacapavir等疗法代表了重大进展，但耐药菌株的出现突出表明迫切需要适应性强、反应迅速的抗病毒药物。这一挑战超出了艾滋病毒的范畴，需要针对各种病毒威胁的可扩展设计策略。在这里，我们证明了人工智能驱动的设计可以通过生成针对HIV-1融合蛋白gp41上以前未开发的界面的环肽结合物来解决这一需求。仅使用序列信息，没有事先的结构或结合位点数据，我们设计并实验验证了单个候选。在基于细胞的实验中，这种抑制剂有效地阻断了两种HIV-1毒株的感染，没有检测到细胞毒性。与SPR的亲和分析证实了与gp41的相互作用。我们的研究结果说明了人工智能引导的肽设计，加上快速的体外验证，可以加速早期治疗发现，并能够及时干预新出现的病毒威胁。

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引用次数: 0

A new locus of foscarnet resistance in the cytomegalovirus UL54 DNA polymerase gene among uncharacterized mutations in recent clinical trials 在最近的临床试验中，巨细胞病毒UL54 DNA聚合酶基因在未表征的突变中发现了新的膦酸钠耐药位点。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2025-12-31 DOI: 10.1016/j.antiviral.2025.106340

Sunwen Chou , Alexis Minyard , Justin Watanabe

In two recent Phase 3 clinical trials of maribavir that also involved existing standard therapies, many uncharacterized cytomegalovirus UL54 DNA polymerase genetic variants were encountered. Six UL54 mutations were selected for phenotyping, based on proximity to published resistance loci and quality of sequencing information. UL54 amino acid substitutions E949K and E949Q conferred foscarnet resistance with slightly decreased ganciclovir and cidofovir susceptibility, representing a novel palm domain resistance locus. UL54 N498S and P598S mutants had slight decreases in ganciclovir and cidofovir susceptibility, with N498S also having a slightly decreased foscarnet susceptibility. No drug resistance was attributed to A786V and A928V. Retesting published phenotypes for UL54 mutants D515E, D542E, A543V and A928T revealed some discordant findings, including ganciclovir resistance for D542E and A543V, and no drug resistance for D515E and A928T. These genotype-phenotype correlations add to the evidence base for clinical diagnostic testing of cytomegalovirus drug resistance.

在最近的两项涉及现有标准疗法的马里巴韦3期临床试验中，遇到了许多未确定的巨细胞病毒UL54 DNA聚合酶遗传变异。根据与已发表的耐药位点的接近程度和测序信息的质量，选择了6个UL54突变进行表型分析。UL54氨基酸取代E949K和E949Q使氟膦酸酯耐药，更昔洛韦和西多福韦的敏感性略有降低，代表了一种新的掌域耐药位点。UL54 N498S和P598S突变体对更昔洛韦和西多福韦的敏感性略有下降，N498S对氟喹酮的敏感性也略有下降。A786V和A928V均未产生耐药。重新检测已公布的UL54突变体D515E、D542E、A543V和A928T的表型，发现了一些不一致的结果，包括D542E和A543V对更昔洛韦耐药，而D515E和A928T不耐药。这些基因型-表型相关性增加了巨细胞病毒耐药性临床诊断检测的证据基础。

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引用次数: 0

2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages 2-脱氧-d -葡萄糖减轻脂多糖诱导的炎症，并限制寨卡病毒、基孔肯雅病毒和玛雅罗病毒在单核细胞来源的巨噬细胞中的复制

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2025-12-24 DOI: 10.1016/j.antiviral.2025.106338

