title: TNF-alpha and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo.
abstract: Genital coinfections increase an individual's risk of becoming infected with HIV-1 by sexual contact. Several mechanisms have been proposed to explain this, such as the presence of ulceration and bleeding caused by the coinfecting pathogen. Here we demonstrate that Langerhans cells (LCs) are involved in the increased susceptibility to HIV-1 in the presence of genital coinfections. Although LCs are a target for HIV-1 infection in genital tissues, we found that immature LCs did not efficiently mediate HIV-1 transmission in an ex vivo human skin explant model. However, the inflammatory stimuli TNF-alpha and Pam3CysSerLys4 (Pam3CSK4), the ligand for the TLR1/TLR2 heterodimer, strongly increased HIV-1 transmission by LCs through distinct mechanisms. TNF-alpha enhanced transmission by increasing HIV-1 replication in LCs, whereas Pam3CSK4 acted by increasing LC capture of HIV-1 and subsequent trans-infection of T cells. Genital infections such as Candida albicans and Neisseria gonorrhea not only triggered TLRs but also induced TNF-alpha production in vaginal and skin explants. Thus, during coinfection, LCs could be directly activated by pathogenic structures and indirectly activated by inflammatory factors, thereby increasing the risk of acquiring HIV-1. Our data demonstrate a decisive role for LCs in HIV-1 transmission during genital coinfections and suggest antiinflammatory therapies as potential strategies to prevent HIV-1 transmission.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marein A W P
authors.initials: MA
authors.lastname: de Jong
authors.forename: Lot
authors.initials: L
authors.lastname: de Witte
authors.forename: Menno J
authors.initials: MJ
authors.lastname: Oudhoff
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Gringhuis
authors.forename: Philippe
authors.initials: P
authors.lastname: Gallay
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D001706:Biopsy; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility / Q000139:chemically induced; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D005260:Female; D015658:HIV Infections / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D007801:Langerhans Cells / Q000187:drug effects* / Q000821:virology*; D055666:Lipopeptides; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D014621:Vagina / Q000601:surgery; D014779:Virus Replication / Q000187:drug effects
chemical_list: D016207:Cytokines; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010455:Peptides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha
references.citation: Immunobiology. 1988 May;177(2):158-70
references.pmid: 3042614
references.citation: Blood. 2004 Mar 15;103(6):2170-9
references.pmid: 14630806
references.citation: J Virol. 2007 Jul;81(13):6858-68
references.pmid: 17442711
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13766-71
references.pmid: 11095740
references.citation: Trends Microbiol. 2002 Nov;10(11):508-14
references.pmid: 12419615
references.citation: J Exp Med. 2004 Nov 15;200(10):1279-88
references.pmid: 15545354
references.citation: J Clin Invest. 2005 Nov;115(11):3256-64
references.pmid: 16239964
references.citation: J Exp Med. 1996 Jan 1;183(1):215-25
references.pmid: 8551225
references.citation: J Biol Chem. 2005 Dec 2;280(48):40293-300
references.pmid: 16199531
references.citation: J Infect Dis. 2007 Nov 15;196(10):1509-16
references.pmid: 18008231
references.citation: Top HIV Med. 2004 Oct-Nov;12(4):104-7
references.pmid: 15516707
references.citation: Anal Biochem. 2004 Jun 15;329(2):293-9
references.pmid: 15158490
references.citation: Eur J Immunol. 2001 Feb;31(2):360-8
references.pmid: 11180099
references.citation: J Virol. 2004 Jul;78(14):7602-9
references.pmid: 15220435
references.citation: Exp Dermatol. 2003 Oct;12(5):700-11
references.pmid: 14705812
references.citation: Curr Opin Immunol. 2004 Aug;16(4):483-7
references.pmid: 15245743
references.citation: AIDS Res Hum Retroviruses. 1989 Apr;5(2):139-46
references.pmid: 2785393
references.citation: J Womens Health (Larchmt). 2003 Jun;12(5):487-94
references.pmid: 12869296
references.citation: Annu Rev Immunol. 2003;21:335-76
references.pmid: 12524386
references.citation: Antimicrob Agents Chemother. 2002 Jun;46(6):1896-905
references.pmid: 12019106
references.citation: J Virol. 2002 Oct;76(19):9868-76
references.pmid: 12208964
references.citation: Science. 1999 Nov 12;286(5443):1353-7
references.pmid: 10558989
references.citation: J Exp Med. 1994 Dec 1;180(6):2181-90
references.pmid: 7964493
references.citation: Cell. 2007 Dec 14;131(6):1059-71
references.pmid: 18083097
references.citation: Trends Mol Med. 2008 Jan;14(1):12-9
references.pmid: 18055263
references.citation: J Invest Dermatol. 1992 Nov;99(5):48S-50S
references.pmid: 1431209
references.citation: Clin Exp Immunol. 2007 Jan;147(1):176-83
references.pmid: 17177977
references.citation: FEBS Lett. 2001 Jun 1;498(1):116-20
references.pmid: 11389909
references.citation: FEBS Lett. 2005 Jul 4;579(17):3660-8
references.pmid: 15963988
references.citation: J Immunol. 2006 Dec 1;177(11):7959-67
references.pmid: 17114468
references.citation: J Biol Chem. 2003 Nov 21;278(47):46252-60
references.pmid: 12966099
references.citation: J Exp Med. 1995 Jun 1;181(6):2237-47
references.pmid: 7760009
references.citation: J Virol. 2004 Nov;78(21):11980-7
references.pmid: 15479838
references.citation: J Immunol. 2007 Oct 1;179(7):4357-66
references.pmid: 17878330
references.citation: Am J Pathol. 2002 Sep;161(3):867-73
references.pmid: 12213715
references.citation: Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336-40
references.pmid: 2494664
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19464-9
references.pmid: 18040049
references.citation: Nat Med. 2007 Mar;13(3):367-71
references.pmid: 17334373
references.citation: Eur J Clin Microbiol Infect Dis. 2004 Sep;23(9):672-6
references.pmid: 15322932
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):738-43
references.pmid: 16407131
references.citation: J Acquir Immune Defic Syndr. 2000 May 1;24(1):48-56
references.pmid: 10877495
references.citation: Cell. 1994 Aug 12;78(3):389-98
references.pmid: 7914836
references.citation: Glycoconj J. 2001 Jun;18(6):475-85
references.pmid: 12084983
references.citation: J Immunol. 2007 Feb 15;178(4):1986-90
references.pmid: 17277101
references.citation: Science. 1999 Jul 30;285(5428):736-9
references.pmid: 10426996
references.citation: N Engl J Med. 1997 Apr 10;336(15):1072-8
references.pmid: 9091805
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8401-6
references.pmid: 12815099
references.citation: Sex Transm Infect. 1999 Feb;75(1):3-17
references.pmid: 10448335
references.citation: J Virol. 2004 Oct;78(20):10848-55
references.pmid: 15452205
references.citation: J Exp Med. 1998 May 18;187(10):1623-31
references.pmid: 9584140
references.citation: J Dermatol Sci. 2005 Dec;40(3):147-55
references.pmid: 16226431
references.citation: Sex Transm Dis. 1992 Mar-Apr;19(2):61-77
references.pmid: 1595015
references.citation: J Exp Med. 2000 Nov 20;192(10):1491-500
references.pmid: 11085750
references.citation: J Virol. 1991 Mar;65(3):1053-6
references.pmid: 1995941