HIV-1 Vpu Downregulates Tim-3 from the Surface of Infected CD4<sup>+</sup> T Cells.

Details

Serval ID
serval:BIB_4D4AA7D54C2B
Type
Article: article from journal or magazin.
Collection
Publications
Title
HIV-1 Vpu Downregulates Tim-3 from the Surface of Infected CD4<sup>+</sup> T Cells.
Journal
Journal of virology
Author(s)
Prévost J., Edgar C.R., Richard J., Trothen S.M., Jacob R.A., Mumby M.J., Pickering S., Dubé M., Kaufmann D.E., Kirchhoff F., Neil SJD, Finzi A., Dikeakos J.D.
ISSN
1098-5514 (Electronic)
ISSN-L
0022-538X
Publication state
Published
Issued date
17/03/2020
Peer-reviewed
Oui
Volume
94
Number
7
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Along with other immune checkpoints, T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is expressed on exhausted CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells and is upregulated on the surface of these cells upon infection by human immunodeficiency virus type 1 (HIV-1). Recent reports have suggested an antiviral role for Tim-3. However, the molecular determinants of HIV-1 which modulate cell surface Tim-3 levels have yet to be determined. Here, we demonstrate that HIV-1 Vpu downregulates Tim-3 from the surface of infected primary CD4 <sup>+</sup> T cells, thus attenuating HIV-1-induced upregulation of Tim-3. We also provide evidence that the transmembrane domain of Vpu is required for Tim-3 downregulation. Using immunofluorescence microscopy, we determined that Vpu is in close proximity to Tim-3 and alters its subcellular localization by directing it to Rab 5-positive (Rab 5 <sup>+</sup> ) vesicles and targeting it for sequestration within the trans- Golgi network (TGN). Intriguingly, Tim-3 knockdown and Tim-3 blockade increased HIV-1 replication in primary CD4 <sup>+</sup> T cells, thereby suggesting that Tim-3 expression might represent a natural immune mechanism limiting viral spread.IMPORTANCE HIV infection modulates the surface expression of Tim-3, but the molecular determinants remain poorly understood. Here, we show that HIV-1 Vpu downregulates Tim-3 from the surface of infected primary CD4 <sup>+</sup> T cells through its transmembrane domain and alters its subcellular localization. Tim-3 blockade increases HIV-1 replication, suggesting a potential negative role of this protein in viral spread that is counteracted by Vpu.
Keywords
CD4-Positive T-Lymphocytes/virology, Cell Membrane/metabolism, Down-Regulation, Gene Expression Regulation, HEK293 Cells, HIV-1/metabolism, HeLa Cells, Hepatitis A Virus Cellular Receptor 2/metabolism, Human Immunodeficiency Virus Proteins/metabolism, Humans, Interferon-beta/metabolism, RNA, Small Interfering/metabolism, Viral Regulatory and Accessory Proteins/metabolism, trans-Golgi Network/metabolism, HIV, Tim-3, Vpu, membrane trafficking, viral release
Pubmed
Web of science
Create date
09/05/2023 12:59
Last modification date
29/11/2024 16:56
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