ADP Ribosylation Factor 1 Activity Is Required To Recruit AP-1 to the Major Histocompatibility Complex Class I (MHC-I) Cytoplasmic Tail and Disrupt MHC-I Trafficking in HIV-1-Infected Primary T Cells

Abstract

HIV-1-infected cells are partially resistant to anti-HIV cytotoxic T lymphocytes (CTLs) due to the effects of the HIV Nef protein on antigen presentation by major histocompatibility complex class I (MHC-I), and evidence has been accumulating that this function of Nef is important in vivo. HIV Nef disrupts the normal expression of MHC-I by stabilizing a protein-protein interaction between the clathrin adaptor protein AP-1 and the MHC-I cytoplasmic tail. There is also evidence that Nef activates a phosphatidylinositol 3 kinase (PI3K)-dependent GTPase, ADP ribosylation factor 6 (ARF-6), to stimulate MHC-I internalization. However, the relative importance of these two pathways is unclear. Here we report that a GTPase required for AP-1 activity (ARF-1) was needed for Nef to disrupt MHC-I surface levels, whereas no significant requirement for ARF-6 was observed in Nef-expressing T cell lines and in HIV-infected primary T cells. An ARF-1 inhibitor blocked the ability of Nef to recruit AP-1 to the MHC-I cytoplasmic tail, and a dominant active ARF-1 mutant stabilized the Nef-MHC-I-AP-1 complex. These data support a model in which Nef and ARF-1 stabilize an interaction between MHC-I and AP-1 to disrupt the presentation of HIV-1 epitopes to CTLs.

Adaptor Protein 1 Promotes Cross-Presentation through the Same Tyrosine Signal in Major Histocompatibility Complex Class I as That Targeted by HIV-1

“…8). This hypothesis is consistent with other studies demonstrating that dominant active ARF-1 mutants that hyperstabilize the Nef-MHC-I-AP-1 complex in T cells also inhibit MHC-I downmodulation by Nef (36). From these observations, we propose that efficient MHC-I downmodulation by HIV requires that Nef and/or AP-1 have the capacity to dynamically cycle off the affected molecules to recruit downstream proteins in the degradation pathway and to target the newly synthesized cargo molecules (Fig.…”

Gelsolin activity controls efficient early HIV-1 infection

“…By activating type Iα phosphatidylinositol-4-phosphate 5-kinase (PI4P5-K Iα) at virus-cell contact regions, HIV-1 is known to trigger the production of this PIP 2 -fusogenic lipid to promote fusion pore formation and viral infection [22], and the depletion of syntenin-1 allows a higher pool of free PIP 2 to accumulate at the plasma membrane after HIV-1 attachment [10]. Furthermore, PIP 2 -associated plasma membrane changes driven by Arf6 are crucial for early HIV-1 infection, ensuring cell surface regeneration when the virus fuses with and enters permissive cells [24,36,39]. It should be noted that gelsolin is regulated by both PIP 2 and intracellular Ca 2+ , which may represent additional control points for actin dynamics in the plasma membrane [20,32,40-43].…”

HIV-1 Nef: a master manipulator of the membrane trafficking machinery mediating immune evasion

“…Based on studies in HeLa or CEM-SS T cells, it has been reported that MHC-I is internalized into endosomal compartments coated with the small membrane associated GTPases ARF6 or ARF1 [33,34], which regulate membrane trafficking by inducing changes to actin dynamics. More research is needed to identify the specific membrane trafficking regulators mediating this process.…”