Antiviral research最新文献_第9页

Single-dose injection of human neutralizing antibody against ZIKV preserves male fertility and protects against lethal infection 单剂量注射人抗寨卡病毒中和抗体保护男性生育能力和预防致命感染。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-22 DOI: 10.1016/j.antiviral.2025.106240

Hao Zhang , Ziyang Sheng , Feiyang Xue , Han Wang , Na Gao , Shiqi He , Yuetong Li , Dongying Fan , Peigang Wang , Lei Yu , Jing An

Zika virus (ZIKV) is a mosquito-transmitted flavivirus. Unlike other flavivirus members, ZIKV has a distinct tropism for the reproductive system. Previous studies have demonstrated that ZIKV has adverse impacts on the male reproductive system, particularly in testis and epididymis. However, no specific prophylactic and therapeutic agents are available against ZIKV till now. A human monoclonal antibody, 2B10, has been shown to be protective against microcephaly. Here, we intraperitoneally administered a single injection of 2B10 after ZIKV infection to explore its therapeutic potential on viral damage in testis and epididymis in both IFN-α/β and IFN-γ receptor-deficient (AG6) mouse and IFN-α/β receptor-deficient (A6) mouse models. The results showed that 2B10 significantly decreased the viremia and viral loads in organs in two types of male mice, markedly mitigated ZIKV-induced histo-morphologic disruption and inflammatory infiltration and maintained hormone levels. The integrity of tight junctions in the testis and epididymis was also maintained at normal levels by 2B10 administration. In long-term observation in ZIKV-infected A6 mice, 2B10 could confer effective protection of male fertility. In the AG6 model, 2B10 fully protected mice from lethal challenge. These results suggested that 2B10 provides effective protection in post-exposure therapy for ZIKV infection in mice. Since 2B10 is a human antibody, it might be a promising intervention candidate for maintaining male reproductive health during ZIKV infection in the endemic area.

寨卡病毒（ZIKV）是一种蚊子传播的黄病毒。与其他黄病毒成员不同，寨卡病毒对生殖系统有明显的倾向。以往的研究表明，寨卡病毒对男性生殖系统，特别是睾丸和附睾有不利影响。然而，目前尚无针对寨卡病毒的特异性预防和治疗药物。人单克隆抗体2B10已被证明对小头症有保护作用。本研究在ZIKV感染后腹腔单次注射2B10，探讨其对IFN-α/β和IFN-γ受体缺陷（AG6）小鼠和IFN-α/β受体缺陷（A6）小鼠模型睾丸和附睾病毒损伤的治疗潜力。结果表明，2B10可显著降低两种雄性小鼠器官内的病毒血症和病毒载量，显著减轻zikv诱导的组织形态学破坏和炎症浸润，维持激素水平。2B10给药后，睾丸和附睾紧密连接的完整性维持在正常水平。对感染zikv的A6小鼠进行长期观察，发现2B10能有效保护雄性生殖力。在AG6模型中，2B10完全保护小鼠免受致死攻击。这些结果提示2B10对小鼠寨卡病毒感染暴露后治疗具有有效的保护作用。由于2B10是一种人抗体，它可能是在寨卡病毒流行地区维持男性生殖健康的一种有希望的干预候选物。

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引用次数: 0

Mammalian-targeted antiviral peptide reduces dengue virus type 1 infection in Aedes aegypti 哺乳动物靶向抗病毒肽可减少埃及伊蚊中1型登革热病毒感染

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-21 DOI: 10.1016/j.antiviral.2025.106241

Danya Medina-Carrasco , Glay Chinea Santiago , Hilda Elisa Garay Pérez , Gladys Gutiérrez-Bugallo , Luis Gabriel González-Lodeiro , Anubis Vega-Rúa , Vivian Huerta Galindo

