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Mosaic neuraminidase-based vaccine induces antigen-specific T cell responses against homologous and heterologous influenza viruses 基于马赛克神经氨酸酶的疫苗可诱导抗原特异性 T 细胞对同源和异源流感病毒产生反应。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1016/j.antiviral.2024.105978
Zirong Han , Qianyi Mai , Yangguo Zhao , Xinglai Liu , Mingting Cui , Minchao Li , Yaoqing Chen , Yuelong Shu , Jianhui Gan , Weiqi Pan , Caijun Sun

Seasonal influenza is an annually severe crisis for global public health, and an ideal influenza vaccine is expected to provide broad protection against constantly drifted strains. Compared to highly flexible hemagglutinin (HA), increasing data have demonstrated that neuraminidase (NA) might be a potential target against influenza variants. In the present study, a series of genetic algorithm-based mosaic NA were designed, and then cloned into recombinant DNA and replication-defective Vesicular Stomatitis Virus (VSV) vector as a novel influenza vaccine candidate. Our Results showed that DNA prime/VSV boost strategy elicited a robust NA-specific Th1-dominated immune response, but the traditional inactivated influenza vaccine elicited a Th2-dominated immune response. More importantly, the superior NA-specific immunity induced by our strategy could confer both a full protection against lethal homologous influenza challenge and a partial protection against heterologous influenza infection. These findings will provide insights on designing NA-based universal vaccine strategy against influenza variants.

季节性流感每年都会给全球公共卫生带来严重危机,理想的流感疫苗应能针对不断变异的毒株提供广泛的保护。与高度灵活的血凝素(HA)相比,越来越多的数据表明神经氨酸酶(NA)可能是对抗流感变异株的潜在靶标。在本研究中,我们设计了一系列基于遗传算法的镶嵌 NA,然后将其克隆到重组 DNA 和复制缺陷水泡性口炎病毒(VSV)载体中,作为新型流感疫苗的候选株。我们的研究结果表明,DNA质粒/VSV增强策略能激发以Th1为主的强NA特异性免疫反应,而传统的灭活流感疫苗则能激发以Th2为主的免疫反应。更重要的是,我们的策略所诱导的超强NA特异性免疫既能对致命的同源流感挑战提供全面保护,也能对异源流感感染提供部分保护。这些发现将为设计以NA为基础的通用疫苗策略来对抗流感变种提供启示。
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引用次数: 0
Amidino-rocaglates (ADRs), a class of synthetic rocaglates, are potent inhibitors of SARS-CoV-2 replication through inhibition of viral protein synthesis 脒基洛卡酸盐(ADRs)是一类合成洛卡酸盐,通过抑制病毒蛋白质的合成,对 SARS-CoV-2 的复制有很强的抑制作用。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1016/j.antiviral.2024.105976
Patrick T. Keiser , Wenhan Zhang , Michael Ricca , Alan Wacquiez , Autumn Grimins , Regina Cencic , J.J. Patten , Pranav Shah , Elias Padilha , John H. Connor , Jerry Pelletier , Shawn M. Lyons , Mohsan Saeed , Lauren E. Brown , John A. Porco Jr. , Robert A. Davey

Coronaviruses are highly transmissible respiratory viruses that cause symptoms ranging from mild congestion to severe respiratory distress. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for new antivirals with broad-acting mechanisms to combat increasing emergence of new variants. Currently, there are only a few antivirals approved for treatment of SARS-CoV-2. Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis. In this study, we evaluated amidino-rocaglates (ADRs), a class of synthetic rocaglates with the most potent eIF4A-inhibitory activity to-date, for inhibition of SARS-CoV-2 infection. This class of compounds showed low nanomolar potency against multiple SARS-CoV-2 variants and in multiple cell types, including human lung-derived cells, with strong inhibition of virus over host protein synthesis and low cytotoxicity. The most potent ADRs were also shown to be active against two highly pathogenic and distantly related coronaviruses, SARS-CoV and MERS-CoV. Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent.

冠状病毒是一种传播性极强的呼吸道病毒,可引起从轻微充血到严重呼吸困难的各种症状。最近爆发的严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)突出表明,需要具有广谱作用机制的新型抗病毒药物来应对日益增多的新变种。目前,只有少数抗病毒药物被批准用于治疗 SARS-CoV-2 。在此之前,rocaglate 天然产物 silvestrol 和合成的 rocaglates(如 CR-1-31b)通过抑制真核翻译起始因子 4A1(eIF4A)的功能和病毒蛋白质的合成而被证明具有抗病毒作用。在本研究中,我们评估了脒基环烷酸酯(ADRs)对 SARS-CoV-2 感染的抑制作用,这是迄今为止具有最强 eIF4A 抑制活性的一类合成环烷酸酯。这类化合物对多种 SARS-CoV-2 变体和多种细胞类型(包括人肺源性细胞)都显示出低纳摩尔的效力,对病毒和宿主蛋白质合成的抑制作用强,细胞毒性低。最有效的 ADRs 对两种高致病性和远缘冠状病毒(SARS-CoV 和 MERS-CoV)也具有活性。从机理上讲,已知 eIF4A1 基因突变会减少罗卡格雷特的相互作用,而 eIF4A1 基因突变的细胞会减少 ADR 导致的细胞功能丧失,这与蛋白质合成的靶向性是一致的。总之,ADR及其衍生物可能为SARS-CoV-2提供新的潜在治疗方法,从而达到开发广谱抗冠状病毒药物的目的。
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引用次数: 0
Synergistic activity of an RNA polymerase PA-PB1 interaction inhibitor with oseltamivir against human and avian influenza viruses in cell culture and in ovo 一种 RNA 聚合酶 PA-PB1 相互作用抑制剂与奥司他韦在细胞培养和卵中对人流感病毒和禽流感病毒的协同活性。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1016/j.antiviral.2024.105980
Anna Bonomini , Jiwei Zhang , Han Ju , Alessia Zago , Martina Pacetti , Oriana Tabarrini , Serena Massari , Xinyong Liu , Beatrice Mercorelli , Peng Zhan , Arianna Loregian

In search of novel therapeutic options to treat influenza virus (IV) infections, we previously identified a series of inhibitors that act by disrupting the interactions between the PA and PB1 subunits of the viral RNA polymerase. These compounds showed broad-spectrum antiviral activity against human influenza A and B viruses and a high barrier to the induction of drug resistance in vitro. In this short communication, we investigated the effects of combinations of the PA-PB1 interaction inhibitor 54 with oseltamivir carboxylate (OSC), zanamivir (ZA), favipiravir (FPV), and baloxavir marboxil (BXM) on the inhibition of influenza A and B virus replication in vitro. We observed a synergistic effect of the 54/OSC and 54/ZA combinations and an antagonistic effect when 54 was combined with either FPV or BXM. Moreover, we demonstrated the efficacy of 54 against highly pathogenic avian influenza viruses (HPAIVs) both in cell culture and in the embryonated chicken eggs model. Finally, we observed that 54 enhances OSC protective effect against HPAIV replication in the embryonated eggs model. Our findings represent an advance in the development of alternative therapeutic strategies against both human and avian IV infections.

为了寻找治疗流感病毒(IV)感染的新疗法,我们之前发现了一系列抑制剂,它们通过破坏病毒 RNA 聚合酶 PA 和 PB1 亚基之间的相互作用发挥作用。这些化合物对人类甲型和乙型流感病毒具有广谱抗病毒活性,而且在体外诱导耐药性方面具有很高的屏障作用。在这篇短讯中,我们研究了 PA-PB1 相互作用抑制剂 54 与羧酸奥司他韦 (OSC)、扎那米韦 (ZA)、法非拉韦 (FPV) 和巴洛沙韦 marboxil (BXM) 的组合对体外甲型和乙型流感病毒复制的抑制作用。我们观察到 54/OSC 和 54/ZA 组合具有协同作用,而 54 与 FPV 或 BXM 组合则具有拮抗作用。此外,我们还在细胞培养和胚胎鸡卵模型中证实了 54 对禽流感 IV 株的疗效。最后,我们还观察到,在鸡胚蛋模型中,54 能增强 OSC 对禽 IV 型病毒复制的保护作用。我们的研究结果标志着在开发针对人类和禽类 IV 型病毒感染的替代治疗策略方面取得了进展。
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引用次数: 0
Orally dissolving film as a potential vaccine delivery carrier to prevent influenza virus infection 将口腔溶解膜作为预防流感病毒感染的潜在疫苗输送载体。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-05 DOI: 10.1016/j.antiviral.2024.105979
Keon-Woong Yoon , Ki Back Chu , Gi-Deok Eom , Jie Mao , Sung Soo Kim , Fu-Shi Quan

Orally dissolving films (ODF) are designed to be dissolved on the tongue and absorbed in the mouth. It offers multiple advantages over the commonly used needle-based vaccines, especially in terms of convenience allowing safe, painless, and easy self-administration. As the efficacy of ODF-encapsulated influenza vaccines has not been demonstrated, we assessed the protection elicited by inactivated influenza virus (A/PR/8/34, PR8) vaccine delivered using ODFs in mice. Trehalose and pullulan components of the ODF ensured that the HA antigens of the inactivated PR8 virus retained their stability while ensuring the rapid release of the vaccines upon exposure to murine saliva. Mice were immunized thrice by placing the PR8-ODF on the tongues of mice at 4-week intervals, and vaccine-induced protection was evaluated upon lethal homologous challenge infection. The PR8-ODF vaccination elicited virus-specific serum IgG and IgA antibody responses, hemagglutinin inhibition (HAI), and viral neutralization. Upon challenge infection, ODF vaccination showed higher levels of IgG and IgA antibody responses in the lungs and antibody-secreting cell (ASC) responses in both lung and spleen compared to unimmunized controls. These results corresponded with the enhanced T cell and germinal center B cell responses in the lungs and spleens. Importantly, ODF vaccination significantly reduced lung virus titers and inflammatory cytokines (IFN-γ, IL-6) production compared to unvaccinated control. ODF vaccination ensured 100% survival and prevented weight loss in mice. These findings suggest that influenza vaccine delivery through ODFs could be a promising approach for oral vaccine development.

口腔溶解膜(ODF)可在舌头上溶解并在口腔中吸收。与常用的针剂疫苗相比,口服溶解膜疫苗具有多种优势,尤其是在安全、无痛、简便的自我注射方面。由于 ODF 封装流感疫苗的功效尚未得到证实,我们评估了使用 ODF 给小鼠注射灭活流感病毒(A/PR/8/34,PR8)疫苗所产生的保护作用。ODF 中的海藻糖和纤维素成分可确保灭活的 PR8 病毒的 HA 抗原保持稳定,同时确保疫苗在暴露于小鼠唾液后迅速释放。每隔 4 周将 PR8-ODF 放在小鼠舌头上,对小鼠进行三次免疫接种,并在致死性同源挑战感染时评估疫苗诱导的保护作用。接种PR8-ODF疫苗可引起病毒特异性血清IgG和IgA抗体反应、血凝素抑制(HAI)和病毒中和。与未接种疫苗的对照组相比,接种 ODF 疫苗后在肺部出现更高水平的 IgG 和 IgA 抗体反应,在肺部和脾脏出现更高水平的抗体分泌细胞 (ASC) 反应。这些结果与肺部和脾脏中增强的 T 细胞和生殖中心 B 细胞反应相吻合。重要的是,与未接种疫苗的对照组相比,接种ODF可显著降低肺部病毒滴度和炎性细胞因子(IFN-γ、IL-6)的产生。接种ODF疫苗可确保小鼠100%存活并防止体重减轻。这些研究结果表明,通过ODF输送流感疫苗是一种很有前景的口服疫苗开发方法。
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引用次数: 0
An mpox quadrivalent mRNA vaccine protects mice from lethal vaccinia virus challenge 一种 mpox 四价 mRNA 疫苗能保护小鼠免受致命的疫苗病毒挑战。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-31 DOI: 10.1016/j.antiviral.2024.105974
Entao Li , Qizan Gong , Jiachen Zhang , Xiaoping Guo , Wenyu Xie , Da Chen , Yanqiong Shen , Dongxiang Hong , Zhihao Li , Qianqian Wang , Chao Wang , Yucai Wang , Sandra Chiu

The outbreak of 2022 monkeypox virus (MPXV) infection in nonendemic regions is a global public health concern. A highly effective and safe MPXV vaccine that is available to the general public is urgently needed to control the mpox pandemic. Here, we developed a multivalent mRNA vaccine candidate, MPXV-1103, which expresses the full-length B6, A35, A29 and M1 proteins with three flexible linkers (G4S1)3 in a single sequence. Compared with the monovalent MPXV mRNA vaccine candidates or the quadrivalent mRNA vaccine from mixtures of the four monovalent MPXV mRNA vaccines, MPXV-1103 elicits a robust humoral response and an MPXV-specific T-cell response and protects mice from lethal vaccinia virus (VACV) challenge, with no live virus detected in the nasal or lungs even at dosages as low as 1 μg. Furthermore, analysis of complete blood counts and photomicrographs of tissue from the main organs of mice vaccinated with MPXV-1103 at doses of 5 μg and 20 μg revealed that two doses of MPXV-1103 did not cause any observable pathological changes in the mice. Collectively, our results suggest that MPXV-1103, with features of high efficacy, safety and a simplified manufacturing process, is a promising vaccine candidate for defending against MPXV infection.

2022 年猴痘病毒 (MPXV) 感染在非流行地区的爆发是一个全球性的公共卫生问题。为控制猴痘病毒的大流行,迫切需要一种高效、安全且可供大众使用的猴痘病毒疫苗。在此,我们开发了一种多价 mRNA 候选疫苗 MPXV-1103,它在单一序列中表达了全长的 B6、A35、A29 和 M1 蛋白以及三个柔性连接体(G4S1)3。与单价 MPXV mRNA 候选疫苗或由四种单价 MPXV mRNA 疫苗的混合物制成的四价 mRNA 疫苗相比,MPXV-1103 能引起强大的体液反应和 MPXV 特异性 T 细胞反应,并保护小鼠免受致命性疫苗病毒 (VACV) 的挑战,即使剂量低至 1 μg,鼻腔或肺部也检测不到活病毒。此外,对接种 5 μg 和 20 μg 剂量 MPXV-1103 的小鼠进行的全血细胞计数和主要器官组织显微照片分析表明,两种剂量的 MPXV-1103 均未对小鼠造成任何可观察到的病理变化。总之,我们的研究结果表明,MPXV-1103 具有高效、安全和生产工艺简化等特点,是一种很有希望的用于预防 MPXV 感染的候选疫苗。
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引用次数: 0
Anti-HBc mirrors the activation of HBV-specific CD8+ T cell immune response and exhibits a direct effect on HBV control 抗 HBc 可反映 HBV 特异性 CD8+ T 细胞免疫反应的激活,并对 HBV 控制产生直接影响。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-31 DOI: 10.1016/j.antiviral.2024.105975
Guofu Ye , Chengcong Chen , Yongjun Zhou , Libo Tang , Jianzhong Cai , Yiyan Huang , Jiayue Yang , Yaoting Feng , Liangxing Chen , Yuhao Wang , Yanchen Ma , Guanfeng Lin , Yingsong Wu , Xiaotao Jiang , Jinlin Hou , Yongyin Li

Background

Hepatitis B core antibody (anti-HBc) is commonly present in patients with chronic hepatitis B virus (HBV) infection and serves as a marker of humoral immunity. Herein, we aim to investigate the correlation between anti-HBc and antiviral immune response and its putative role in HBV control.

Methods

Quantitative anti-HBc and levels of anti-HBc subtypes were measured in chronic hepatitis B (CHB) patients. The effects of anti-HBc on immune cells and HBV replication were evaluated using the HBV mouse models and human hepatoma cell lines.

Results

Baseline levels of IgG1 and IgG3 anti-HBc were elevated in CHB patients with favorable treatment response, and correlated with the virological response observed at week 52. Additionally, increased levels of IgM and IgG1 anti-HBc were observed exclusively in CHB patients with liver inflammation. Notably, significant correlations were identified between quantitative levels of anti-HBc and the frequencies of HBcAg-specific CD8+ T cells. Intriguingly, HBcAg efficiently activates T cells aided by B cells in vitro experiments. Moreover, anti-HBc inhibits HBV replication either by a direct effect or through complement-mediated cytotoxicity in HBV-producing cell lines.

Conclusions

Anti-HBc reflects the activation of an HBV-specific CD8+ T cell immune response and may have anti-HBV activity.

背景:乙型肝炎核心抗体(抗-HBc)常见于慢性乙型肝炎病毒(HBV)感染患者,是体液免疫的标志物。在此,我们旨在研究抗 HBc 与抗病毒免疫反应之间的相关性及其在 HBV 控制中的作用:方法:测定慢性乙型肝炎(CHB)患者的抗 HBc 定量和抗 HBc 亚型水平。使用 HBV 小鼠模型和人类肝癌细胞系评估了抗 HBc 对免疫细胞和 HBV 复制的影响:结果:治疗反应良好的慢性乙型肝炎患者的 IgG1 和 IgG3 抗 HBc 基线水平升高,并与第 52 周观察到的病毒学反应相关。此外,IgM 和 IgG1 抗 HBc 水平的升高只出现在有肝脏炎症的慢性乙型肝炎患者中。值得注意的是,抗 HBc 的定量水平与 HBcAg 特异性 CD8+ T 细胞的频率之间存在明显的相关性。耐人寻味的是,在体外实验中,HBcAg 能在 B 细胞的帮助下有效激活 T 细胞。此外,抗 HBc 可通过直接作用或补体介导的细胞毒性抑制 HBV 生产细胞系中的 HBV 复制:结论:抗 HBc 反映了 HBV 特异性 CD8+ T 细胞免疫反应的激活,可能具有抗 HBV 活性。
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引用次数: 0
β-d-N4-hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus β-d-N4-羟基胞嘧啶是莫仑吡韦的一种代谢产物,在体外对狂犬病毒具有抗病毒活性。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-31 DOI: 10.1016/j.antiviral.2024.105977
Kei Konishi , Shinji Kusakabe , Nijiho Kawaguchi , Takao Shishido , Naoto Ito , Michiko Harada , Satoshi Inoue , Ken Maeda , William W. Hall , Yasuko Orba , Hirofumi Sawa , Michihito Sasaki , Akihiko Sato

Rabies is a fatal neurological disorder caused by rabies virus (RABV) infection. Approximately 60,000 patients die from rabies annually, and there are no effective treatments for this disease. Nucleoside analogs are employed as antiviral drugs based on their broad antiviral spectrum, and certain nucleoside analogs have been reported to exhibit anti-RABV activity. The nucleoside analog β-d-N4-hydroxycytidine (NHC) has antiviral effects against a range of RNA viruses. Molnupiravir (MPV), a prodrug of NHC, is clinically used as an oral antiviral drug for coronavirus infections. Despite its broad-spectrum activity, the antiviral activity of NHC against RABV remains unclear. In this study, we reveal that NHC exhibits comparable in vitro anti-RABV activity as ribavirin and favipiravir (also known as T-705) with a 90% effective concentration of 6 μM in mouse neuroblastoma cells. NHC reduced viral loads in neuronal and nonneuronal cells in a dose-dependent manner. Both laboratory and field RABVs (fixed and street strains, respectively) were susceptible to NHC. However, no increase in survival or reduction in viral titers in the brain was observed in RABV-infected mice treated prophylactically with MPV. These findings highlight the potential and challenges of NHC in the treatment of RABV infection.

狂犬病是一种由狂犬病毒(RABV)感染引起的致命神经系统疾病。每年约有 6 万名患者死于狂犬病,目前尚无有效的治疗方法。核苷类似物具有广泛的抗病毒谱,因此被用作抗病毒药物,据报道,某些核苷类似物具有抗狂犬病病毒的活性。核苷类似物 β-d-N4-hydroxycytidine (NHC) 对一系列 RNA 病毒具有抗病毒作用。莫能吡韦(MPV)是 NHC 的一种原药,临床上用作治疗冠状病毒感染的口服抗病毒药物。尽管 NHC 具有广谱抗病毒活性,但其对 RABV 的抗病毒活性仍不清楚。在这项研究中,我们发现 NHC 在小鼠神经母细胞瘤细胞中的体外抗 RABV 活性与利巴韦林和法非比拉韦(又称 T-705)相当,其 90% 的有效浓度为 6 μM。NHC 能以剂量依赖的方式降低神经细胞和非神经细胞中的病毒载量。实验室和野外 RABV(分别为固定株和街头株)都对 NHC 易感。然而,用 MPV 预防性治疗 RABV 感染的小鼠的存活率没有提高,脑内病毒滴度也没有降低。这些发现凸显了 NHC 在治疗 RABV 感染方面的潜力和挑战。
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引用次数: 0
Activating adaptive immunity by bispecific, T-cell engager antibodies bridging infected and immune-effector cells is a promising novel therapy for chronic hepatitis B 通过连接感染细胞和免疫效应细胞的双特异性 T 细胞吸引抗体来激活适应性免疫,是治疗慢性乙型肝炎的一种前景广阔的新疗法。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-30 DOI: 10.1016/j.antiviral.2024.105972
Zhe Xie , Ulrike Protzer

Bispecific antibodies (bsAbs) are engineered immunoglobulins that combine two different antigen-binding sites in one molecule. BsAbs can be divided into two molecular formats: IgG-like and non-IgG-like antibodies. Structural elements of each format have implications for engaging the immune system. T cell engager antibodies (TCEs) are bsAbs designed to engage T cells with target cells. TCEs can be applied not only in cancer but also in infectious disease therapy to activate T-cell responses. In this review, we focus on current literature on the design and use of bsAbs as an innovative strategy to enhance adaptive antiviral immune responses. We summarized the novel T cell-related immunotherapies with a focus on TCEs, that are developed for the treatment of chronic hepatitis B. Chronic infection with the hepatitis B virus (HBV) had a death toll of 1.1 million humans in 2022, mainly due to liver cirrhosis and hepatocellular carcinoma developing in the more than 250 million humans chronically infected. A curative treatment approach for chronic hepatitis B is lacking. Combining antiviral therapy with immune therapies activating T-cell responses is regarded as the most promising therapeutic approach to curing HBV and preventing the sequelae of chronic infection. Attracting functionally intact T cells that are not HBV-specific and, therefore, have not yet been exposed to regulatory mechanisms and activating those at the target site in the liver is a very interesting therapeutic approach that could be achieved by TCEs. Thus, TCEs redirecting T cells toward HBV-positive cells represent a promising strategy for treating chronic hepatitis B and HBV-associated hepatocellular carcinoma.

