Porcine reproductive and respiratory syndrome (PRRS) is a devastating disease in pigs, characterized by reproductive and respiratory problems. It is caused by an arterivirus with a specific tropism for macrophages. Recently, more virulent strains emerged in Europe and Asia causing high mortalities. Vaccines are losing their efficacy and in order to find an answer to this problem, better insights in virus entry and immune response are essential. The promoter’s laboratory has already identified a large part of the virus entry (receptors/viral ligands, importance of sialic acids on viral ligands, role of low pH/proteases) and, based on this information, developed a new inactivated vaccine. However, there are still several pieces of the puzzle missing. First, the internalization mechanism is not fully understood. Sialoadhesin is the main internalization molecule, but does not contain a known endocytic motif in its cytoplasmic tail. Cellular co-factors are most probably involved and will be identified. Furthermore, it will be analysed if sialoadhesin recycles to the cell surface upon endocytosis. Second, further downwards in the entry process, it was found that proteases are involved during virus disassembly. In the present project, this protease and the viral ligand that is cleaved will be identified. In a last part of the project, it will be examined why new highly virulent strains are able to infect monocytic cells that do not carry sialoadhesin; a new receptor will be traced.