Dengue virus is the most important arbovirus for public health worldwide. Aedes aegypti is the DENV primary vector and acquires the virus during blood meal from a viremic human. BCN0941 is a structure-based designed antiviral peptide that inhibits early stages of DENV infection in mammalian cells [WO2015131858A2]. Studies of structure-activity relationship indicate that the molecular target of the antiviral activity of BCN0941 is the Low-density lipoprotein receptor related protein-1 (LRP1), an evolutionary conserved receptor that we have identified as putative DENV receptor in mammalian cells. In this work, we evaluated the antiviral activity of BCN0941 peptide against DENV serotype 1 in mosquito cells. In vitro assays were performed in cell lines C6/36 (Aedes albopictus) and Aag2 (Aedes aegypti). The antiviral activity in vivo in a metapopulation of field-collected A. aegypti mosquitoes was also evaluated. BCN0941 peptide exhibited the capacity to decrease viral infection in both experimental set up, in vivo and in vitro, up to a 50 % and 60 % of the treatment controls respectively, as determined by immunofluorescence. BCN0941 may be an effective DENV transmission-blocking drug due to its dual action in decreasing the viral load in infected people and the mosquito vector.

登革热病毒是全球公共卫生最重要的虫媒病毒。埃及伊蚊是登革热病毒的主要媒介，并在从病毒血症人的血液中获得病毒。BCN0941是一种基于结构设计的抗病毒肽，可抑制哺乳动物细胞早期DENV感染[WO2015131858A2]。构效关系研究表明，BCN0941抗病毒活性的分子靶点是低密度脂蛋白受体相关蛋白-1 (LRP1)，这是一种进化保守的受体，我们已经确定它可能是哺乳动物细胞中的DENV受体。在这项工作中，我们评估了BCN0941肽对蚊子细胞中DENV血清型1的抗病毒活性。体外检测细胞C6/36（白纹伊蚊）和Aag2（埃及伊蚊）。对野外采集的埃及伊蚊超种群体内抗病毒活性进行了评价。通过免疫荧光测定，BCN0941肽在体内和体外实验中均表现出减少病毒感染的能力，分别达到治疗对照组的50%和60%。BCN0941可能是一种有效的DENV传播阻断药物，具有降低感染者和蚊虫载体病毒载量的双重作用。

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引用次数: 0

High-throughput split-GFP antiviral screening assay against fusogenic paramyxoviruses 高通量分裂- gfp抗融合副粘病毒筛选试验。

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-21 DOI: 10.1016/j.antiviral.2025.106242

Laura Vandemaele , Thibault Francken , Joost Schepers , Winston Chiu , Niels Cremers , Hugo Klaassen , Charlène Marcadet , Lorena Sanchez Felipe , Arnaud Marchand , Patrick Chaltin , Pieter Leyssen , Johan Neyts , Manon Laporte

The paramyxovirus family includes important pathogens such as measles and mumps viruses, as well as emerging pathogens with pandemic potential such as Nipah virus. Despite the threat to public health and the frequent identification of novel paramyxoviruses, no antiviral drugs are currently available. A hallmark of most paramyxoviruses is the induction of cell-cell fusion leading to syncytia formation. To facilitate antiviral drug discovery, we leveraged this trait and established a high-throughput split-green fluorescent protein (GFP) antiviral screening assay suitable for high-content imaging through the quantification of virus-induced GFP⁺ syncytia. The assay was validated with well-known broad-spectrum antiviral compounds against representative members of five different Paramyxovirinae genera. Using this split-GFP assay, a small-molecule repurposing library of approximately 3000 compounds was screened against recombinant Cedar virus (CedV), a nonpathogenic henipavirus. Two molecules were identified: Cathepsin Inhibitor 1 with henipavirus-specific activity and PF-543 with pan-paramyxovirus activity. Both molecules inhibit viral replication by blocking cell-cell fusion. The split-GFP assay presented here will enable the development of extensive drug discovery initiatives aimed at identifying much-needed pan-henipavirus/paramyxovirus inhibitors.

