Viral and cellular regulation of T-cell amino acid metabolism

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) 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.