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
Institution
Title
HIV-1 Vpu Downregulates Tim-3 from the Surface of Infected CD4<sup>+</sup> T Cells.
Journal
Journal of virology
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
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
Publisher's website
Create date
09/05/2023 12:59
Last modification date
29/11/2024 16:56