副粘病毒家族包括麻疹和腮腺炎病毒等重要病原体，以及尼帕病毒等具有大流行潜力的新出现病原体。尽管对公共卫生构成威胁，并且经常发现新型副粘病毒，但目前尚无抗病毒药物可用。大多数副粘病毒的一个特点是诱导细胞-细胞融合导致合胞体的形成。为了促进抗病毒药物的发现，我们利用这一特性，通过对病毒诱导的GFP+合胞体的定量分析，建立了适用于高含量成像的高通量分裂绿色荧光蛋白（GFP）抗病毒筛选试验。该试验与众所周知的广谱抗病毒化合物对五个不同副粘病毒属的代表成员进行了验证。利用这种分裂- gfp试验，筛选了一个含有约3000种化合物的小分子重组文库，以对抗重组雪松病毒（一种非致病性亨尼帕病毒）。鉴定出两个分子：具有亨尼帕病毒特异性活性的组织蛋白酶抑制剂1和具有泛副粘病毒活性的PF-543。这两种分子都通过阻断细胞-细胞融合来抑制病毒复制。这里提出的分裂- gfp测定将使广泛的药物发现倡议的发展，旨在确定急需的泛亨尼帕病毒/副粘病毒抑制剂。

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引用次数: 0

Cholesterol 25-hydroxylase inhibits Newcastle disease virus replication by its architectural damage and blocking HN protein 胆固醇25-羟化酶通过其结构损伤和阻断HN蛋白抑制新城疫病毒复制。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-18 DOI: 10.1016/j.antiviral.2025.106239

Satyendu Nandy, Siddharth Neog, Sachin Kumar

Cholesterol 25-hydroxylase (CH25H) is a membrane-bound endoplasmic reticulum protein that converts cholesterol into 25-hydroxycholesterol (25HC). Recent studies showed that CH25H is an interferon-stimulated gene (ISG) that helps fight various viruses and has broad antiviral effects. However, the role of chicken CH25H (chCH25H) in controlling Newcastle disease virus (NDV) infection and replication remains unexplored. This study examined the impact of chCH25H on NDV infection in chicken embryo fibroblast cells. The results showed that cells try to upregulate the chCH25H expression temporally upon viral infection. Moreover, the overexpression of chCH25H reduced NDV infection in cells while reducing endogenous chCH25H levels increased its replication. Additionally, treating cells and viruses with 25HC, an active metabolic intermediate of chCH25H, significantly reduced NDV replication by blocking the virus from entering cells while causing significant structural damage to the virus architecture. In addition, in ovo results also exhibited that the eggs treated with lipopolysaccharides (LPS), a positive regulator of chCH25H and 25HC, resulted in extensive viral reduction. These findings indicate that chCH25H and 25HC are against NDV replication in chicken fibroblast cells.

胆固醇25-羟化酶（CH25H）是一种膜结合的内质网蛋白，可将胆固醇转化为25-羟基胆固醇（25HC）。最近的研究表明，CH25H是一种干扰素刺激基因（ISG），有助于对抗各种病毒，具有广泛的抗病毒作用。然而，鸡CH25H （chCH25H）在控制新城疫病毒（NDV）感染和复制中的作用仍未被探索。本研究探讨了chCH25H对鸡胚成纤维细胞感染新城疫的影响。结果表明，在病毒感染后，细胞试图暂时上调chCH25H的表达。此外，chCH25H的过表达减少了NDV在细胞中的感染，而内源性chCH25H水平的降低增加了其复制。此外，用25HC （chCH25H的一种活性代谢中间体）处理细胞和病毒，通过阻止病毒进入细胞显著减少NDV复制，同时对病毒结构造成显著的结构损伤。此外，鸡蛋实验结果还表明，用脂多糖（LPS）处理鸡蛋，chCH25H和25HC的正调节因子，导致病毒大量减少。这些结果表明，chCH25H和25HC对NDV在鸡成纤维细胞中的复制具有抑制作用。

