Tetherin Inhibits Retrovirus Release and Is Antagonized by HIV-1 Vpu

Nature. 2008 Jan 24;451(7177):425-30. doi: 10.1038/nature06553. Epub 2008 Jan 16.

Abstract

Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.

Publication types

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

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Cell Line
  • Cell Membrane / virology
  • Endocytosis
  • GPI-Linked Proteins
  • Gene Expression Profiling
  • HIV Infections / metabolism
  • HIV Infections / therapy
  • HIV Infections / virology
  • HIV-1 / metabolism*
  • HeLa Cells
  • Human Immunodeficiency Virus Proteins / antagonists & inhibitors
  • Human Immunodeficiency Virus Proteins / metabolism*
  • Humans
  • Interferon-alpha / pharmacology
  • Leukemia Virus, Murine / metabolism
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Transport
  • Viral Regulatory and Accessory Proteins / antagonists & inhibitors
  • Viral Regulatory and Accessory Proteins / metabolism*
  • Virion / metabolism
  • Virus Replication
  • gag Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Antigens, CD
  • BST2 protein, human
  • GPI-Linked Proteins
  • Human Immunodeficiency Virus Proteins
  • Interferon-alpha
  • Membrane Glycoproteins
  • Mutant Proteins
  • Viral Regulatory and Accessory Proteins
  • gag Gene Products, Human Immunodeficiency Virus
  • vpu protein, Human immunodeficiency virus 1