Y.S. Tamayo-Molina, Yisel García-Marin, Silvio Urcuqui-Inchima

Re-emerging arthropod-borne viruses such as Mayaro (MAYV), Chikungunya (CHIKV), and Zika (ZIKV) pose a growing global health concern as Aedes mosquito populations expand. These arboviruses infect innate immune cells, particularly monocyte-derived macrophages (MDMs), which support viral replication and serve as reservoirs that facilitate dissemination. Because no effective antiviral treatments are available, strategies that modulate macrophage responses and restrict viral replication are urgently needed. Here, we evaluated the immunomodulatory and antiviral effects of 2-deoxy-D-glucose (2-DG) in human MDMs. First, we assessed how 2-DG shapes transcriptional responses to lipopolysaccharide (LPS), a canonical TLR4 agonist. Co-treatment with 2-DG and LPS induced genes linked to inflammatory, antiviral, and endoplasmic reticulum (ER) stress pathways. Notably, IL10 mRNA and IL-10 protein displayed an inverse relationship with metabolic stress yet correlated positively with inflammatory and antiviral gene expression, whereas GADD34 was positively associated with both inflammatory and ER stress responses, suggesting an integrative regulatory role. We next investigated whether 2-DG pretreatment limits replication of MAYV, CHIKV, and ZIKV in infected MDMs. Antiviral assays demonstrated that 2-DG reduced replication of all three arboviruses by approximately one log₁₀. Additional analyses revealed distinct temporal sensitivities: MAYV and CHIKV showed early and late susceptibility, whereas ZIKV exhibited a distinct kinetic profile. Mechanistic experiments confirmed that 2-DG acts post-entry primarily and reverses the antiviral phenotype observed in LPS-primed MDMs. Collectively, these findings reveal crosstalk among inflammatory, antiviral, and ER stress pathways and demonstrate that 2-DG modulates LPS-driven inflammation while reducing replication of pathogenic arboviruses in human MDMs.

随着伊蚊种群的扩大，重新出现的节肢动物传播病毒，如马雅罗病毒（MAYV）、基孔肯雅病毒（CHIKV）和寨卡病毒（ZIKV）日益成为全球卫生问题。这些虫媒病毒感染先天免疫细胞，特别是单核细胞来源的巨噬细胞（MDMs），这些细胞支持病毒复制并作为促进传播的储存库。由于没有有效的抗病毒治疗方法，因此迫切需要调节巨噬细胞反应和限制病毒复制的策略。在这里，我们评估了2-脱氧-d -葡萄糖（2-DG）在人MDMs中的免疫调节和抗病毒作用。首先，我们评估了2-DG如何形成对脂多糖（LPS）的转录反应，这是一种典型的TLR4激动剂。与2-DG和LPS共同治疗诱导与炎症、抗病毒和内质网（ER）应激途径相关的基因。值得注意的是，IL10 mRNA和IL-10蛋白与代谢应激呈负相关，但与炎症和抗病毒基因表达呈正相关，而GADD34与炎症和内质网应激反应均呈正相关，表明其具有综合调节作用。接下来，我们研究了2-DG预处理是否限制了MAYV、CHIKV和ZIKV在感染MDMs中的复制。抗病毒试验表明，2-DG使所有三种虫媒病毒的复制减少了约1 log10。其他分析揭示了不同的时间敏感性：MAYV和CHIKV表现出早期和晚期易感性，而ZIKV表现出不同的动力学特征。机制实验证实，2-DG主要在进入后起作用，并逆转了lps引物MDMs中观察到的抗病毒表型。总的来说，这些发现揭示了炎症、抗病毒和内质网应激途径之间的相互作用，并表明2-DG调节lps驱动的炎症，同时减少人类MDMs中致病性虫媒病毒的复制。

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引用次数: 0

Newcastle disease virus TS09-C strain provides long-lasting protection against virulent strain after in-ovo immunization 新城疫病毒TS09-C毒株在卵内免疫后对毒力毒株具有持久的保护作用。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-02-01 Epub Date: 2025-12-10 DOI: 10.1016/j.antiviral.2025.106325

Helong Feng , Junjie Yang , Liren Jiang , Xiaoyu Suo , Yuqiao Zhu , Yu Shang , Hongcai Wang , Zhe Zeng , Lun Yao , Qingping Luo , Guoyuan Wen

