MRC Transition Support CSF Nicholas Matheson

点击翻译按钮获取中文摘要

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.