title: Efficient BST2 antagonism by Vpu is critical for early HIV-1 dissemination in humanized mice.
abstract: BACKGROUND
  Vpu is a multifunctional accessory protein that enhances the release of HIV-1 by counteracting the entrapment of nascent virions on infected cell surface mediated by BST2/Tetherin. Vpu-mediated BST2 antagonism involves physical association with BST2 and subsequent mislocalization of the restriction factor to intracellular compartments followed by SCF(β-TrCP) E3 ligase-dependent lysosomal degradation. Apart from BST2 antagonism, Vpu also induces down regulation of several immune molecules, including CD4 and SLAMF6/NTB-A, to evade host immune responses and promote viral dissemination. However, it should be noted that the multiple functions of Vpu have been studied in cell-based assays, and thus it remains unclear how Vpu influences the dynamic of HIV-1 infection in in vivo conditions.
  
  
  RESULTS
  Using a humanized mouse model of acute infection as well as CCR5-tropic HIV-1 that lack Vpu or encode WT Vpu or Vpu with mutations in the β-TrCP binding domain, we provide evidence that Vpu-mediated BST2 antagonism plays a crucial role in establishing early plasma viremia and viral dissemination. Interestingly, we also find that efficient HIV-1 release and dissemination are directly related to functional strength of Vpu in antagonizing BST2. Thus, reduced antagonism of BST2 due to β-TrCP binding domain mutations results in decreased plasma viremia and frequency of infected T cells, highlighting the importance of Vpu-mediated β-TrCP-dependent BST-2 degradation for optimal initial viral propagation.
  
  
  CONCLUSIONS
  Overall, our findings suggest that BST2 antagonism by Vpu is critical for efficient early viral expansion and dissemination during acute infection and as such is likely to confer HIV-1 increased transmission fitness.
authors.forename: Vibhuti P
authors.initials: VP
authors.lastname: Dave
authors.forename: Fadi
authors.initials: F
authors.lastname: Hajjar
authors.forename: Mame Massar
authors.initials: MM
authors.lastname: Dieng
authors.forename: Élie
authors.initials: É
authors.lastname: Haddad
authors.affiliation: Laboratory of Human Retrovirology, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine avenue west, Montreal, QC H2W 1R7, Canada. eric.cohen@ircm.qc.ca.
authors.forename: Éric A
authors.initials: ÉA
authors.lastname: Cohen
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins / Q000172:deficiency / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D054334:Viral Regulatory and Accessory Proteins / Q000172:deficiency / Q000378:metabolism*; D014766:Viremia; D057074:Virus Release; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D054298:Human Immunodeficiency Virus Proteins; D008562:Membrane Glycoproteins; D054334:Viral Regulatory and Accessory Proteins; C513868:BST2 protein, mouse; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins