The metabolism of the HIV-infected CD4+ T cell

HIV感染的CD4 T细胞的代谢

• 批准号: MR/J008125/1
• 负责人: Hendrik Huthoff
• 金额: $ 57.08万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ008125%2F1
• 关键词: metabolism; HIV; infected; CD4+; cell

Viruses are not considered life-forms because they lack one defining feature that all other organisms share: metabolism. Being in essence a mobile genetic element, a virus is entirely dependent on the metabolism provided by the host it infects for replication. It is well known that viral infections alter the properties of living cells in order to replicate, often leading to disease. While interactions of viruses with their hosts are well studied at the macro-molecular and cellular level, the demand on small molecule building blocks and energy resources, the metabolites, has seldom been investigated. These demands are potentially conflicting with regard to virus replication and cell survival. Pioneering work on herpes viruses has revealed preferences for the use of certain metabolites during infections, which can be exploited for the development of antiviral drugs by denying the virus a supply of its preferred metabolites. This request for support from the MRC proposes to apply this strategy to HIV-1. HIV-1 infections continue to pose a global health threat and in the absence of a cure or vaccine, patients require antiviral treatment for their entire lives. Current treatments rely heavily on the use of modified building blocks of DNA, which target the viral protein that executes the replication of its genome. This treatment is associated with considerable side effects and can eventually fail owing to the development of resistance by the virus, requiring a switch of medication. Therefore, the development of new and improved agents that target HIV is an ongoing effort. In recent years there has been a great interest in targeting the host components that the virus usurps for its replication, as these are less likely to allow the emergence of viral resistance. We propose to investigate the complex dynamics of metabolites in the HIV infected cell to determine the viral metabolic demand. Our preliminary investigations indicate that we can detect depletion of certain metabolites, notably the amino acids that are the building blocks for proteins, in cells infected with HIV-1. Furthermore, we have observed that HIV alters the activity of mitochondria, which are the metabolic factories of the cell. The funds requested to elaborate on these findings will be targeted towards three main aims, being: i) To provide a comprehensive description of the levels and rate of usage of metabolites in the HIV infected cell, ii) to determine the means by which the virus influences the cellular metabolism and iii) to investigate the feasibility of interfering with metabolic processes on which the virus depends as antiviral drug targets.

病毒不被视为生命形式，因为它们缺乏所有其他生物体共有的一个决定性特征：新陈代谢。病毒本质上是一种可移动的遗传元件，其复制完全依赖于其感染的宿主提供的新陈代谢。众所周知，病毒感染会改变活细胞的特性以进行复制，通常会导致疾病。虽然病毒与其宿主的相互作用在大分子和细胞水平上得到了深入研究，但对小分子构建模块和能源、代谢物的需求却很少被研究。这些要求在病毒复制和细胞存活方面可能存在冲突。关于疱疹病毒的开创性工作揭示了感染过程中对某些代谢物的偏好，可以通过阻止病毒提供其偏好的代谢物来利用这些代谢物来开发抗病毒药物。 MRC 的支持请求建议将此策略应用于 HIV-1。 HIV-1 感染继续对全球健康构成威胁，在没有治愈方法或疫苗的情况下，患者需要终生接受抗病毒治疗。目前的治疗方法在很大程度上依赖于使用经过修饰的 DNA 构建模块，这些构建模块以执行其基因组复制的病毒蛋白为目标。这种治疗具有相当大的副作用，并且由于病毒产生耐药性而最终可能失败，需要更换药物。因此，开发新的和改进的针对艾滋病毒的药物是一项持续的努力。近年来，人们对病毒复制所侵占的宿主成分产生了极大的兴趣，因为这些成分不太可能导致病毒耐药性的出现。我们建议研究 HIV 感染细胞中代谢物的复杂动态，以确定病毒代谢需求。我们的初步研究表明，我们可以检测到感染 HIV-1 的细胞中某些代谢物的消耗，特别是作为蛋白质组成部分的氨基酸。此外，我们观察到艾滋病毒改变了线粒体的活性，线粒体是细胞的代谢工厂。详细说明这些发现所需的资金将用于三个主要目标，即：i）提供 HIV 感染细胞中代谢物的水平和使用率的全面描述，ii）确定病毒影响细胞代谢的方式，以及 iii）研究干扰病毒作为抗病毒药物靶标的代谢过程的可行性。

项目成果

HIV-1 pathogenicity and virion production are dependent on the metabolic phenotype of activated CD4+ T cells.

• DOI: 10.1186/s12977-014-0098-4
• 发表时间: 2014-11-25
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Hegedus A;Kavanagh Williamson M;Huthoff H
• 通讯作者: Huthoff H

Upregulation of Glucose Uptake and Hexokinase Activity of Primary Human CD4+ T Cells in Response to Infection with HIV-1.

原代人 CD4+ T 细胞响应 HIV-1 感染的葡萄糖摄取和己糖激酶活性上调。

• DOI: 10.3390/v10030114
• 发表时间: 2018-03-07
• 期刊: Viruses
• 作者: Kavanagh Williamson M;Coombes N;Juszczak F;Athanasopoulos M;Khan MB;Eykyn TR;Srenathan U;Taams LS;Dias Zeidler J;Da Poian AT;Huthoff H
• 通讯作者: Huthoff H