title: Evidence for IFNα-induced, SAMHD1-independent inhibitors of early HIV-1 infection.
abstract: BACKGROUND
  Type I interferon (IFN) treatment of some cells, including dendritic cells, macrophages and monocytic THP-1 cells, restricts HIV-1 infection and prevents viral cDNA accumulation. Sterile alpha motif and HD domain protein 1 (SAMHD1), a dGTP-regulated deoxynucleotide triphosphohydrolase, reduces HIV-1 infectivity in myeloid cells, likely by limiting dNTPs available for reverse transcription, and has been described as IFNα-inducible. Myeloid cell infection by HIV-1 is enhanced by HIV-2/SIVSM Vpx, which promotes SAMHD1 degradation, or by exogenous deoxyribonucleoside (dN) addition.
  
  
  RESULTS
  SAMHD1 expression was not substantially influenced by IFNα treatment of monocyte-derived macrophages or THP-1 cells. The contributions of SAMHD1 to the inhibition of HIV-1 infectivity by IFNα were assessed through the provision of Vpx, exogenous dN addition, or via RNAi-mediated SAMHD1 knock-down. Both Vpx and dN efficiently restored infection in IFNα-treated macrophages, albeit not to the levels seen with these treatments in the absence of IFNα. Similarly using differentiated THP-1 cells, the addition of Vpx or dNs, or SAMHD1 knock-down, also stimulated infection, but failing to match the levels observed without IFNα. Neither Vpx addition nor SAMHD1 knock-down reversed the IFNα-induced blocks to HIV-1 infection seen in dividing U87-MG or THP-1 cells. Therefore, altered SAMHD1 expression or function cannot account for the IFNα-induced restriction to HIV-1 infection seen in many cells and cell lines.
  
  
  CONCLUSIONS
  IFNα establishes an anti-HIV-1 phenotype in many cell types, and appears to accomplish this without potentiating SAMHD1 function. We conclude that additional IFNα-induced suppressors of the early stages of HIV-1 infection await identification.
authors: Department of Infectious Diseases, King's College London, 2nd Floor, Borough Wing, Guy's Hospital, London Bridge, London SE1 9RT, UK.
authors: Caroline
authors: C
authors: Goujon
authors: Torsten
authors: T
authors: Schaller
authors: Rui Pedro
authors: RP
authors: Galão
authors: Sarah M
authors: SM
authors: Amie
authors: Baek
authors: B
authors: Kim
authors: Kevin
authors: K
authors: Olivieri
authors: Stuart J D
authors: SJ
authors: Neil
authors: Michael H
authors: MH
authors: Malim
mesh_terms: D002460:Cell Line; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D000076106:SAM Domain and HD Domain-Containing Protein 1; 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