The metabolism of the HIV-infected CD4+ T cell

病毒不被认为是生命形式，因为它们缺乏一个所有其他生物体共有的定义特征：新陈代谢。病毒本质上是一种移动的遗传因子，完全依赖于它所感染的宿主提供的代谢来复制。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很好的研究，但对小分子结构单元和能量资源（代谢物）的需求却很少研究。这些要求在病毒复制和细胞存活方面可能是冲突的。对疱疹病毒的开创性研究揭示了感染期间使用某些代谢物的偏好，这可以通过拒绝病毒提供其首选代谢物来开发抗病毒药物。要求医学研究理事会提供支持的这一请求建议将这一战略应用于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。目前的治疗严重依赖于使用修饰的DNA构建块，其靶向执行其基因组复制的病毒蛋白。这种治疗伴随着相当大的副作用，并可能由于病毒产生耐药性而最终失败，需要更换药物。因此，开发针对艾滋病毒的新的和改进的药剂是一项持续的努力。近年来，人们对靶向病毒复制所篡夺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力学，以确定病毒的代谢需求。我们的初步研究表明，我们可以检测到某些代谢物的消耗，特别是在感染HIV-1的细胞中作为蛋白质构建单元的氨基酸。此外，我们还观察到HIV改变了线粒体的活性，而线粒体是细胞的代谢工厂。为详细说明这些发现而要求的资金将用于三个主要目标，即：i）全面描述艾滋病毒感染细胞中代谢物的使用水平和速度，ii）确定病毒影响细胞代谢的方式，iii）研究干扰病毒作为抗病毒药物靶点所依赖的代谢过程的可行性。

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.