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Natural killer (NK) cells are cells of the immune system that can fight infections and cancer. Their responses are controlled by a number of cell surface receptors including the killer cell immunoglobulin-like receptors (KIR). There are many different KIR but extensive studies have shown that NK cells and specific KIR genes can be important factors in determining the outcome of both infections, such as HIV and hepatitis C, and also of cancers, including leukaemia and liver cancer. To date harnessing specific sub-populations of NK cells for therapeutic benefit has been difficult because of a lack of understanding of NK cell biology. This has meant that NK cell based therapies are relatively crude and do not take account of the fact that different NK cells express different cell-surface receptors that may be relevant only in specific diseases. For instance the gene KIR2DL3 is associated with protection against hepatitis C, and the gene KIR2DS2 is associated with a better response to treatment in non-small cell lung cancer. Work in our group has pioneered how NK cell reactivity can be altered by small peptides expressed on the surface of cells. The aim of this project is to develop our ideas so that a therapeutic reagent can be obtained. We will do this by targeting both the KIR2DL3 and KIR2DS2 genes, and identifying peptides that specifically bind these receptors to activate NK cells. We will also look for peptides that can activate KIR3DS1-positive NK cells. This is important because KIR3DS1 is associated with protection against HIV infection and also against the development of liver cancer. Whilst much activity has been focused on HIV, liver cancer continues to be a major health problem worldwide (it is the 6th commonest cancer), and alarmingly is on the increase in the UK. Importantly it is difficult to treat, and there is only one chemotherapeutic reagent currently licensed for this condition. Having identified key peptides that we can use to activate NK cell, we will then use them in vitro to activate NK cells. We will devise optimal strategies for expressing the identified peptides and then optimising the culture conditions necessary for growing large numbers of NK cells expressing the relevant receptor. By the end of the project we hope to have a reagent suitable for therapeutic use, which depending on the results of the investigation maybe directly suitable for phase I studies.