title: Interferon block to HIV-1 transduction in macrophages despite SAMHD1 degradation and high deoxynucleoside triphosphates supply.
abstract: BACKGROUND
  Interferon-α (IFN-α) is an essential mediator of the antiviral response, which potently inhibits both early and late phases of HIV replication. The SAMHD1 deoxynucleoside triphosphate (dNTP) hydrolase represents the prototype of a new antiviral strategy we referred to as "nucleotide depletion". SAMHD1 depletes dNTP levels in myeloid cells below those required for optimal synthesis of HIV viral DNA. HIV-2 and its SIVsm and SIVmac close relatives encode a protein termed Vpx, which counteracts SAMHD1. The potentiality of IFN-α to cooperate with nucleotide depletion has been poorly investigated so far. Here we wondered whether IFN-α affects SAMHD1 expression, Vpx-induced SAMHD1 degradation, Vpx-mediated rescue of HIV-1 transduction and the dNTP supply in monocyte-derived macrophages (MDMs).
  
  
  RESULTS
  IFN-α inhibited HIV-1 transduction in monocytes and in MDMs while SAMHD1 expression was not up-regulated. Vpx triggered SAMHD1 degradation in IFN-α treated cells, and weakly restored HIV-1 transduction from the IFN-α block. Vpx helper effect towards HIV-1 transduction was gradually inhibited with increasing doses of IFN-α. dNTP levels were not significantly affected in MDMs and CD4+ primary activated T lymphocytes by IFN-α and, in correlation with SAMHD1 degradation, restoration of dNTP levels by Vpx was efficient in MDMs treated with the cytokine. In contrast, IFN-α inhibited Vpx-mediated SAMHD1 degradation in THP-1 cells, where, accordingly, Vpx could not rescue HIV-1 transduction.
  
  
  CONCLUSIONS
  Our results suggest that the early antiviral effect of IFN-α results from a mechanism independent of nucleotide depletion in MDMs. In addition, they indicate that the macrophage-like THP-1 cell line may provide a system to characterize an IFN-α-induced cell response that inhibits Vpx-mediated SAMHD1 degradation.
authors.affiliation: Inserm, U1016, Institut Cochin, 22 rue Méchain, Paris, 75014, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Dragin
authors.forename: Laura Anh
authors.initials: LA
authors.lastname: Nguyen
authors.forename: Hichem
authors.initials: H
authors.lastname: Lahouassa
authors.forename: Adèle
authors.initials: A
authors.lastname: Sourisce
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.forename: Bertha Cecilia
authors.initials: BC
authors.lastname: Ramirez
authors.forename: Florence
authors.initials: F
authors.lastname: Margottin-Goguet
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D020559:Monomeric GTP-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism; D059748:Proteolysis; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014161:Transduction, Genetic; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D009711:Nucleotides; C074286:VPX protein, Human immunodeficiency virus 2; D054334:Viral Regulatory and Accessory Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins