MRC Transition Support CSF Nicholas Matheson

大约100年前，人类免疫缺陷病毒（HIV）首次传播给人类，感染了全世界近4000万人，每年导致约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是至关重要的。“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的细胞表面蛋白质的数量和数量的变化，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，我发现许多被HIV耗尽的蛋白质都参与了将氨基酸运送到细胞中的过程。这些“氨基酸转运体”的研究相对不足，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被HIV靶向，以及这些转运蛋白对“辅助T细胞”的重要性。辅助T细胞是被HIV感染并在艾滋病患者中逐渐被破坏的免疫系统的主要细胞。在我发现的HIV靶标中，有一种叫做SNAT1和SERINC3/5的蛋白质。我发现，SNAT1将一种叫做丙氨酸的氨基酸运输到细胞中，而丙氨酸的充足供应对于正常的辅助T细胞功能是必不可少的。同样，SERINC蛋白被认为将一种叫做丝氨酸的氨基酸结合到“细胞膜”中，细胞膜包围着细胞，将细胞内部分隔成小隔间。在我获得临床科学家奖学金的前两年半里，我开发了一种净化hiv感染的辅助性T细胞的新方法；完善了从这些细胞中提取氨基酸和其他“代谢物”的方法；并开发了一种革命性的方法来测量氨基酸进出细胞的运输。因此，我现在希望使用这些技术来弄清楚细胞中的哪些代谢过程是由HIV操纵的，以及为什么它们对HIV病毒和辅助T细胞很重要。特别是，它们将使我能够：测量生长细胞中通过SNAT1和SERINC3/5的氨基酸运输；绘制hiv感染原发CD4+ T细胞代谢物和代谢的全球变化；并表征辅助T细胞的其他关键氨基酸转运体，这些转运体是我之前在研究中使用不同的、不相关的方法识别的。综上所述，这些数据将成为该领域其他研究人员的宝贵资源，我希望最终能够开发出针对T细胞中氨基酸转运体的新疗法。

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.