Proteomic profiling of HIV-1 infection of human CD4 + T cells identifies PSGL-1 as an HIV restriction factor

Nat Microbiol. 2019 May;4(5):813-825. doi: 10.1038/s41564-019-0372-2. Epub 2019 Mar 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology*
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • HIV Infections / physiopathology
  • HIV Infections / virology
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Host-Pathogen Interactions*
  • Human Immunodeficiency Virus Proteins / genetics
  • Human Immunodeficiency Virus Proteins / metabolism
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Proteolysis
  • Proteomics
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Ubiquitination
  • Viral Regulatory and Accessory Proteins / genetics
  • Viral Regulatory and Accessory Proteins / metabolism

Substances

  • Human Immunodeficiency Virus Proteins
  • Membrane Glycoproteins
  • P-selectin ligand protein
  • Viral Regulatory and Accessory Proteins
  • vpu protein, Human immunodeficiency virus 1
  • Interferon-gamma
  • SKP Cullin F-Box Protein Ligases