Newcastle disease (ND) is an important infectious disease in poultry, causing substantial economic losses in many countries. Vaccination with live vaccines is a common strategy for ND control, and farmers generally vaccinate multiple times each year because the current ND vaccines have a relatively short protection period. Here, we report that the NDV strain TS09-C, as an in ovo vaccine, provided long-lasting protection for at least 12 months against virulent NDV. TS09-C significantly reduced the tissue viral titer, alleviated histopathological lesions, and induced proliferation of CD8⁺ T cells after challenge. TS09-C in ovo group vs PBS group, 142 immune-related DEGs were screened based on RNA-Seq, including 18 up-regulated DEGs and 124 down-regulated DEGs. The innate immune pathways of these genes, as NOD-like, Toll-like, RIG-I-like, Cytokine-cytokine receptor interaction, and all genes (including pro-inflammatory cytokines IL-1B, IL-6, IL-18, etc) in these pathways were significantly downregulated. These results indicate that NDV strain TS09-C is a long-lasting protection vaccine candidate against ND, and the protection might be due to the reason that TS09-C induces the proliferation of CD8⁺ T cells and inhibits the inflammatory response.

新城疫病是一种重要的家禽传染病，在许多国家造成了巨大的经济损失。接种活疫苗是控制新风的一种常见策略，农民通常每年接种多次疫苗，因为目前的新风疫苗保护期相对较短。在这里，我们报道了NDV菌株TS09-C作为一种蛋内疫苗，提供了至少12个月的持久保护，以抵抗致命的NDV。TS09-C显著降低组织病毒滴度，减轻组织病理病变，诱导CD8+ T细胞攻毒后增殖。通过RNA-Seq方法筛选了142个与免疫相关的DEGs，其中上调DEGs 18个，下调DEGs 124个。这些基因的先天免疫通路，如nod样、toll样、rig -i样、细胞因子-细胞因子受体相互作用，以及这些通路中所有基因（包括促炎细胞因子IL-1B、IL-6、IL-18等）均显著下调。这些结果表明，NDV菌株TS09-C是ND的长效保护候选疫苗，其保护作用可能与TS09-C诱导CD8+ T细胞增殖和抑制炎症反应有关。

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引用次数: 0

Isochlorogenic acid A impairs hepatitis B virus replication by interference with various steps of hepatitis B virus life cycle involving HO-1-mediated ROS modulation 异绿原酸A通过干扰乙型肝炎病毒生命周期的各个步骤，包括ho -1介导的ROS调节，从而损害乙型肝炎病毒的复制

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-01-01 Epub Date: 2025-12-04 DOI: 10.1016/j.antiviral.2025.106323

Giscard Wilfried Koyaweda , Mirco Glitscher , Anja Schollmeier , Daniela Bender , Eberhard Hildt

Chronic hepatitis B virus (HBV) infection is a major health problem, affecting around 254 million people worldwide. Current treatments have side effects and can lead to resistance. Therefore, natural compounds derived from plants are being studied as potential antivirals. Isochlorogenic acid A (ICAA), which is derived from caffeoylquinic acid, exerts antiviral and hepatoprotective effects. The antioxidant effect of ICAA, triggered by upregulation of heme oxygenase 1 (HO-1), has been suggested as potential antiviral mechanism. However, the underlying mechanisms remain enigmatic. Our aim is to elucidate the mode of action of the antiviral effect of ICAA on HBV. Stable or transient transfected cells expressing HBV as well as HBV-infected cells were instrumental. (Sub)viral particles were characterized by biophysical and biochemical methods. Subcellular distribution of viral proteins was studied using confocal laser scanning microscopy. Viral genomes and transcripts were quantified by qPCR.

Treatment with ICAA decreased levels of HBV surface and e antigens (HBsAg and HBeAg), as well as viral transcripts, genomes and most important cccDNA. Furthermore, impaired virus assembly was evident from accumulation of naked capsids suggesting improper capsid formation and impaired envelopment. ICAA-dependent effects on HBV correlate with upregulation of HO-1 and modulation of intracellular ROS Our data indicate a possible link between changes in the intracellular ROS level and altered free -SH groups in viral structural proteins, possibly influencing proper disulphide bond formation and thereby assembly. In conclusion ICAA-dependent effects on HBV life cycle are based on several pillars as modulation of intracellular ROS and impaired morphogenesis and replication.

