Open AccessHIV-1 Vpu Downregulates Tim-3 from the Surface of Infected CD4 + T Cells
Author(s) -
Jérémie Prévost,
Cassandra R Edgar,
Jonathan Richard,
Steven M. Trothen,
Rajesh Jacob,
Mitchell J. Mumby,
Suzanne Pickering,
Mathieu Dubé,
Daniel E. Kaufmann,
Frank Kirchhoff,
Stuart J. D. Neil,
Andrés Finzi,
Jimmy D. Dikeakos
Publication year - 2020
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.01999-19
Subject(s) - biology , transmembrane protein , viral replication , virology , transmembrane domain , subcellular localization , microbiology and biotechnology , human immunodeficiency virus (hiv) , surface protein , virus , genetics , receptor , cytoplasm
Along with other immune checkpoints, T cell i mmunoglobulin and m ucin 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 h uman i mmunodeficiency v irus 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 t rans - G olgi n etwork (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.