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引用次数: 0

Functional characteristics of plitidepsin as an antiviral treatment against monkeypox virus infection 多重抑郁素抗病毒治疗猴痘病毒感染的功能特点。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-15 DOI: 10.1016/j.antiviral.2025.106238

Guillermo Albericio , Daniel Rodríguez-Martín , Pablo Avilés , Carmen Cuevas , María J. Guillén-Navarro , María A. Noriega , Sara Flores , Pedro J. Sánchez-Cordón , David Astorgano , Patricia Pérez , Mariano Esteban , Juan García-Arriaza

Monkeypox virus (MPXV), closely related to variola virus, causes mpox, a zoonotic disease traditionally endemic to Central Africa. However, recent outbreaks have increased human transmission of MPXV clades. In 2022, global MPXV spread was linked to clade IIb, whereas in 2024, the more pathogenic clade Ib became predominant. These trends raised concerns about sustained human transmission, prompting the WHO to declare mpox a Public Health Emergency of International Concern. Despite the availability of smallpox vaccines, their protective efficacy against mpox remains limited. Additionally, the limited efficacy of current smallpox antivirals, such as Tecovirimat and Brincidofovir, alongside growing concerns about the emergency of tecovirimat resistance mutants, underscores the need for new therapeutic options. Given these challenges, novel antiviral strategies with different mechanisms of action are urgently needed to control MPXV outbreaks. Plitidepsin, a cyclodepsipeptide drug initially approved for cancer treatment, has demonstrated potent antiviral activity against multiple viruses by targeting eukaryotic elongation factor 1 alpha (eEF1A). Here, we have evaluated the antiviral activity of plitidepsin against MPXV infection. In cultured cells, plitidepsin exhibited strong antiviral effects, with a favorable therapeutic index and low cytotoxicity. In CAST/EiJ mice, a highly susceptible MPXV model, plitidepsin significantly reduced viral replication in the lungs. Additionally, treated mice displayed a marked reduction in inflammatory lung lesions and proinflammatory cytokines, suggesting immunomodulatory effects. These findings indicate plitidepsin as a promising candidate for mpox treatment. Further studies are needed to explore its potential as a standalone or combination therapy, supporting clinical evaluation for mpox treatment.

猴痘病毒（MPXV）与天花病毒密切相关，可引起麻疹，这是一种传统上在中非流行的人畜共患疾病。然而，最近的疫情增加了MPXV分支的人间传播。在2022年，全球MPXV传播与IIb分支有关，而在2024年，致病性更高的Ib分支占主导地位。这些趋势引起了人们对持续人际传播的担忧，促使世卫组织宣布mpox为国际关注的突发公共卫生事件。尽管有天花疫苗，但它们对m痘的保护作用仍然有限。此外，目前的天花抗病毒药物，如特可维玛和Brincidofovir的疗效有限，加上对特可维玛耐药突变体紧急情况的日益关注，强调需要新的治疗选择。鉴于这些挑战，迫切需要具有不同作用机制的新型抗病毒策略来控制MPXV的暴发。Plitidepsin是一种最初被批准用于癌症治疗的环抑郁肽药物，通过靶向真核延伸因子1 α (eEF1A)，已经证明了对多种病毒的有效抗病毒活性。在这里，我们评估了plitidepsin对MPXV感染的抗病毒活性。在培养细胞中，plitidepsin表现出较强的抗病毒作用，具有良好的治疗指数和较低的细胞毒性。在CAST/EiJ小鼠（一种高度易感的MPXV模型）中，plitidepsin显著减少了病毒在肺部的复制。此外，治疗小鼠的炎性肺病变和促炎细胞因子显着减少，表明免疫调节作用。这些发现表明plitidepsin是一种很有希望的m痘治疗候选药物。需要进一步的研究来探索其作为单独或联合治疗的潜力，以支持m痘治疗的临床评估。

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引用次数: 0

Pralatrexate effectively inhibits the replication of monkeypox virus in vitro and in vivo 普拉特雷酯在体外和体内均能有效抑制猴痘病毒的复制。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-11 DOI: 10.1016/j.antiviral.2025.106232

Jianshu Li , Siyu Li , Chaode Gu , Shaowen Shi , Xiao Li , Zhendong Guo , Zongzheng Zhao , Miao He , Zhiwei Wu

The monkeypox virus (MPXV), an orthopoxvirus, has caused a number of major outbreaks and emerged as a global public health threat. Although drugs have been approved for the treatment of mpox, the efficacy and side effects remain unknown, which calls for the development of safe and effective drugs. Pralatrexate (PDX) is a fourth-generation antifolate drug with inhibitory activity against a wide range of viruses. In this study, we demonstrated the antiviral activity of PDX against MPXV in vitro and in vivo. Our results showed that PDX potently inhibited the MPXV replication at very low drug concentrations in vitro, and could significantly inhibit MPXV activity in dormice. In conclusion, this study found that PDX is an effective antiviral drug against MPXV infection, showing potential as a novel therapy for MPXV infection.

猴痘病毒（MPXV）是一种正痘病毒，已引起多次重大疫情，并成为全球公共卫生威胁。虽然已经批准了治疗m痘的药物，但其疗效和副作用尚不清楚，这就要求开发安全有效的药物。praatrexate （PDX）是第四代抗叶酸药物，对多种病毒具有抑制活性。在本研究中，我们在体外和体内证明了PDX对MPXV的抗病毒活性。我们的研究结果表明，PDX在体外很低的药物浓度下就能有效抑制MPXV的复制，并能显著抑制MPXV在睡鼠体内的活性。综上所述，本研究发现PDX是一种有效的MPXV感染抗病毒药物，有可能成为MPXV感染的新疗法。

引用次数: 0

Generation of a panel of mutants that are resistant to standard of care therapies in a clinically relevant strain of human cytomegalovirus for drug resistance profiling 在临床相关的人巨细胞病毒毒株中产生对标准护理疗法耐药的一组突变体，以进行耐药性分析

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-11 DOI: 10.1016/j.antiviral.2025.106237

Meghan F. Carter, Kassidy Knight, Yetunde Kayode, Eain A. Murphy

Infection with human cytomegalovirus (HCMV) can result in a significant disease burden within the immunosuppressed and immunocompromised patient populations. Current standard of care (SOC) relies on direct-acting antivirals which target a limited group of viral proteins including the viral polymerase (UL54), terminase (UL56), and protein kinase (UL97). Incomplete inhibition of virally encoded proteins result in a selective pressure towards the generation of “breakthrough” drug resistant variants. One limitation in evaluating novel antivirals is the difficulty in profiling their antiviral activity against variants resistant to current SOC interventions, as these resistant variants have arisen in different genetic backgrounds with distinct replication kinetics and yields.

To limit strain variation we generated a targeted mutant panel of viruses in a bacterial artificial chromosome (BAC) derived clinically relevant laboratory strain of HCMV, TB40e, that expresses the fluorescent proteins mCherry upon viral entry and eGFP at times after viral DNA replication. This unique construct allows for the monitoring of viral entry and viral DNA replication independently. This panel consists of WT and seven mutant viruses harboring mutations that confer resistance to ganciclovir, maribavir, cidofovir, and letermovir. In addition, we characterized a host-targeted sirtuin 2 deacetylase (Sirt2) inhibitor, FLS-359, against the SOC resistant variants. We observed that mutant viruses demonstrated increased EC₅₀ concentrations for SOC inhibition, and that host directed FLS-359 demonstrated broad-spectrum antiviral activity against known SOC drug-resistant mutants. This panel represents a much-needed comparatively innovative platform for screening the efficacy of new direct-acting antivirals and host-directed antivirals against HCMV variants refractive to therapeutic interventions.

