Nef-mediated disruption of HLA-A2 transport to the cell surface in T cells

Human immunodeficiency virus type 1 (HIV-1) Nef is a key pathogenic factor necessary for the development of AIDS. One important function of Nef is to reduce cell surface levels of major histocompatibility complex class I (MHC-I) molecules, thereby protecting HIV-infected cells from recognition by cytotoxic T lymphocytes. The mechanism of MHC-I downmodulation by Nef has not been clearly elucidated, and its reported effect on MHC-I steady-state levels ranges widely, from 2-fold in HeLa cells to 200-fold in HIV-infected primary T cells. Here, we directly compared downmodulation of HLA-A2 in HIV-infected HeLa cells to that in T cells. We found that similar amounts of Nef protein resulted in a much more dramatic downmodulation of HLA-A2 in T cells than in HeLa cells. A comparison of Nef's effects on HLA-A2 endocytosis, recycling, and transport rates indicated that the most prominent effect of Nef on HLA-A2 in T cells was to inhibit transport to the cell surface. The phosphatidylinositol 3-kinase inhibitor, LY294002, previously reported to inhibit Nef-mediated MHC-I downmodulation in astrocytic cells, did not directly affect Nef's ability to block transport of MHC-I to the cell surface in T cells.