MRC Transition Support CSF Nicholas Matheson

人类免疫缺陷病毒（HIV）首次传染给人类已有近100年的历史，目前全世界有近4000万人感染HIV，每年造成约100万人死于艾滋病。因此，了解艾滋病毒如何能够复制和传播，以及为什么艾滋病毒感染会导致艾滋病至关重要。“蛋白质组学”是对“蛋白质”的大规模研究，蛋白质是活细胞和生物体的关键组成部分。我以前使用蛋白质组学来测量感染HIV的细胞表面蛋白质数量和数量的变化，并确定了许多被病毒特异性耗尽的蛋白质。蛋白质本身是由长链的“氨基酸”组成的，我发现的许多被艾滋病毒耗尽的蛋白质都参与了将氨基酸转运到细胞中的过程。这些“氨基酸转运蛋白”相对而言研究不足，可能是新药的有吸引力的候选者。因此，我希望了解为什么氨基酸转运蛋白是艾滋病毒的目标，以及这些转运蛋白对“辅助T细胞”的重要性，辅助T细胞是艾滋病毒感染的免疫系统的主要细胞，并在艾滋病患者中逐渐被破坏。在我确定的HIV靶点中，有一种蛋白质叫做SNAT 1和SERINC 3/5。我发现SNAT 1将一种叫做丙氨酸的氨基酸转运到细胞中，而大量的丙氨酸供应对正常的辅助性T细胞功能至关重要。同样，SERINC蛋白被认为将一种称为丝氨酸的氨基酸整合到“细胞膜”中，细胞膜包围细胞并将其内部分隔成隔室。在我的临床医生科学家奖学金的前2.5年里，我已经：开发了一种纯化HIV感染的辅助性T细胞的新方法;完善了一种从这些细胞中提取氨基酸和其他“代谢物”的方法;并开发了一种测量氨基酸进出细胞运输的变革性方法。因此，我现在希望使用这些技术来弄清楚细胞中哪些代谢过程是由HIV操纵的，以及为什么它们对HIV病毒和辅助性T细胞很重要。特别是，它们将使我能够：测量生长细胞中SNAT 1和SERINC 3/5的氨基酸转运;绘制HIV感染的原代CD 4 + T细胞中代谢物和代谢的全球变化;以及其他辅助性T细胞的关键氨基酸转运蛋白，这些转运蛋白是在我之前的研究中用不同的、不相关的方法鉴定出来的。总的来说，这些数据将成为该领域其他研究人员的宝贵资源，我希望最终能够为靶向T细胞中氨基酸转运蛋白的患者开发新的治疗方法。

Approximately 100 years since it was first transmitted to humans, the Human Immunodeficiency Virus (HIV) infects almost 40 million people worldwide, and causes around 1 million AIDS-related deaths every year. It is therefore critical to understand how HIV has been able to replicate and spread, and why HIV infection causes AIDS. "Proteomics" is the large-scale study of "proteins", the critical building blocks of living cells and organisms. I previously used proteomics to measure changes in the number and quantity of proteins at the surface of cells infected with HIV, and identified many proteins specifically depleted by the virus. Proteins are themselves made up of long chains of "amino acids", and many of the proteins I found to be depleted by HIV are involved in transporting amino acids into cells. These "amino acid transporters" are relatively understudied, and may be attractive candidates for new drugs. I therefore wish to understand why amino acid transporters are targeted by HIV, and the importance of these transporters for "helper T cells", the main cells of the immune system infected by HIV and progressively destroyed in patients with AIDS. Amongst the HIV targets I identified were proteins called SNAT1 and SERINC3/5. I discovered that SNAT1 transports an amino acid called alanine into cells, and that an abundant supply of alanine is essential for normal helper T cell function. Likewise, SERINC proteins are thought to incorporate an amino acid called serine into "cell membranes", which surround cells and separate their interiors into compartments. During the first 2.5 years of my Clinician Scientist Fellowship, I have: developed a new way of purifying HIV-infected helper T cells; perfected a way to extract amino acids and other "metabolites" from these cells; and developed a transformative approach to measuring transport of amino acids in and out of cells. I therefore now wish to use these techniques to figure out which metabolic processes in cells are manipulated by HIV, and why they are important for the HIV virus and helper T cells.In particular, they will enable me to: measure amino acid transport by SNAT1 and SERINC3/5 in growing cells; map global changes in metabolites and metabolism in HIV-infected primary CD4+ T cells; and characterise other critical amino acid transporters of helper T cells identified using different, unrelated approaches earlier in my fellowship. Taken together, these data will be a valuable resource for other researchers in the field and will, I hope, ultimately lead to the development of new treatments for patients targeting amino acid transporters in T cells.