期刊
JOURNAL OF VIROLOGY
卷 94, 期 7, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01999-19
关键词
HIV; Vpu; Tim-3; viral release; membrane trafficking
类别
资金
- Canadian Institutes of Health Research (CIHR) [389413]
- Canadian Foundation for Innovation
- University of Western Ontario
- CIHR Foundation [352417]
- NIH [R01 AI148379]
- American Foundation for AIDS Research (amfAR) Mathilde Krim Fellowship in Basic Biomedical Research
- CIHR [377124]
- Wellcome Trust senior research fellowship [WT098049AIA]
- Quebec Health Research Fund (FRQS)
- DFG
- Canada Research Chair on Retroviral Entry [RCHS0235-950-232424]
- MRC [G0801937] Funding Source: UKRI
Along with other immune checkpoints, T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is expressed on exhausted CD4 and CD8 ' 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(+) 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(+)) 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(+) 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(+) 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.
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