title: Innate sensing of foamy viruses by human hematopoietic cells.
abstract: Foamy viruses (FV) are nonpathogenic retroviruses that have cospeciated with primates for millions of years. FV can be transmitted through severe bites from monkeys to humans. Viral loads remain generally low in infected humans, and no secondary transmission has been reported. Very little is known about the ability of FV to trigger an innate immune response in human cells. A few previous reports suggested that FV do not induce type I interferon (IFN) in nonhematopoietic cells. Here, we examined how human hematopoietic cells sense FV particles and FV-infected cells. We show that peripheral blood mononuclear cells (PBMCs), plasmacytoid dendritic cells (pDCs), and the pDC-like cell line Gen2.2 detect FV, produce high levels of type I IFN, and express the IFN-stimulated gene MxA. Fewer than 20 FV-infected cells are sufficient to trigger an IFN response. Both prototypic and primary viruses stimulated IFN release. Donor cells expressing a replication-defective virus, carrying a mutated reverse transcriptase, induced IFN production by target cells as potently as wild-type virus. In contrast, an FV strain with env deleted, which does not produce viral particles, was inactive. IFN production was blocked by an inhibitor of endosomal acidification (bafilomycin A1) and by an endosomal Toll-like receptor (TLR) antagonist (A151). Silencing experiments in Gen2.2 further demonstrated that TLR7 is involved in FV recognition. Therefore, FV are potent inducers of type I IFN by pDCs and by PBMCs. This previously underestimated activation of the innate immune response may be involved in the control of viral replication in humans.
authors.affiliation: Institut Pasteur, Virus and Immunity Unit, URA CNRS 3015, Paris, France.
authors.forename: Réjane
authors.initials: R
authors.lastname: Rua
authors.forename: Alice
authors.initials: A
authors.lastname: Lepelley
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.forename: Olivier
authors.initials: O
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000821:virology; D012192:Retroviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D016092:Spumavirus / Q000276:immunology* / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology
chemical_list: D007370:Interferon Type I; D051199:Toll-Like Receptor 7
references.citation: Expert Rev Anti Infect Ther. 2009 Jun;7(5):569-80
references.pmid: 19485797
references.citation: J Med Primatol. 1987;16(5):277-89
references.pmid: 2826791
references.citation: J Virol. 2003 Nov;77(21):11855-8
references.pmid: 14557671
references.citation: Immunol Rev. 2009 Jan;227(1):87-94
references.pmid: 19120478
references.citation: Nat Rev Microbiol. 2008 Nov;6(11):815-26
references.pmid: 18923409
references.citation: EMBO J. 2000 Jul 3;19(13):3436-45
references.pmid: 10880456
references.citation: Nat Immunol. 2010 Nov;11(11):1005-13
references.pmid: 20871604
references.citation: J Virol. 2011 Jun;85(12):5840-52
references.pmid: 21490095
references.citation: J Virol. 1998 Feb;72(2):1610-5
references.pmid: 9445065
references.citation: Lancet. 2004 Mar 20;363(9413):932-7
references.pmid: 15043960
references.citation: J Gen Virol. 1999 Aug;80 ( Pt 8):2003-2009
references.pmid: 10466797
references.citation: Virology. 2011 Feb 5;410(1):48-55
references.pmid: 21087785
references.citation: Nature. 2010 Sep 9;467(7312):214-7
references.pmid: 20829794
references.citation: PLoS Pathog. 2011 Feb;7(2):e1001284
references.pmid: 21379343
references.citation: J Virol. 2004 Oct;78(20):11405-10
references.pmid: 15452263
references.citation: Virology. 2005 Dec 20;343(2):256-66
references.pmid: 16278001
references.citation: Emerg Infect Dis. 2007 Sep;13(9):1314-20
references.pmid: 18252101
references.citation: Curr Top Microbiol Immunol. 2003;277:1-26
references.pmid: 12908766
references.citation: Curr Opin Microbiol. 2004 Aug;7(4):400-6
references.pmid: 15358259
references.citation: J Virol. 2010 Apr;84(8):4095-9
references.pmid: 20130055
references.citation: J Clin Invest. 2005 Nov;115(11):3265-75
references.pmid: 16224540
references.citation: Virology. 1991 Sep;184(1):43-54
references.pmid: 1651600
references.citation: Blood. 2009 Aug 27;114(9):1794-802
references.pmid: 19553637
references.citation: J Virol. 1999 Mar;73(3):1747-55
references.pmid: 9971751
references.citation: J Virol. 2005 Jul;79(14):8724-31
references.pmid: 15994766
references.citation: Science. 1996 Mar 15;271(5255):1579-82
