Viral and cellular regulation of T-cell amino acid metabolism

人类免疫缺陷病毒（HIV）首次传播给人类大约100年后，现在全世界感染了近4000万人，每年造成100多万与艾滋病有关的死亡。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。在博士期间，我用蛋白质组学测量了感染HIV的细胞表面蛋白质的数量和数量的变化，发现bbb100蛋白被病毒特异性地耗尽了。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”的研究相对较少，可能是新疗法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HIV的目标，以及这些转运蛋白对“t细胞”的重要性，t细胞是免疫系统的主要细胞，被HIV感染并在艾滋病患者中逐渐被破坏。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t细胞的正常功能至关重要。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。因此，在我项目的第一部分，我希望确定为什么丙氨酸对t细胞很重要，并研究SERINC3/5在t细胞丝氨酸结合中的作用。“代谢”是指发生在活细胞和生物体中的化学反应，其中许多反应涉及氨基酸。在其他情况下，已知t细胞代谢的变化对调节t细胞功能很重要。因此，在我的项目的第二部分，我希望以更一般的方式调查感染艾滋病毒的细胞中哪些代谢反应发生了改变，并了解这些变化如何使病毒受益。最后，在我的项目的第三部分，我希望将我在蛋白质组学方面的技能与一种名为“CRISPR”的新技术结合起来，识别氨基酸转运体和代谢反应，这对正常的t细胞功能至关重要，即使在没有HIV感染的情况下。综合起来，这些数据将成为该领域其他研究人员的宝贵资源，我希望，这些数据将导致针对t细胞中氨基酸转运体的患者的新治疗方法的发展。

Approximately 100 years since it was first transmitted to humans, the Human Immunodeficiency Virus (HIV) now infects almost 40 million people worldwide, and causes more than 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. During my PhD, I used proteomics to measure changes in the number and quantity of proteins at the surface of cells infected with HIV, and found that >100 proteins were 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 therapies. I therefore wish to understand why amino acid transporters are targeted by HIV, and the importance of these transporters for "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 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. In the first part of my project, I therefore wish to determine why alanine is important for T-cells, and investigate the role of SERINC3/5 in T-cell serine incorporation. "Metabolism" refers to the chemical reactions which take place in living cells and organisms, and a number of these reactions involve amino acids. In other settings, changes in T-cell metabolism are known to be important in regulating T-cell function. In the second part of my project, I therefore wish to investigate in more general terms which metabolic reactions are altered in HIV-infected cells, and understand how these changes benefit the virus. Finally, in the third part of my project, I wish to combine my skills in proteomics with a new technology called "CRISPR" to identify amino acid transporters and metabolic reactions which are critical for normal T-cell function, even in the absence of HIV infection. Taken together, these data will be a valuable resource for other researchers in the field and will, I hope, lead to the development of new treatments for patients targeting amino acid transporters in T-cells.