双特异性抗体(bsAbs)是在一个分子中结合了两个不同抗原结合位点的工程免疫球蛋白。双特异性抗体可分为两种分子形式:IgG 样抗体和非 IgG 样抗体。每种形式的结构元素都会影响免疫系统的参与。T 细胞吸引抗体(TCEs)是专为吸引 T 细胞与靶细胞而设计的 bsAbs。TCEs 不仅可用于癌症治疗,还可用于传染病治疗,以激活 T 细胞反应。在这篇综述中,我们重点讨论了目前有关设计和使用 bsAbs 作为增强适应性抗病毒免疫反应的创新策略的文献。2022 年,慢性乙型肝炎病毒(HBV)感染造成的死亡人数达 110 万,主要原因是超过 2.5 亿慢性感染者出现肝硬化和肝细胞癌。目前还缺乏治疗慢性乙型肝炎的方法。将抗病毒疗法与激活 T 细胞反应的免疫疗法相结合,被认为是治愈 HBV 和预防慢性感染后遗症的最有希望的治疗方法。吸引功能完好的非 HBV 特异性 T 细胞,并在肝脏靶点激活这些细胞,是一种非常有趣的治疗方法,TCEs 可以实现这一目标。因此,将 T 细胞重新定向到 HBV 阳性细胞的 TCE 是治疗慢性乙型肝炎和 HBV 相关肝细胞癌的一种很有前景的策略。
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引用次数: 0
Inhibition of human cytomegalovirus entry into mucosal epithelial cells 抑制人类巨细胞病毒进入黏膜上皮细胞
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-27 DOI: 10.1016/j.antiviral.2024.105971
Li He , Laura Hertel , Claire D. James , Iain M. Morgan , Aloysius J. Klingelhutz , Tong-Ming Fu , Lawrence M. Kauvar , Michael A. McVoy

Human cytomegalovirus (CMV) causes serious developmental disabilities in newborns infected in utero following oral acquisition by the mother. Thus, neutralizing antibodies in maternal saliva have potential to prevent maternal infection and, consequently, fetal transmission and disease. Based on standard cell culture models, CMV entry mediators (and hence neutralizing targets) are cell type-dependent: entry into fibroblasts requires glycoprotein B (gB) and a trimeric complex (TC) of glycoproteins H, L, and O, whereas endothelial and epithelial cell entry additionally requires a pentameric complex (PC) of glycoproteins H and L with UL128, UL130, and UL131A. However, as the mediators of mucosal cell entry and the potential impact of cellular differentiation remained unclear, the present studies utilized mutant viruses, neutralizing antibodies, and soluble TC-receptor to determine the entry mediators required for infection of mucocutaneus cell lines and primary tonsil epithelial cells. Entry into undifferentiated cells was largely PC-dependent, but PC-independent entry could be induced by differentiation. TC-independent entry was also observed and varied by cell line and differentiation. Infection of primary tonsil cells from some donors was entirely TC-independent. In contrast, an antibody to gB or disruption of virion attachment using heparin blocked entry into all cells. These findings indicate that CMV entry into the spectrum of cell types encountered in vivo is likely to be more complex than has been suggested by standard cell culture models and may be influenced by the relative abundance of virion envelope glycoprotein complexes as well as by cell type, tissue of origin, and state of differentiation.

