Abstract
human immunodeficiency virus type 1 (HIV-1) Nef interacts with the clathrin-associated AP-1 and AP-3 adaptor complexes, stabilizing their association with endosomal membranes. These findings led us to hypothesize a general impact of this viral protein on the endosomal system. Here, we have shown that Nef specifically disturbs the morphology of the early/recycling compartment, inducing a redistribution of early endosomal markers and a shortening of the tubular recycling endosomal structures. Furthermore, Nef modulates the trafficking of the transferrin receptor (TfR), the prototypical recycling surface protein, indicating that it also disturbs the function of this compartment. Nef reduces the rate of recycling of TfR to the plasma membrane, causing TfR to accumulate in early endosomes and reducing its expression at the cell surface. These effects depend on the leucine-based motif of Nef, which is required for the membrane stabilization of AP-1 and AP-3 complexes. Since we show that this motif is also required for the full infectivity of HIV-1 virions, these results indicate that the positive influence of Nef on viral infectivity may be related to its general effects on early/recycling endosomal compartments.
Highlights
human immunodeficiency virus type 1 (HIV-1) Nef Is Associated Mainly with Early/Sorting Endosomes and Affects the Distribution of Early Endosomal Markers—Previous studies have shown that HIV-1 Nef is expressed mainly in a perinuclear endosomal compartment where it stabilizes the attachment of adaptor protein (AP)-1 and AP-3 complexes to membranes by an ADP-ribosylation factor 1 (ARF1)-independent mechanism [17, 18]
We have demonstrated here that HIV-1 Nef dramatically affects the morphology and function of the endocytic recycling compartment, leading to alterations of the trafficking of transferrin receptor (TfR), a membrane receptor that recycles to the plasma membrane through sorting/recycling endosomes
Since the leucine-based motif constitutes the critical determinant of Nef required for interaction with the AP-1 and AP-3 complexes and for their stabilization on membranes (18 –20, 22, 25), our results suggest that the requirement of Nef for the full infectivity of HIV-1 virions is related to a general alteration of the sorting/ recycling compartments in virus producing cells
Summary
Vol 280, No 6, Issue of February 11, pp. 5032–5044, 2005 Printed in U.S.A. Nef-induced Alteration of the Early/Recycling Endosomal Compartment Correlates with Enhancement of HIV-1 Infectivity*. In addition to CD4 and major histocompatibility complex class I (MHC-I) molecules (6 – 8), the list of membrane proteins in which intracellular trafficking is affected by Nef includes MHC class II (MHC-II) molecules, the costimulatory CD28 molecule, and the lectin DC-SIGN (9 –11) These alterations likely promote an immune evasion response of infected cells and enhance the spread of viruses within the host during the natural course of HIV infection [12,13,14,15]. We report that Nef expression induces severe alterations in the morphology and functions of the endosomal recycling compartment, an effect that correlates with the Nef-mediated stabilization of AP-1 and AP-3 complexes on endosomal membranes through its leucine-based motif Because this motif is required for the Nef-mediated enhancement of the infectivity of virions produced by CD4negative cells, these results indicate that the functional impairment of the early/recycling compartment induced by Nef may directly relate to optimal viral infectivity
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