title: Cell Surface Downregulation of NK Cell Ligands by Patient-Derived HIV-1 Vpu and Nef Alleles.
abstract: OBJECTIVE
  HIV-1 Vpu and Nef proteins downregulate cell surface levels of natural killer (NK) cell ligands but functional consequences of individual downregulation events are unclear. We tested how well-conserved NK cell ligand downregulation is among Vpu and Nef variants isolated from chronic HIV patients.
  
  
  METHODS
  Proviral vpu and nef sequences were amplified from 27 chronic HIV patients, subcloned, and tested for their ability to downregulate cell surface receptors.
  
  
  RESULTS
  Cell surface downregulation of CD4, CD317/tetherin, and major histocompatibility complex class 1 that exert biological functions other than NK cell activation were well conserved among patient-derived Vpu and Nef variants. Among NK cell ligands, NK-T-B-antigen, poliovirus receptor, and UL16-binding protein were identified as main targets for Vpu and Nef, the downregulation of which by at least 1 viral protein was highly conserved. NK cell ligands displayed specific sensitivity to Vpu (NK-T-B-antigen) or Nef (poliovirus receptor), and downregulation of cell surface UL16-binding protein was identified as a novel and highly conserved activity of HIV-1 Vpu but not Nef.
  
  
  CONCLUSIONS
  The conservation of downregulation of major NK cell ligands by either HIV-1 Vpu or Nef suggests an important pathophysiological role of this activity, which may impact the acute but not the chronic phase of HIV infection.
authors.affiliation: *Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Heidelberg, Germany; †German Center for Infection Research, Heidelberg University, Heidelberg, Germany; ‡Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany; and §German Center for Infection Research, Hannover Medical School, Hannover, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Galaski
authors.forename: Fareed
authors.initials: F
authors.lastname: Ahmad
authors.forename: Nadine
authors.initials: N
authors.lastname: Tibroni
authors.forename: Francois M
authors.initials: FM
authors.lastname: Pujol
authors.forename: Birthe
authors.initials: B
authors.lastname: Müller
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
mesh_terms: D000483:Alleles; D015703:Antigens, CD / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D055607:Receptors, Natural Killer Cell / Q000096:biosynthesis*; D011991:Receptors, Virus / Q000096:biosynthesis*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D054298:Human Immunodeficiency Virus Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D055607:Receptors, Natural Killer Cell; D011991:Receptors, Virus; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C423230:ULBP2 protein, human; C514837:nef protein, Human immunodeficiency virus 1; C066100:poliovirus receptor; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins