title: TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes.
abstract: BACKGROUND
  Monocytes, the primary myeloid cell-type in peripheral blood, are resistant to HIV-1 infection as a result of the lentiviral restriction factor SAMHD1. Toll-like receptors recognize microbial pathogen components, inducing the expression of antiviral host proteins and proinflammatory cytokines. TLR agonists that mimic microbial ligands have been found to have activity against HIV-1 in macrophages. The induction of restriction factors in monocytes by TLR agonist activation has not been well studied. To analyze restriction factor induction by TLR activation in monocytes, we used the imidazoquinoline TLR7/8 agonist R848 and infected with HIV-1 reporter virus that contained packaged viral accessory protein Vpx, which allows the virus to escape SAMHD1-mediated restriction.  RESULTS: R848 prevented the replication of Vpx-containing HIV-1 and HIV-2 in peripheral blood mononuclear cells and monocytes. The block was post-entry but prior to reverse transcription of the viral genomic RNA. The restriction was associated with destabilization of the genomic RNA molecules of the in-coming virus particle. R848 treatment of activated T cells did not protect them from infection but treated monocytes produced high levels of proinflammatory cytokines, including type-I IFN that protected bystander activated T cells from infection.
  
  
  CONCLUSIONS
  The activation of TLR7/8 induces two independent restrictions to HIV-1 replication in monocytes: a cell-intrinsic block that acts post-entry to prevent reverse transcription; and a cell-extrinsic block, in which monocytes produce high levels of proinflammatory cytokines (primarily type-I IFN) that protects bystander monocytes and T lymphocytes. The cell-intrinsic block may result from the induction of a novel restriction factor, which can be termed Lv5 and acts by destabilizing the in-coming viral genomic RNA, either by the induction of a host ribonuclease or by disrupting the viral capsid. TLR agonists are being developed for therapeutic use to diminish the size of the latent provirus reservoir in HIV-1 infected individuals. Such drugs may both induce latent provirus expression and restrict virus replication during treatment.
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.|Department of HIV and Other Retroviruses, Robert Koch Institute, Berlin, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Hofmann
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Vanwalscappel
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: Nicolin
authors.initials: N
authors.lastname: Bloch
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA. Nathaniel.landau@med.nyu.edu.
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Landau
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007370:Interferon Type I / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000821:virology*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D012367:RNA, Viral; D048348:Reverse Transcription; D000076106:SAM Domain and HD Domain-Containing Protein 1; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D007093:Imidazoles; D007370:Interferon Type I; D012367:RNA, Viral; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins; C402365:resiquimod
keywords: HIV restriction; Monocytes; R848; Restriction factor; TLR7/8