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Development of prophylactic and therapeutic vaccines optimised for cellular processing and presentation to t lymphocytes and targeted to professional antigen presenting cells (protarvac)

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Transportation aid for the immune system

Peptides from within the cytoplasm are transported and then ultimately presented at the plasma membrane as an indication of the 'health status' of a cell. Recent research has focused on how to make these sequences more transportable within the cell.

Health

The health of the European population is threatened by viruses like HIV and Hepatitis C virus (HCV). It has been estimated that between one and five percent of citizens test seropositive for HCV. In the absence of efficient therapies, the Protarvac project aimed to develop novel vaccines based on the increased efficiency of production of epitopes, the peptide sequences that will ultimately be recognised by cells of the immune system. Underlying the specific objectives of the project team from L' Institut national de la santé et de la recherche médicale (INSERM) is the action of the Transporter associated with antigen processing (TAP). Basically, this protein carries peptides mainly from the cytosol to the membrane system, the endoplasmic reticulum. The peptides can then later be presented to provide a picture of how healthy the cell is. If a cell is infected with a virus, the nature of the peptides will indicate this situation and the cell will become a target for cytotoxic T cells. The crux of the idea for the research came from the fact that not all peptides are carried with equal efficiency. To increase the effectiveness for peptide transport, they added selected sequences to the peptides as extensions to the molecules, an approach not explored previously. The team found that transport of epitopes was much enhanced. Firstly, the process of epitope presentation to T lymphocytes was overall increased. Secondly, standard amino acid sequences with one to three residues enhanced TAP affinity depending on initial level of attraction to the transporter. Another strand to the research is the potential for creating poly-epitopes. To achieve this, the extensions were used to link epitopes. The sequence design encouraged enzyme cleavage before the linker and therefore the efficient presentation of individual peptides to the endoplasmic reticulum. Results from this research can therefore be used in rational vaccine design involving epitope linkers. Overall, the principles researched stand to strengthen the base of the European biotechnology industry.

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