title: HIV-1 infection inhibits cytokine production in human thymic macrophages.
abstract: OBJECTIVE
  The thymus serves as a critical site of T-lymphocyte ontogeny and selection. Thymic infection by HIV-1 is known to disrupt thymocyte maturation by both direct and indirect means; however, the mechanism behind these effects remains poorly defined. Macrophages represent one of the most important peripheral targets of HIV-1 infection, are resident in the thymic stroma, and play a central role in thymocyte maturation.
  
  
  METHODS
  Studies presented here define three primary features and outcomes of thymic macrophages (TM) and HIV-1 infection: (1) The distinctive TM phenotype (surface markers and cytokine production measured by immunofluorescence, fluorescence-activated cell sorting, and reverse transcriptase polymerase chain reaction) relative to macrophages from other sources (blood [monocyte-derived macrophages] and bone marrow); (2) infection of TM by different HIV-1 subtypes (X4, R5, and X4/R5) measured by enzyme-linked immunosorbent assay and polymerase chain reaction; and (3) consequences of HIV-1 infection on cytokine production by TM measured by reverse transcriptase polymerase chain reaction.
  
  
  RESULTS
  The results demonstrate that TM display a distinctive phenotype of HIV-1 receptors (CD4(lo), CXCR4(lo), CCR5(med), CCR3(hi)), chemokine production (macrophage inflammatory protein-1α(+); regulated on activation, normal T expressed and secreted(+); macrophage inflammatory protein-1b(-); stromal cell-derived factor -1(-)); and cytokine production (tumor necrosis factor-α(+), interleukin-8(+), macrophage colony-stimulating factor(+), interleukin-6(-)) relative to either monocyte-derived macrophages or bone marrow. TM were infected in vitro with R5 and X4/R5-tropic HIV-1 subtypes, and developed syncytia formation during long-term X4/R5 culture. In contrast, TM supported only transient replication of X4-tropic HIV-1. Lastly, infection of TM with HIV-1 abolished the production of all cytokines tested in long-term in vitro cultures.
  
  
  CONCLUSIONS
  Taken together, these results indicate that TM are a potential direct target of in situ HIV-1 infection, and that this infection may result in the disruption of macrophage functions that govern normal thymocyte maturation.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA. rozmyslo@mail.med.upenn.edu
authors.forename: Tomasz
authors.initials: T
authors.lastname: Rozmyslowicz
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Murphy
authors.forename: Dareus O
authors.initials: DO
authors.lastname: Conover
authors.forename: Glen N
authors.initials: GN
authors.lastname: Gaulton
mesh_terms: D016207:Cytokines / Q000096:biosynthesis*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D016207:Cytokines
references.citation: J Exp Med. 1988 Sep 1;168(3):1061-80
references.pmid: 2459287
references.citation: J Exp Med. 1993 Jun 1;177(6):1821-6
references.pmid: 7684437
references.citation: AIDS Res Hum Retroviruses. 1998 Feb 10;14(3):233-40
references.pmid: 9491913
references.citation: AIDS. 2008 Jan 11;22(2):171-84
references.pmid: 18097219
references.citation: Nat Med. 1998 May;4(5):563-8
references.pmid: 9585229
references.citation: J Virol. 1998 Jan;72(1):772-7
references.pmid: 9420285
references.citation: Leukemia. 2000 Oct;14(10):1821-32
references.pmid: 11021758
references.citation: Immunology. 1983 Sep;50(1):139-48
references.pmid: 6885108
references.citation: Semin Immunol. 1997 Dec;9(6):397-404
references.pmid: 9405269
references.citation: J Biol Chem. 1997 Nov 7;272(45):28206-9
references.pmid: 9353270
references.citation: Nature. 1986 Oct 30-Nov 5;323(6091):819-22
references.pmid: 2430188
references.citation: Annu Rev Immunol. 2003;21:265-304
references.pmid: 12524385
references.citation: Radiat Res. 2002 Mar;157(3):281-9
references.pmid: 11839090
references.citation: Science. 1986 May 23;232(4753):977-80
references.pmid: 3754653
references.citation: J Biol Chem. 1994 Jan 7;269(1):77-85
references.pmid: 8276881
references.citation: AIDS. 1997 Mar 15;11(4):403-14
references.pmid: 9084786
references.citation: Blood. 1998 Mar 1;91(5):1479-95
references.pmid: 9473211
references.citation: Science. 1995 Dec 15;270(5243):1811-5
references.pmid: 8525373
references.citation: Cell. 1996 Jun 28;85(7):1149-58
references.pmid: 8674120
references.citation: AIDS. 1993 Dec;7(12):1601-5
references.pmid: 8286069
references.citation: J Leukoc Biol. 1994 Sep;56(3):247-56
references.pmid: 8083597
references.citation: Cell. 1996 Jun 28;85(7):1135-48
references.pmid: 8674119
references.citation: AIDS Res Hum Retroviruses. 1998 Nov 20;14(17):1581-8
references.pmid: 9840291
references.citation: Surv Immunol Res. 1985;4(3):179-91
references.pmid: 3911325
references.citation: Cytokine. 1999 Aug;11(8):571-8
references.pmid: 10433803
references.citation: Pediatrics. 1992 Feb;89(2):297-301
references.pmid: 1734399
references.citation: J Clin Invest. 1999 Dec;104(12):1739-49
references.pmid: 10606628
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5215-20
references.pmid: 10220446
references.citation: Oncologist. 1999;4(5):370-8
references.pmid: 10551553
references.citation: Blood. 1983 Dec;62(6):1271-9
references.pmid: 6357308
references.citation: J Exp Med. 1993 Oct 1;178(4):1151-63
references.pmid: 8376927
references.citation: Eur J Haematol. 2001 Sep;67(3):142-51
references.pmid: 11737246
references.citation: AIDS. 2003 Jan 3;17(1):33-42
references.pmid: 12478067
references.citation: J Exp Med. 1996 Apr 1;183(4):1851-6
references.pmid: 8666941
references.citation: Stem Cells. 1998;16(2):79-88
references.pmid: 9554031
references.citation: J Exp Med. 1993 Aug 1;178(2):391-401
references.pmid: 7688021
references.citation: J Immunol. 2000 Feb 15;164(4):1855-61
references.pmid: 10657634
references.citation: Immunol Res. 1998;18(2):61-78
references.pmid: 9844826
references.citation: Immunity. 1995 Jan;2(1):25-36
references.pmid: 7600300
references.citation: AIDS. 2000 Jul 7;14(10):1317-25
references.pmid: 10930145
references.citation: Cell Tissue Res. 1981;214(2):431-41
references.pmid: 6970622
references.citation: Semin Immunol. 1990 Jan;2(1):35-44
references.pmid: 2151796
references.citation: Annu Rev Immunol. 1996;14:73-99
references.pmid: 8717508
references.citation: Immunol Res. 1998;17(1-2):75-82
references.pmid: 9479569
references.citation: Retrovirology. 2010 Apr 09;7:33
references.pmid: 20380696
references.citation: Nature. 1997 Feb 13;385(6617):645-9
references.pmid: 9024664
references.citation: Nat Rev Immunol. 2002 Oct;2(10):760-72
references.pmid: 12360214