Lentiviral Nef suppresses iron uptake in a strain specific manner through inhibition of Transferrin endocytosis

Abstract

BackgroundIncreased cellular iron levels are associated with high mortality in HIV-1 infection. Moreover iron is an important cofactor for viral replication, raising the question whether highly divergent lentiviruses actively modulate iron homeostasis. Here, we evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from different lentiviral strains.ResultsSurface Transferrin receptor (TfR) levels are unaffected by Nef proteins of HIV-1 and its simian precursors but elevated in cells expressing Nefs from most other primate lentiviruses due to reduced TfR internalization. The SIV Nef-mediated reduction of TfR endocytosis is dependent on an N-terminal AP2 binding motif that is not required for downmodulation of CD4, CD28, CD3 or MHCI. Importantly, SIV Nef-induced inhibition of TfR endocytosis leads to the reduction of Transferrin uptake and intracellular iron concentration and is accompanied by attenuated lentiviral replication in macrophages.ConclusionInhibition of Transferrin and thereby iron uptake by SIV Nef might limit viral replication in myeloid cells. Furthermore, this new SIV Nef function could represent a virus-host adaptation that evolved in natural SIV-infected monkeys.

AP-2 Is the Crucial Clathrin Adaptor Protein for CD4 Downmodulation by HIV-1 Nef in Infected Primary CD4 + T Cells

“…In contrast, interaction of Nef with ␤-COP was weak and nonconserved, and of note, only HIV-1 NA7 and NL4-3 Nef bound to ACOT8. In agreement with previous data (19), HIV-2-and simian immunodeficiency virus (SIV)-derived Nef proteins potently interacted with AP-2 ( Fig. 2), most likely due to the presence of tyrosine-based AP-2 binding motifs, which are absent in HIV-1 and SIVcpz Nefs (15).…”

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

“…However, one recent study suggested that the effect of Nef on TfR1 may be strain specific. 32 The increased cellular iron levels observed in our studies may be a consequence of virus attempting to establish a favorable environment for its own replication. As tissue iron accumulation is seen in many HIV-associated diseases, including neurodegeneration and diastolic cardiac dysfunction, [33][34][35][36][37] it is tempting to speculate that altered cellular iron homeostasis secondary to HIV infection may, at least partially, contribute to the organ damage associated with HIV infection.…”

HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

“…1D and E). This included previously described targets such as CXCR4 (CD184) and MHC-I receptors but also transferrin receptor (CD71), which was reported to be downregulated by Nef in an allele-and cell typedependent manner (69)(70)(71). In addition, a number of new targets with potentially interesting links to HIV biology were identified, such as CD37, Lamp-1 (CD107a), Lamp-2 (CD107b), ICAM-1 (CD102), or gamma interferon receptor (CD119).…”