慢性乙型肝炎病毒（HBV）感染是一个重大健康问题，影响到全世界约2.54亿人。目前的治疗方法有副作用，并可能导致耐药性。因此，人们正在研究从植物中提取的天然化合物作为潜在的抗病毒药物。异绿原酸A （ICAA）是由咖啡酰奎宁酸衍生而来，具有抗病毒和肝保护作用。ICAA的抗氧化作用可能与血红素加氧酶1 （HO-1）的上调有关。然而，潜在的机制仍然是个谜。我们的目的是阐明ICAA对HBV抗病毒作用的作用模式。稳定或短暂转染表达HBV的细胞以及HBV感染的细胞都是有用的。（亚）病毒颗粒采用生物物理和生化方法进行了表征。用激光共聚焦扫描显微镜研究了病毒蛋白的亚细胞分布。采用qPCR对病毒基因组和转录本进行定量分析。ICAA治疗降低了HBV表面和e抗原（HBsAg和HBeAg）水平，以及病毒转录物、基因组和最重要的cccDNA。此外，裸露衣壳的积累明显损害了病毒组装，这表明衣壳形成不当和包膜受损。icaa对HBV的依赖性作用与HO-1的上调和细胞内ROS的调节相关。我们的数据表明，细胞内ROS水平的变化与病毒结构蛋白中游离sh群的改变之间可能存在联系，可能影响适当的二硫键形成和组装。总之，icaa对HBV生命周期的影响是基于细胞内ROS的调节以及形态发生和复制受损等几个支柱。

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引用次数: 0

JC polyomavirus-encoded miRNA jcv-miR-J1-5p downregulates BK polyomavirus infection JC多瘤病毒编码miRNA jv - mir - j1 -5p下调BK多瘤病毒感染

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2026-01-01 Epub Date: 2025-11-25 DOI: 10.1016/j.antiviral.2025.106313

Baptiste Demey , Aurélien Aubry , Virginie Morel , Louison Collet , Catherine Francois , Sandrine Castelain , Francois Helle , Etienne Brochot

BK and JC Polyomavirus are closely related and establish persistence in infected subjects. Recent studies suggest that JC Polyomavirus replication prevents BK Polyomavirus-related pathologies in kidney transplant recipients. One potential mechanism of this competition could involve viral microRNAs cross-reacting, as they are highly homologous between species. In fact, bkv-miR-B1-3p is strictly identical to jcv-miR-J1-3p, whereas species-specific miRNAs bkv-miR-B1-5p and jcv-miR-J1-5p differ barely.

Early detection of jcv-miR-J1-5p in urine significantly reduces the risk of BK Polyomavirus DNAemia in kidney transplant recipients in a case-control study including 39 patients (odds ratio [95 % Confidence Interval] = 0.00 [0.00–0.65], p = 0.012). In vitro modeling revealed that prior infection with JC Polyomavirus reduces the ability of BK Polyomavirus to grow in immortalized human renal proximal tubular epithelial cells, without significant expression of JC Polyomavirus proteins. The JC Polyomavirus-specific miRNA jcv-miR-J1-5p was discovered to decrease BK Polyomavirus TAg mRNA expression, without affecting early genome replication, like the known regulatory effect of BK Polyomavirus-encoded bkv-miR-B1-3p and bkv-miR-B1-5p. An archetypal strain of JC Polyomavirus engineered to quench miRNA maturation did not inhibit BK Polyomavirus infection, unlike the wild-type strain, confirming that the inhibitory effect of JC Polyomavirus is due to miRNAs.

These results suggest that JC Polyomavirus-specific miRNA jcv-miR-J1-5p limits BK Polyomavirus infectivity and early TAg expression, with an intensity similar to BK Polyomavirus miRNAs. This mechanism might explain in vivo competition for viral replication between BK Polyomavirus and JC Polyomavirus infections.