人巨细胞病毒（HCMV）感染可导致免疫抑制和免疫功能低下患者群体的重大疾病负担。目前的护理标准（SOC）依赖于直接作用的抗病毒药物，这些药物靶向有限的病毒蛋白，包括病毒聚合酶（UL54）、终止酶（UL56）和蛋白激酶（UL97）。病毒编码蛋白的不完全抑制导致产生“突破性”耐药变异的选择性压力。评估新型抗病毒药物的一个限制是很难分析它们对当前SOC干预的抗性变异的抗病毒活性，因为这些抗性变异出现在不同的遗传背景下，具有不同的复制动力学和产量。为了限制菌株变异，我们在细菌人工染色体（BAC）衍生的HCMV临床相关实验室菌株TB40e中生成了一个靶向突变病毒组，该病毒在病毒进入时表达荧光蛋白mCherry，在病毒DNA复制后有时表达eGFP。这种独特的结构允许独立监测病毒进入和病毒DNA复制。该小组由WT和7个突变病毒组成，这些突变病毒具有对更昔洛韦、马里巴韦、西多福韦和莱特莫韦产生耐药性的突变。此外，我们还鉴定了一种宿主靶向Sirt2去乙酰化酶（Sirt2）抑制剂FLS-359，用于抗SOC耐药变体。我们观察到突变病毒对SOC抑制的EC50浓度增加，宿主定向的FLS-359对已知的SOC耐药突变体表现出广谱抗病毒活性。该小组代表了一个急需的相对创新的平台，用于筛选新的直接作用抗病毒药物和宿主靶向抗病毒药物对治疗干预的HCMV变异的疗效。

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引用次数: 0

SARS-CoV-2 neutralization and protection of hamsters via nasal administration of a humanized neutralizing antibody 通过鼻给药人源化中和抗体对仓鼠的SARS-CoV-2中和和保护作用。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-09 DOI: 10.1016/j.antiviral.2025.106235

Mikhail Lebedin , Nikolai Petrovsky , Kairat Tabynov , Kaissar Tabynov , Yuri Lebedin

Monoclonal antibodies are widely used for the treatment of infectious human diseases, including COVID-19. Since the start of the pandemic, eight monoclonal antibodies against SARS-CoV-2 were granted emergency use authorization. The high mutation rate of the SARS-CoV-2 virus has led to the emergence of highly transmissible variants that can evade vaccine-induced immunity. In this study, we generated a panel of murine monoclonal antibodies (mAb) to identify a subset that broadly neutralized SARS-CoV-2 variants and explored whether mucosal administration of such antibodies could protect against infection. Intranasal delivery of XR10, the most promising murine mAb, protected hamsters against infection by Delta variant. We next humanized XR10 mAb using a combination of CDR-grafting and Vernier zones preservation approaches (CRVZ) to create a panel of humanized XR10 variants. We ranked the variants based on their spike binding ability and virus neutralization. Of these, XR10v48 demonstrated the best ability to neutralize SARS-CoV-2 variants and was protective in hamsters when given as a single 50 μg/kg intranasal dose at the time of viral challenge. XR10v48 featured 34 key amino acid residues retained from the murine progenitor. With SARS-CoV-2 escape mutants continuing to emerge this work highlights a potential workflow to generate humanized broadly cross-neutralizing mAb for potential use as a nasal spray for SARS-CoV-2 prophylaxis.

单克隆抗体广泛用于治疗人类传染性疾病，包括COVID-19。自大流行开始以来，已有8种针对SARS-CoV-2的单克隆抗体获得紧急使用授权。SARS-CoV-2病毒的高突变率导致了高传染性变体的出现，这些变体可以逃避疫苗诱导的免疫。在这项研究中，我们生成了一组小鼠单克隆抗体（mAb），以鉴定一个广泛中和SARS-CoV-2变体的亚群，并探索粘膜给药这种抗体是否可以预防感染。经鼻给药XR10（最有希望的小鼠单抗）可以保护仓鼠免受Delta变异的感染。接下来，我们使用cdr嫁接和游标区保存方法（CRVZ）的组合对XR10单抗进行人源化，以创建一个人源化的XR10变体面板。我们根据它们的刺突结合能力和病毒中和性对变异进行了排序。其中，XR10v48表现出最好的中和SARS-CoV-2变异的能力，并且在病毒攻击时单次给予50 μg/kg鼻内剂量对仓鼠具有保护作用。XR10v48具有从小鼠祖细胞中保留的34个关键氨基酸残基。随着SARS-CoV-2逃逸突变体的不断出现，这项工作强调了一种潜在的工作流程，即产生人源化的广泛交叉中和单抗，可能用作预防SARS-CoV-2的鼻喷雾剂。

