HIV-1 Vpu Antagonizes BST-2 by Interfering Mainly With the Trafficking of Newly Synthesized BST-2 to the Cell Surface

Traffic. 2011 Dec;12(12):1714-29. doi: 10.1111/j.1600-0854.2011.01277.x. Epub 2011 Oct 3.

Abstract

Bone marrow stromal cell antigen-2 (BST-2) inhibits human immunodeficiency virus type 1 (HIV-1) release by cross-linking nascent virions on infected cell surface. HIV-1 Vpu is thought to antagonize BST-2 by downregulating its surface levels via a mechanism that involves intracellular sequestration and lysosomal degradation. Here, we investigated the functional importance of cell-surface BST-2 downregulation and the BST-2 pools targeted by Vpu using an inducible proviral expression system. Vpu established a surface BST-2 equilibrium at ∼60% of its initial levels within 6 h, a condition that coincided with detection of viral release. Analysis of BST-2 post-endocytic trafficking revealed that the protein is engaged in a late endosomal pathway independent of Vpu. While Vpu moderately enhanced cell-surface BST-2 clearance, it strongly affected the protein resupply to the plasma membrane via newly synthesized proteins. Noticeably, Vpu affected clearance of surface BST-2 more substantially in Jurkat T cells than in HeLa cells, suggesting a cell-dependent impact of Vpu on the pool of surface BST-2. Collectively, our data reveal that Vpu imposes a new BST-2 equilibrium, incompatible with efficient restriction of HIV-1 release, by combining an acceleration of surface BST-2 natural clearance, whose degree might be cell-type dependent, to a severe impairment of the protein resupply to the plasma membrane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Down-Regulation
  • Endocytosis / genetics
  • Endosomes / genetics
  • Endosomes / metabolism
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • HEK293 Cells
  • HIV-1 / metabolism*
  • HeLa Cells
  • Human Immunodeficiency Virus Proteins / genetics*
  • Human Immunodeficiency Virus Proteins / metabolism*
  • Humans
  • Jurkat Cells
  • Protein Transport
  • T-Lymphocytes
  • Viral Regulatory and Accessory Proteins / genetics*
  • Viral Regulatory and Accessory Proteins / metabolism*

Substances

  • Antigens, CD
  • BST2 protein, human
  • GPI-Linked Proteins
  • Human Immunodeficiency Virus Proteins
  • Viral Regulatory and Accessory Proteins
  • vpu protein, Human immunodeficiency virus 1