references.pmid: 8599113
references.citation: J Virol. 1993 Nov;67(11):6618-24
references.pmid: 8411364
references.citation: Nature. 2005 Mar 17;434(7031):376-80
references.pmid: 15772660
references.citation: Intervirology. 1993;35(1-4):196-207
references.pmid: 8407246
references.citation: J Immunol. 2006 Jan 1;176(1):248-55
references.pmid: 16365416
references.citation: Med Microbiol Immunol. 2010 Aug;199(3):197-207
references.pmid: 20445989
references.citation: J Med Primatol. 2006 Aug;35(4-5):225-35
references.pmid: 16872286
references.citation: J Clin Invest. 2008 Oct;118(10):3431-9
references.pmid: 18776940
references.citation: J Mol Biol. 1994 Oct 21;243(2):245-57
references.pmid: 7932753
references.citation: Microbes Infect. 2007 Nov-Dec;9(14-15):1636-43
references.pmid: 18062906
references.citation: Curr Top Microbiol Immunol. 2003;277:181-96
references.pmid: 12908773
references.citation: Adv Drug Deliv Rev. 2009 Mar 28;61(3):195-204
references.pmid: 19211030
references.citation: J Gen Virol. 1995 Mar;76 ( Pt 3):661-7
references.pmid: 7534815
references.citation: J Gen Virol. 1999 Jul;80 ( Pt 7):1591-1598
references.pmid: 10423126
references.citation: J Virol. 2004 May;78(10):5223-32
references.pmid: 15113904
references.citation: Curr Top Microbiol Immunol. 2003;277:161-80
references.pmid: 12908772
references.citation: Immunity. 2011 May 27;34(5):637-50
references.pmid: 21616434
references.citation: Science. 2009 Sep 18;325(5947):1512
references.pmid: 19762636
references.citation: J Virol. 2008 Jun;82(12):5981-5
references.pmid: 18400853
references.citation: J Virol. 1997 Oct;71(10):7305-11
references.pmid: 9311807
references.citation: J Virol. 2006 Jan;80(2):605-14
references.pmid: 16378963
references.citation: Clin Microbiol Rev. 2001 Jan;14(1):165-76
references.pmid: 11148008
references.citation: J Virol. 2008 May;82(9):4275-83
references.pmid: 18305040
references.citation: J Virol. 1996 May;70(5):2774-80
references.pmid: 8627751
references.citation: Blood. 2010 Mar 18;115(11):2177-85
references.pmid: 20007807
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17453-8
references.pmid: 17956986
references.citation: Immunity. 2011 Jul 22;35(1):135-45
references.pmid: 21723157
references.citation: Virology. 1996 Jul 1;221(1):240-4
references.pmid: 8661433
references.citation: Proc Natl Acad Sci U S A. 2005 May 31;102(22):7982-7
references.pmid: 15911774
references.citation: Nature. 2011 May 25;474(7353):654-7
references.pmid: 21613998
references.citation: Res Virol. 1996 Jan-Feb;147(1):29-37
references.pmid: 8882338
references.citation: J Virol. 2003 Jul;77(14):8141-6
references.pmid: 12829852
references.citation: Science. 2004 Mar 5;303(5663):1529-31
references.pmid: 14976261
references.citation: J Virol. 1996 Feb;70(2):1250-4
references.pmid: 8551590
references.citation: J Virol. 1999 Nov;73(11):9619-24
references.pmid: 10516073
references.citation: Nature. 2011 Jun 29;474(7353):658-61
references.pmid: 21720370
references.citation: Nat Immunol. 2009 Oct;10(10):1065-72
references.pmid: 19609254
references.citation: EMBO J. 1993 Nov;12(11):4439-44
references.pmid: 8223453
references.citation: EMBO J. 2001 Jul 2;20(13):3495-505
references.pmid: 11432836
references.citation: Gene Ther. 2010 Dec;17(12):1423-9
references.pmid: 20631802
references.citation: Virol J. 2011 May 02;8:198
references.pmid: 21529378
references.citation: Res Virol. 1990 Jan-Feb;141(1):31-43
references.pmid: 1691523
references.citation: J Biol Chem. 2009 Feb 27;284(9):5819-26
references.pmid: 19074429
references.citation: Trends Microbiol. 2000 Jun;8(6):284-9
references.pmid: 10838587
references.citation: J Natl Cancer Inst. 1971 Feb;46(2):299-307
references.pmid: 4329955
references.citation: J Virol. 2003 Apr;77(8):4722-30
references.pmid: 12663779
references.citation: J Virol. 2007 Jan;81(2):1000-12
references.pmid: 17079292
references.citation: J Gen Virol. 2004 Nov;85(Pt 11):3313-3317
references.pmid: 15483245
references.citation: Nat Med. 1998 Apr;4(4):403-7
references.pmid: 9546784
references.citation: Cell. 2009 Aug 7;138(3):576-91
references.pmid: 19631370
references.citation: Transfusion. 2010 Jan;50(1):200-7
references.pmid: 19719470
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13974-9
references.pmid: 16174727
references.citation: J Virol. 1999 Apr;73(4):2613-21
references.pmid: 10074106
references.citation: Emerg Infect Dis. 2008 Aug;14(8):1200-8
references.pmid: 18680642