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引用次数: 0

Decreased CD4+ T cell counts drive aberrant B cell repertoire alterations in people living with HIV CD4+ T细胞计数降低导致HIV感染者B细胞库异常改变。

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-08 DOI: 10.1016/j.antiviral.2025.106236

Lina Huang , Xiangyu Zhang , Yu Shi , Rishen Liang , Qianqian Chen , Jing Yang , Xiaoni Zhang , Anning Fang , Qian Zhang , Chengchao Ding , Jiabin Wu , Jianjun Wu , Yong Gao

Understanding the evolution of broadly neutralizing antibody (bNAb) activity in people living with HIV is crucial for vaccine design and immunization strategies. It has been proposed that antibody cross-reactive activity is associated with lower CD4⁺ T cell counts during people living with HIV, but the underlying mechanisms remain unclear. To further explore the correlation between antibody reactivity and CD4⁺ T cell counts, we recruited people living with HIV with varying CD4⁺ T cell counts: (i) CD4⁺ T cell ≤50 cells/μL, (ii) 50 cells/μL < CD4⁺ T cell ≤200 cells/μL, (iii) 200 cells/μL < CD4⁺ T cell ≤500 cells/μL, (iv) 500 cells/μL < CD4⁺ T cell. We assessed the antigen-specific antibodies in serum using SOSIP.664 trimers from four different subtypes. Immune repertoire sequencing was used to characterize the B cell receptor (BCR) repertoire of these individuals. The evaluation of antigen-specific antibodies with different SOSIP.664 trimers showed enhanced reactivity in individuals with low CD4⁺ T cell counts compared to those with high/normal CD4⁺ T cell counts. Analysis of antibody gene repertoires through BCR high throughput sequencing revealed an increased proportion of IgG with heavy chain complementarity-determining region 3 (CDRH3) loops exceeding 20 amino acids in individuals with CD4⁺ T cell counts below 50 cells/μL. Notably, the IGHV1-46 and IGHV4-34 germlines, which are suggestive of most polyreactive B cells, were preferentially used in individuals with low CD4⁺ T cell counts. These results suggest that limited engagement of CD4⁺ T cells could facilitate the survival of aberrant B cell repertoire with long CDRH3 regions.

了解艾滋病毒感染者广泛中和抗体（bNAb）活性的演变对疫苗设计和免疫策略至关重要。有人提出，抗体交叉反应活性与HIV感染者CD4+ T细胞计数降低有关，但其潜在机制尚不清楚。为了进一步探讨抗体反应性与CD4+ T细胞计数的相关性，我们招募了CD4+ T细胞计数不同的HIV感染者：(i) CD4+ T细胞≤50个细胞/μL，（ii） 50个细胞/μL < CD4+ T细胞≤200个细胞/μL，（iii） 200个细胞/μL < CD4+ T细胞≤500个细胞/μL，（iv） 500个细胞/μL < CD4+ T细胞。我们使用4种不同亚型的SOSIP.664三聚体检测血清中的抗原特异性抗体。免疫库测序用于表征这些个体的B细胞受体（BCR）库。不同SOSIP.664三聚体抗原特异性抗体的评估显示，与CD4+ T细胞计数高/正常的个体相比，CD4+ T细胞计数低的个体的反应性增强。通过BCR高通量测序对抗体基因库进行分析发现，CD4+ T细胞计数低于50个细胞/μL的个体中，CDRH3（重链互补决定区3）环超过20个氨基酸的IgG比例增加。值得注意的是，IGHV1-46和IGHV4-34种系，提示大多数多反应性B细胞，优先用于CD4+ T细胞计数低的个体。这些结果表明，CD4+ T细胞的有限接触可以促进具有长CDRH3区域的异常B细胞库的存活。

