HIV (human immunodeficiency virus) infection leads to AIDS (acquired immunodeficiency syndrome), due to loss of defense against infections. This is a consequence of declining CD4+ lymphocyte numbers and function. These cells are one of the main target for infection by the virus. The reason of the functional deterioration and decline of these cells is multi-factorial but still poorly understood. Observations in patients suggest an important role for the viral protein Nef, since patients infected with virus that lost a functional Nef protein do not, or only after very long periods, develop AIDS. Nef contributes to immune defects by inhibiting T cell development. Based on recent evidence from literature and our own data, we hypothesize a central role for the Notch receptor in this. This cell surface receptor is known to be important in animal development, including that of blood cells. Reducing Notch signaling by Nef could not only affect T cell development, but also T helper cell differentiation, or the sensitivity of infected T cells to regulatory T cells. In this project, we want to unravel how the protein functions in T lymphocytes to achieve these functions. This research will involve the use of different virus strains, gene transfer and knock-down of gene expression. The results will not only allow to better understand the virus, but hopefully also provide us with leads to new therapeutic strategies to treat HIV infection and AIDS.