Mechanisms of HIV-1 Nef mediated disruption of MHC-I trafficking.

Abstract

HIVA Nef is a key pathogenic factor necessary for the development of the acquired immunodeficiency syndrome (AIDS). One important function of Nef is to reduce cell surface levels of major histocompatibility complex class I molecules (MHC-I), thereby protecting HIV-infected cells from recognition by cytotoxic T lymphocytes (CTLs). However, the mechanism of MHC-I downmodulation by Nef has not been clearly elucidated. There is evidence that Nef acts early in the secretory pathway to redirect MHC-I from the <italic>trans</italic>-Golgi network to the endolysosomal pathway. However, a competing model suggests that Nef acts much later by accelerating MHC-I turnover at the cell surface. A comparison of Nef's effects on HLA-A2 endocytosis, recycling and transport rate indicated that the most prominent effect of Nef on HLA-A2 in T cells was to inhibit transport to the cell surface. To clarify the mechanism used by Nef in T cells we demonstrated that Nef targets early forms of MHC-1 molecules in the endoplasmic reticulum by preferentially binding hypo-phosphorylated cytoplasmic tails. The Nef-MHC-I complex migrates normally into the Golgi apparatus, but subsequently fails to arrive at the cell surface and become phosphorylated. Cell-type specific differences in the rate of MHC-I transport through the secretory pathway correlate with responsiveness to Nef and coprecipitation of adaptor protein complex-I (AP-1). We propose that the assembly of a Nef-MHC-I-AP-1 complex early in the secretory pathway is important for Nef activity. The ability of Nef to promote this complex causes the diversion of MHC-I transport away from the cell surface and into the endolysosomal pathway, leading to degradation of the MHC-I molecule.