Small Molecule Inhibition of HIV-1–Induced MHC-I Down-Regulation Identifies a Temporally Regulated Switch in Nef Action

Abstract

Nef assembles a multi-kinase complex triggering MHC-I down-regulation. We identify an inhibitor that blocks MHC-I down-regulation, identifying a temporally regulated switch in Nef action from directing MHC-I endocytosis to blocking cell surface delivery. These findings challenge current dogma and reveal a regulated immune evasion program.

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

“…53 The PACS genes appeared first in metazoans where they have early-and conserved roles in secretory pathway traffic. 22,23,[54][55][56][57] Sequence alignment and functional analyses reveal that the vertebrate PACS proteins underwent evolutionary adaptation with the acquisition of nuclear-trafficking motifs and, in the case of PACS-2, an Akt phosphorylation site at Ser 437 . 57 The acquisition of nucleartrafficking functions in PACS-2 coincided with the ability of vertebrate p53 to direct cytoprotective p21-dependent cell cycle arrest in addition to its evolutionarily conserved proapoptotic functions.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…This chink in the armor of HIV-1 provides an alternative approach to combat the virus by reversing the Nef-mediated immune evasion pathway. In support of this possibility, treatment of HIV-1-infected primary CD4 + T-cells with small-molecule inhibitors of the multi-kinase complex restores cell surface expression of MHC-I and sensitizes them to killing by CD8 + T-cells (Hung et al, 2007;Dikeakos et al, 2010;and M. Ostrowski, personal communication).…”

“…The activated multikinase complex increases the amount of phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) underneath the plasma membrane, which recruits an ARF6 GEF to activate ARF6 and accelerate endocytosis of cell-surface MHC-I (Blagoveshchenskaya et al, 2002). Nef then connects the internalized MHC-I molecules to PACS-1 and AP-1 on an endosomal compartment to prevent their recycling to the cell surface and instead sequester them in the TGN, thereby protecting the virus from immune surveillance (Blagoveshchenskaya et al, 2002;Chaudhry et al, 2008;Noviello et al, 2008;Dikeakos et al, 2010;Dirk et al, 2016). Unlike KSHV and many other viruses, HIV-1 Nef does not induce degradation of downregulated MHC-I (Blagoveshchenskaya et al, 2002;Dikeakos et al, 2010;Dirk et al, 2016).…”

“…Nef then connects the internalized MHC-I molecules to PACS-1 and AP-1 on an endosomal compartment to prevent their recycling to the cell surface and instead sequester them in the TGN, thereby protecting the virus from immune surveillance (Blagoveshchenskaya et al, 2002;Chaudhry et al, 2008;Noviello et al, 2008;Dikeakos et al, 2010;Dirk et al, 2016). Unlike KSHV and many other viruses, HIV-1 Nef does not induce degradation of downregulated MHC-I (Blagoveshchenskaya et al, 2002;Dikeakos et al, 2010;Dirk et al, 2016). This chink in the armor of HIV-1 provides an alternative approach to combat the virus by reversing the Nef-mediated immune evasion pathway.…”

“…For example, in obese mice challenged by a high-fat diet, PACS-2 is responsible for a chronic increase in MAM formation (Arruda et al, 2014), leading to toxic mitochondrial Ca 2+ overload that consequently impairs mitochondrial oxidative capacity, exacerbates insulin The steps shown here depict the 'signaling mode' of HIV-1 Nef-induced immune evasion, which HIV-1 implements during the first 48 h post infection. A detailed discussion of Nef-induced immune evasion is presented elsewhere (Dikeakos et al, 2010;Pawlak and Dikeakos 2015).…”