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引用次数: 0

Assessment of significant hepatic damage in young patients with chronic hepatitis B to initiate the antiviral treatment: The APLB score 评估年轻慢性乙型肝炎患者开始抗病毒治疗的显著肝损害：APLB评分

IF 4.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Antiviral research

Pub Date : 2025-07-05 DOI: 10.1016/j.antiviral.2025.106234

Yi-Fan Guo , Yihui Rong , Yan-Ping Chen , Song Yang , Guangde Zhou , Xiao-Xia Niu , Xiao-Huan Wu , Yue-Ran Liu , Wen-Jing Zhang , Le Li , Yan Liu , Wen-Chang Wang , Xu-Yang Li , Chun-Yan Wang , Wucai Yang , Chang Guo , Lin Tan , Fu-Sheng Wang , Dong Ji

Whether patients aged ≤30 years with chronic hepatitis B (CHB) and normal alanine transaminase (ALT) levels (<40 U/L) should receive antiviral therapy is controversial. In this study, we aimed to identify high-risk factors of significant hepatic damage (SHD) and established a scoring system to guide the decision to administer antiviral treatment. Eligible patients who underwent a liver biopsy were retrospectively screened and randomly assigned to either a training or validation set. Hepatic fibrosis (S0-4) and inflammation (G0-4) were assessed using the Scheuer scoring system. The independent risk factors associated with SHD (≥G2/S2) were identified using univariable and multivariable logistic regression analyses, and a new scoring system based on these factors was established. Among the 883 enrolled patients, 548 (62.1 %) were male, and 250 (28.5 %) presented with SHD. ALT, platelet count, HBV DNA, and liver stiffness measurement were identified as independent risk factors. A new scoring model based on these factors, named APLB, was developed. The area under the curve of APLB was 0.731 (95 % confidence interval, 0.695–0.764), which was significantly higher than those of the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) index. An APLB score <6 points ruled out SHD with 80.2 % sensitivity, while scores >12 points diagnosed SHD with 97.5 % specificity. In conclusion, the APLB scoring model demonstrated superior diagnostic performance compared with the APRI and the FIB-4 index, and it has the potential to guide the decision to initiate antiviral therapy in this patient group.

年龄≤30岁且谷丙转氨酶（ALT）水平正常（40 U/L）的慢性乙型肝炎（CHB）患者是否应该接受抗病毒治疗存在争议。在本研究中，我们旨在确定显著肝损害（SHD）的高危因素，并建立一个评分系统来指导给予抗病毒治疗的决策。回顾性筛选接受肝活检的符合条件的患者，并随机分配到训练组或验证组。采用Scheuer评分系统评估肝纤维化（S0-4）和炎症（G0-4）。采用单变量和多变量logistic回归分析确定与SHD相关的独立危险因素（≥G2/S2），并基于这些因素建立新的评分体系。在883例入组患者中，548例（62.1%）为男性，250例（28.5%）为SHD。ALT、血小板计数、HBV DNA和肝脏硬度测量被确定为独立的危险因素。基于这些因素，提出了一种新的评分模型，称为APLB。APLB曲线下面积为0.731(95%可信区间0.695 ~ 0.764)，显著高于天冬氨酸转氨酶与血小板比值指数（APRI）和纤维化-4指数（FIB-4）。APLB评分为6分，排除SHD的敏感性为80.2%，而诊断SHD的评分为12分，特异性为97.5%。综上所述，与APRI和FIB-4指数相比，APLB评分模型具有更好的诊断性能，并有可能指导该患者组启动抗病毒治疗的决策。

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