Human immunodeficiency virus (HIV) actively modulates the protein stability of host cells to optimize viral replication. To systematically examine this modulation in HIV infection, we used isobaric tag-based mass spectrometry to quantify changes in the abundance of over 14,000 proteins during HIV-1 infection of human primary CD4+ T cells. We identified P-selectin glycoprotein ligand 1 (PSGL-1) as an HIV-1 restriction factor downregulated by HIV-1 Vpu, which binds to PSGL-1 and induces its ubiquitination and degradation through the ubiquitin ligase SCFβ-TrCP2. PSGL-1 is induced by interferon-γ in activated CD4+ T cells to inhibit HIV-1 reverse transcription and potently block viral infectivity by incorporating in progeny virions. This infectivity block is antagonized by Vpu via PSGL-1 degradation. We further show that PSGL-1 knockdown can significantly abolish the anti-HIV activity of interferon-γ in primary CD4+ T cells. Our study identifies an HIV restriction factor and a key mediator of interferon-γ’s anti-HIV activity.
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The computational code used in this study is available from the corresponding authors upon request.
The data that support the findings of this study are available from the corresponding authors upon request. The raw proteomic data have been uploaded to the ProteomeXchange data repository with the ID number: PXD011233.
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This work was supported by grants from the State Key Research Development Program of China to X.T. (no. 2016YFC1200303) and F.Z. (no. 2017YFA0505100), the China National Funds for Excellent Young Scientists (no. 31722030), grants from the National Natural Science Foundation of China to X.-F.Y. (no. 81772169) and F.Z. (no. 31670836), a grant from the Shanghai Institute of Higher Learning to F.Z. (no. TP2015003) and a grant from the NIMH, US Public Health Service to Y.W. (no. 5R01MH102144). We thank Q. Wang and X. Ye (Institute of Microbiology of the Chinese Academy of Sciences) for the use of the Biosafety level 3 Tissue Culture Facility. We thank H. Qi, N. Yan, H. Deng, A. Elia and N. Zheng for critical reading of the manuscript.
The authors declare no competing interests.
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Supplementary Figures 1–6, Supplementary Table 1 and legends for Supplementary Datasets.
Raw mass spectrometry intensities of all identified proteins.
List of proteins with differential abundances among cell populations.
Gene ontology analysis of proteins with differential abundances among cell populations.
List of interferon-stimulated genes.
List of read counts of RNA-seq analysis.
List of genes with differential mRNA levels among cell populations.
List of positively selected genes.
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Liu, Y., Fu, Y., Wang, Q. et al. Proteomic profiling of HIV-1 infection of human CD4+ T cells identifies PSGL-1 as an HIV restriction factor. Nat Microbiol 4, 813–825 (2019). https://doi.org/10.1038/s41564-019-0372-2
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