Interactions between HIV1 Nef and Vacuolar ATPase Facilitate the Internalization of CD4

Abstract

CD4 is the primary receptor for the human immunodeficiency virus (HIV). Nef is an accessory protein of HIV that decreases the expression of CD4 on the surface of infected cells. In this study, we identified the Nef binding protein 1 (NBP1), which interacts specifically with Nef in vitro and in vivo. Since it shares sequence similarity with the catalytic subunit of the vacuolar ATPase (V-ATPase) and complements the loss of this VMA13 gene in yeast, NBP1 is the human homolog of Vma13p. Direct interactions between Nef and NBP1 were correlated with the ability of Nef to internalize CD4. The expression of the antisense NBP1 abrogated these effects. We conclude that NBP1 helps to connect Nef with the endocytic pathway.

RNA interference and HIV‐1 infection

“…In addition, two other cellular proteins, a human thioesterase II (hTE-II) and a vacuolar proton ATPase pump (also named NBP1 for Nef-binding protein 1) are involved in the Nef-mediated downmodulation of CD4 [130,131]. hTE hydrolyses thioester bonds of fatty acyl-CoAs in vitro, however its physiological role is unknown.…”

“…NBP1 binds Nef and the 2 subunit of AP-2. This interaction may enhance the otherwise weak binding between Nef and AP-2 [131,135].…”

“…Based on these data, we hypothesised that blockage of viral CD4-downregulation, either by cellular proteins inhibition involved in this mechanism [130,131] or by delivering truncated CD4 molecules, might be an effective novel approach to therapy. Lentiviral vectors expressing the HIV CD4 receptor, and both CXCR4 and CCR5 co-receptors, could be employed to selectively target infected cells.…”

Vav exchange factor counteracts the HIV‐1 Nef‐mediated decrease of plasma membrane GM1 and NF‐AT activity in T cells

“…In T cells, GM1 is localized in intracellular compartments and is released to the plasma membrane following TCR and CD28 engagement [8]. Therefore, it is conceivable that Nef, which has been described to interact with many components of the cytoskeletal machinery by regulating the constitutive endocytosis of CD4 and MHC class I molecules [31][32][33], may interfere with the exocytic/endocytic trafficking of GM1. To test this hypothesis, Jurkat T cells were either infected with the VSV-G pseudotyped HIV-1 NL4-3 ( Fig.…”

Protéines Nef du VIH et K3/K5 du virus associé au sarcoma de Kaposi : des « parasites »de la voie d’endocytose

“…En effet, Nef interagit directement avec les sous-unités µ et β des complexes AP-1, AP-2 et AP-3 [6,9,10], ainsi qu'avec la sous-unité β des complexes COPI (coatomer protein complex I) [11,12] impliqués dans le trafic vésiculaire au sein de la voie de sécrétion, mais qui interviennent également dans le transport entre endosomes précoces et tardifs [13]. Des interactions de Nef avec la sous-unité catalytique de l'ATPase vacuolaire (V-ATPase) nécessaire à l'acidification des compartiments endosomiques, ainsi qu'avec la protéine PACS-1 ont également été rapportées [14,15]. PACS-1 interagit avec les complexes AP-1 et AP-3 et participe au trafic entre endosomes et TGN [16].…”