BK和JC多瘤病毒密切相关，并在感染对象中建立持久性。最近的研究表明，JC多瘤病毒的复制可预防肾移植受者的BK多瘤病毒相关病理。这种竞争的一种潜在机制可能涉及病毒microrna的交叉反应，因为它们在物种之间高度同源。事实上，bkv-miR-B1-3p与jjv - mir - j1 -3p严格相同，而物种特异性mirna bkv-miR-B1-5p和jjv - mir - j1 -5p几乎没有区别。在一项包括39例患者的病例对照研究中，尿中早期检测jcv-miR-J1-5p可显著降低肾移植受者发生BK多瘤病毒dna血症的风险（优势比[95%置信区间]= 0.00 [0.00-0.65],p = 0.012）。体外模型显示，先前感染JC多瘤病毒可降低BK多瘤病毒在永生化人肾近端小管上皮细胞中的生长能力，但JC多瘤病毒蛋白的表达不显著。发现JC多瘤病毒特异性miRNA jcv-miR-J1-5p可降低BK多瘤病毒TAg mRNA表达，但不影响早期基因组复制，如已知的BK多瘤病毒编码的bkv-miR-B1-3p和bkv-miR-B1-5p的调节作用。与野生型菌株不同，JC多瘤病毒原型株抑制miRNA成熟并没有抑制BK多瘤病毒感染，这证实JC多瘤病毒的抑制作用是由miRNA引起的。这些结果表明，JC多瘤病毒特异性miRNA jcv-miR-J1-5p限制了BK多瘤病毒的感染性和早期TAg的表达，其强度与BK多瘤病毒miRNA相似。这一机制可能解释了BK多瘤病毒和JC多瘤病毒感染在体内的病毒复制竞争。

{"title":"JC polyomavirus-encoded miRNA jcv-miR-J1-5p downregulates BK polyomavirus infection","authors":"Baptiste Demey , Aurélien Aubry , Virginie Morel , Louison Collet , Catherine Francois , Sandrine Castelain , Francois Helle , Etienne Brochot","doi":"10.1016/j.antiviral.2025.106313","DOIUrl":"10.1016/j.antiviral.2025.106313","url":null,"abstract":"<div><div>BK and JC Polyomavirus are closely related and establish persistence in infected subjects. Recent studies suggest that JC Polyomavirus replication prevents BK Polyomavirus-related pathologies in kidney transplant recipients. One potential mechanism of this competition could involve viral microRNAs cross-reacting, as they are highly homologous between species. In fact, bkv-miR-B1-3p is strictly identical to jcv-miR-J1-3p, whereas species-specific miRNAs bkv-miR-B1-5p and jcv-miR-J1-5p differ barely.</div><div>Early detection of jcv-miR-J1-5p in urine significantly reduces the risk of BK Polyomavirus DNAemia in kidney transplant recipients in a case-control study including 39 patients (odds ratio [95 % Confidence Interval] = 0.00 [0.00–0.65], p = 0.012). <em>In vitro</em> modeling revealed that prior infection with JC Polyomavirus reduces the ability of BK Polyomavirus to grow in immortalized human renal proximal tubular epithelial cells, without significant expression of JC Polyomavirus proteins. The JC Polyomavirus-specific miRNA jcv-miR-J1-5p was discovered to decrease BK Polyomavirus TAg mRNA expression, without affecting early genome replication, like the known regulatory effect of BK Polyomavirus-encoded bkv-miR-B1-3p and bkv-miR-B1-5p. An archetypal strain of JC Polyomavirus engineered to quench miRNA maturation did not inhibit BK Polyomavirus infection, unlike the wild-type strain, confirming that the inhibitory effect of JC Polyomavirus is due to miRNAs.</div><div>These results suggest that JC Polyomavirus-specific miRNA jcv-miR-J1-5p limits BK Polyomavirus infectivity and early TAg expression, with an intensity similar to BK Polyomavirus miRNAs. This mechanism might explain <em>in vivo</em> competition for viral replication between BK Polyomavirus and JC Polyomavirus infections.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"245 ","pages":"Article 106313"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616823","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}

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