The short cytoplasmic tail of HLA-G determines its resistance to HIV-1 Nef-mediated cell surface downregulation.

During infection with the human immunodeficiency virus type 1 (HIV-1), selective downregulation of major histocompatibility complex (MHC) class I molecules by Nef protein allows infected cells to be protected from natural killer (NK) cell lysis and to escape the HIV-specific cytotoxic T-lymphocyte response. The nonclassical MHC class I molecule human leukocyte antigen (HLA)-G is mainly expressed in placental tissues and in thymic epithelial cells. Using chimeric molecules and flow cytometry, we show that in contrast with HLA-A2, the non classical MHC class I molecule HLA-G is resistant to Nef-induced cell surface downregulation solely because of the length of its intracytoplasmic domain. Moreover, confocal microscopy analysis indicates that Nef does not delocalize HLA-G molecules from the cell surface, whereas HLA-G molecules extended with the cytoplasmic tail of HLA-A2 accumulate intracellularly with Nef. Together, these data demonstrate that the short cytoplasmic tail of HLA-G confers resistance to Nef-induced downregulation and intracellular accumulation. This resistance may have functional consequences during the course of HIV infection.