人类巨细胞病毒(CMV)会导致宫内感染的新生儿在母亲经口感染后出现严重的发育障碍。因此,母体唾液中的中和抗体有可能预防母体感染,进而预防胎儿传播和疾病。根据标准的细胞培养模型,CMV 的进入介质(以及中和目标)是细胞类型依赖性的:进入成纤维细胞需要糖蛋白 B(gB)和由糖蛋白 H、L 和 O 组成的三聚体复合物(TC),而进入内皮细胞和上皮细胞则需要由糖蛋白 H 和 L 与 UL128、UL130 和 UL131A 组成的五聚体复合物(PC)。然而,由于粘膜细胞进入的介质和细胞分化的潜在影响仍不清楚,本研究利用突变病毒、中和抗体和可溶性 TC 受体来确定感染粘膜细胞系和原发性扁桃体上皮细胞所需的进入介质。进入未分化细胞主要依赖 PC,但分化可诱导 PC 依赖性进入。此外,还观察到依赖于 TC 的进入,并因细胞系和分化情况而异。一些供体的原代扁桃体细胞感染完全不依赖于 TC。相反,gB 抗体或使用肝素破坏病毒附着会阻止病毒进入所有细胞。这些研究结果表明,CMV 进入体内各种细胞可能比标准细胞培养模型所显示的更为复杂,可能受到病毒包膜糖蛋白复合物的相对丰度以及细胞类型、来源组织和分化状态的影响。
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引用次数: 0
Nirmatrelvir and molnupiravir maintain potent in vitro and in vivo antiviral activity against circulating SARS-CoV-2 omicron subvariants Nirmatrelvir 和 Molnupiravir 在体外和体内对循环的 SARS-CoV-2 Omicron 亚变体都具有很强的抗病毒活性。
IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-25 DOI: 10.1016/j.antiviral.2024.105970
Romel Rosales , Briana L. McGovern , M. Luis Rodriguez , Rocio Leiva-Rebollo , Randy Diaz-Tapia , Jared Benjamin , Devendra K. Rai , Rhonda D. Cardin , Annaliesa S. Anderson , Emilia Mia Sordillo , Harm van Bakel , Viviana Simon , Adolfo García-Sastre , Kris M. White

Variants of SARS-CoV-2 pose significant challenges in public health due to their increased transmissibility and ability to evade natural immunity, vaccine protection, and monoclonal antibody therapeutics. The emergence of the highly transmissible Omicron variant and subsequent subvariants, characterized by an extensive array of over 32 mutations within the spike protein, intensifies concerns regarding vaccine evasion. In response, multiple antiviral therapeutics have received FDA emergency use approval, targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro) regions, known to have relatively fewer mutations across novel variants. In this study, we evaluated the efficacy of nirmatrelvir (PF-07321332) and other clinically significant SARS-CoV-2 antivirals against a diverse panel of SARS-CoV-2 variants, encompassing the newly identified Omicron subvariants XBB1.5 and JN.1, using live-virus antiviral assays. Our findings demonstrate that while the last Omicron subvariants exhibited heightened pathogenicity in our animal model, nirmatrelvir and other clinically relevant antivirals consistently maintained their efficacy against all tested variants, including the XBB1.5 subvariant.

SARS-CoV-2 的变异体由于其传播性增强,能够逃避自然免疫、疫苗保护和单克隆抗体疗法,给公共卫生带来了重大挑战。具有高度传播性的 Omicron 变体和随后出现的亚变体,其特点是尖峰蛋白中出现了超过 32 个突变,这加剧了人们对疫苗逃避能力的担忧。作为回应,多种抗病毒疗法已获得美国食品及药物管理局的紧急使用批准,这些疗法针对的是 SARS-CoV-2 RNA 依赖性 RNA 聚合酶(RdRp)和主蛋白酶(Mpro)区域,已知这些区域在各种新型变体中的突变相对较少。在这项研究中,我们使用活病毒抗病毒试验评估了 nirmatrelvir (PF-07321332) 和其他具有临床意义的 SARS-CoV-2 抗病毒药物对多种 SARS-CoV-2 变异株的疗效,其中包括新发现的 Omicron 亚变异株 XBB1.5 和 JN.1。我们的研究结果表明,虽然最后的 Omicron 亚变异体在我们的动物模型中表现出更强的致病性,但 nirmatrelvir 和其他临床相关的抗病毒药物对包括 XBB1.5 亚变异体在内的所有测试变异体始终保持有效。
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引用次数: 0
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Antiviral research
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