Integrating subcellular multi-omics to identify druggable metabolic markers of latent HIV infection in CD4 T-cells
整合亚细胞多组学来识别 CD4 T 细胞中潜在 HIV 感染的可药物代谢标志物
基本信息
- 批准号:MR/Y013093/1
- 负责人:
- 金额:$ 86.12万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2024
- 资助国家:英国
- 起止时间:2024 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Four decades after its identification, the human immunodeficiency virus (HIV) continues to infect almost 40 million people worldwide, causing hundreds of thousands of deaths each year. Infection by HIV mainly targets white blood cells and, if left untreated, can lead to a severe, potentially fatal, acquired immunodeficiency syndrome (AIDS). Antiviral drugs have been developed and have drastically improved the life expectancy and quality of people living with HIV. However, these drugs require lifelong administration, and do not lead to a cure. Importantly, HIV persists in a dormant (latent) form in a subset of white blood cells (called CD4 T-lymphocytes) for the entire lifespan of infected individuals. This latency allows the virus to elude antiviral drugs and the immune system. Several studies have been conducted with the aim to identify features of persistently infected cells that could allow us to specifically target these cells for elimination and, thus, potentially cure the infection. Although multiple features have been proposed, few have the specificity required for safe therapeutic application, and most of the studies have failed to decrease the frequency of persistently infected cells. No current treatment to target persistently HIV-infected cells is approved. One of the therapeutic approaches undergoing clinical testing is based on our research showing that persistently infected cells have specific alterations in energy metabolism. Our studies, as well as those of other groups, however, focussed on whole cells. In reality, most cellular energy production is located within highly specialised subcellular compartments. To allow us to identify functional, structural, and/or spatial features of metabolic regulation that distinguish cells harbouring the virus from those that do not, the proposed project will produce an in-depth characterization (identikit) of persistently HIV-infected cells. We will approach this work both using CD4 T-lymphocytes infected with HIV in vitro and using CD4 T-lymphocytes isolated from the blood of individuals living with HIV. We will first separate cells infected in vitro based on the presence and stage of infection, and then individually study the main cellular sites of energy production and storage (i.e., nucleus/cytoplasm and mitochondria). The data obtained will comprehensively capture the content of proteins and metabolites, as well as the genetic regulation underpinning their production. These data will be computationally combined and complemented by experimental assessments of the functionality of each major cellular metabolic step in order to identify distinguishing features of persistently infected cells that can be explored for their potential to serve as therapeutic targets. We will then use computer models to predict effective drug candidates and put these predictions in practice by testing drugs in the laboratory for their target affinity and ability to selectively eliminate persistently infected cells. Overall, this study will aim to provide a unified profile of metabolic determinants of HIV persistence and furnish pre-clinical evidence for novel therapeutic strategies to eliminate infected cells resistant to currently available antiviral drugs. Ultimately, this work could lead to a therapeutic approach to remove the virus from its cellular hideout in infected individuals.
人类免疫缺陷病毒(艾滋病毒)在被发现40年后,继续感染全世界近4 000万人,每年造成数十万人死亡。艾滋病毒感染主要针对白色血细胞,如果不治疗,可导致严重的、可能致命的获得性免疫缺陷综合征(艾滋病)。抗病毒药物已经开发出来,大大提高了艾滋病毒感染者的预期寿命和生活质量。然而,这些药物需要终身服用,并且不会导致治愈。重要的是,HIV在受感染个体的整个生命周期中以休眠(潜伏)形式存在于白色血细胞亚群(称为CD 4 T淋巴细胞)中。这种潜伏期使病毒能够逃避抗病毒药物和免疫系统。已经进行了几项研究,目的是确定持续感染细胞的特征,这些特征可以使我们特异性地靶向这些细胞进行消除,从而有可能治愈感染。虽然已经提出了多种特征,但很少有安全治疗应用所需的特异性,并且大多数研究未能降低持续感染细胞的频率。目前还没有针对持续性HIV感染细胞的治疗方法被批准。正在进行临床测试的治疗方法之一是基于我们的研究,表明持续感染的细胞在能量代谢方面有特定的改变。然而,我们的研究以及其他小组的研究都集中在整个细胞上。事实上,大多数细胞能量产生位于高度专业化的亚细胞区室中。为了使我们能够识别代谢调节的功能,结构和/或空间特征,将携带病毒的细胞与不携带病毒的细胞区分开来,拟议的项目将产生持续性HIV感染细胞的深入表征(identikit)。我们将使用体外感染HIV的CD 4 T淋巴细胞和从HIV感染者血液中分离的CD 4 T淋巴细胞进行这项工作。我们将首先根据感染的存在和阶段分离体外感染的细胞,然后单独研究能量产生和储存的主要细胞位点(即,细胞核/细胞质和线粒体)。所获得的数据将全面捕获蛋白质和代谢物的含量,以及支持其生产的遗传调控。这些数据将通过计算组合并通过对每个主要细胞代谢步骤的功能性的实验评估进行补充,以确定可探索其作为治疗靶点的潜力的持续感染细胞的显著特征。然后,我们将使用计算机模型来预测有效的候选药物,并通过在实验室中测试药物的靶向亲和力和选择性消除持续感染细胞的能力来将这些预测付诸实践。总的来说,这项研究的目的是提供一个统一的艾滋病毒持久性的代谢决定因素,并提供临床前证据的新的治疗策略,以消除感染细胞耐药,目前可用的抗病毒药物。最终,这项工作可能会导致一种治疗方法,将病毒从感染个体的细胞藏身处清除。
项目成果
期刊论文数量(0)
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Iart Luca Shytaj其他文献
Broad-spectrum antiviral activity of two structurally analogous CYP3A inhibitors against pathogenic human coronaviruses emin vitro/em
两种结构类似的 CYP3A 抑制剂对致病性人类冠状病毒的体外广谱抗病毒活性
- DOI:
10.1016/j.antiviral.2023.105766 - 发表时间:
2024-01-01 - 期刊:
- 影响因子:4.000
- 作者:
Lara Gallucci;James Bazire;Andrew D. Davidson;Iart Luca Shytaj - 通讯作者:
Iart Luca Shytaj
Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS
- DOI:
10.1186/s12977-015-0178-0 - 发表时间:
2015-06-18 - 期刊:
- 影响因子:3.900
- 作者:
Andrea Savarino;Iart Luca Shytaj - 通讯作者:
Iart Luca Shytaj
Iart Luca Shytaj的其他文献
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