Stromal Down-Regulation of Macrophage CD4/CCR5 Expression and NF-κB Activation Mediates HIV-1 Non-Permissiveness in Intestinal Macrophages
Tissue macrophages are derived exclusively from blood monocytes, which as monocyte-derived macrophages support HIV-1 replication. However, among human tissue macrophages only intestinal macrophages are non-permissive to HIV-1, suggesting that the unique microenvironment in human intestinal mucosa renders lamina propria macrophages non-permissive to HIV-1. We investigated this hypothesis using blood monocytes and intestinal extracellular matrix (stroma)-conditioned media (S-CM) to model the exposure of newly recruited monocytes and resident macrophages to lamina propria stroma, where the cells take up residence in the intestinal mucosa. Exposure of monocytes to S-CM blocked up-regulation of CD4 and CCR5 expression during monocyte differentiation into macrophages and inhibited productive HIV-1 infection in differentiated macrophages. Importantly, exposure of monocyte-derived macrophages simultaneously to S-CM and HIV-1 also inhibited viral replication, and sorted CD4+ intestinal macrophages, a proportion of which expressed CCR5+, did not support HIV-1 replication, indicating that the non-permissiveness to HIV-1 was not due to reduced receptor expression alone. Consistent with this conclusion, S-CM also potently inhibited replication of HIV-1 pseudotyped with vesicular stomatitis virus glycoprotein, which provides CD4/CCR5-independent entry. Neutralization of TGF-β in S-CM and recombinant TGF-β studies showed that stromal TGF-β inhibited macrophage nuclear translocation of NF-κB and HIV-1 replication. Thus, the profound inability of intestinal macrophages to support productive HIV-1 infection is likely the consequence of microenvironmental down-regulation of macrophage HIV-1 receptor/coreceptor expression and NF-κB activation.
Vyšlo v časopise:
Stromal Down-Regulation of Macrophage CD4/CCR5 Expression and NF-κB Activation Mediates HIV-1 Non-Permissiveness in Intestinal Macrophages. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1002060
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002060
Souhrn
Tissue macrophages are derived exclusively from blood monocytes, which as monocyte-derived macrophages support HIV-1 replication. However, among human tissue macrophages only intestinal macrophages are non-permissive to HIV-1, suggesting that the unique microenvironment in human intestinal mucosa renders lamina propria macrophages non-permissive to HIV-1. We investigated this hypothesis using blood monocytes and intestinal extracellular matrix (stroma)-conditioned media (S-CM) to model the exposure of newly recruited monocytes and resident macrophages to lamina propria stroma, where the cells take up residence in the intestinal mucosa. Exposure of monocytes to S-CM blocked up-regulation of CD4 and CCR5 expression during monocyte differentiation into macrophages and inhibited productive HIV-1 infection in differentiated macrophages. Importantly, exposure of monocyte-derived macrophages simultaneously to S-CM and HIV-1 also inhibited viral replication, and sorted CD4+ intestinal macrophages, a proportion of which expressed CCR5+, did not support HIV-1 replication, indicating that the non-permissiveness to HIV-1 was not due to reduced receptor expression alone. Consistent with this conclusion, S-CM also potently inhibited replication of HIV-1 pseudotyped with vesicular stomatitis virus glycoprotein, which provides CD4/CCR5-independent entry. Neutralization of TGF-β in S-CM and recombinant TGF-β studies showed that stromal TGF-β inhibited macrophage nuclear translocation of NF-κB and HIV-1 replication. Thus, the profound inability of intestinal macrophages to support productive HIV-1 infection is likely the consequence of microenvironmental down-regulation of macrophage HIV-1 receptor/coreceptor expression and NF-κB activation.
Zdroje
1. KedzierskaKCroweSMTurvilleSCunninghamAL 2003 The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages. Rev Med Virol 13 39 56
2. GorryPRChurchillMCroweSMCunninghamALGabuzdaD 2005 Pathogenesis of macrophage tropic HIV-1. Curr HIV Res 3 53 60
3. CarterCAEhrlichLS 2008 Cell biology of HIV-1 infection of macrophages. Annu Rev Microbiol 62 425 443
4. CollmanRHassanNFWalkerRGodfreyBCutilliJ 1989 Infection of monocyte-derived macrophages with human immunodeficiency virus type 1 (HIV-1). Monocyte-tropic and lymphocyte-tropic strains of HIV-1 show distinctive patterns of replication in a panel of cell types. J Exp Med 170 1149 1163
5. RichEAChenISZackJALeonardMLO'BrienWA 1992 Increased susceptibility of differentiated mononuclear phagocytes to productive infection with human immunodeficiency virus-1 (HIV-1). J Clin Invest 89 176 183
6. SharovaNSwinglerCSharkeyMStevensonM 2005 Macrophages archive HIV-1 virions for dissemination in trans. EMBO J 24 2481 2489
7. EmbretsonJZupancicMRibasJLBurkeARaczP 1993 Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362 359 362
8. ZhuTMuthuiDHolteSNickleDFengF 2002 Evidence for human immunodeficiency virus type 1 replication in vivo in CD14+ monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. J Virol 76 707 716
9. CroweSZhuTMullerWA 2003 The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection. J Leukoc Biol 74 635 641
10. OrensteinJMFoxCWahlSM 1997 Macrophages as a source of HIV during opportunistic infections. Science 276 1857 1861
11. WahlSMGreenwell-WildTPengGHale-DonzeHDohertyTM 1998 Mycobacterium avium complex (MAC) augments macrophage HIV-1 production and increases CCR5 expression. Proc Natl Acad Sci USA 95 12574 12579
12. WahlSMAllenJBMcCartney-FrancisNMorganti-KossmannMCKossmannT 1991 Macrophage- and astrocyte-derived transforming growth factor β as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome. J Exp Med 173 981 991
13. ShenRRichterHEClementsRHNovakLHuffK 2009 Macrophages in vaginal but not in intestinal mucosa are monocyte-like and permissive to HIV-1. J Virol 83 3258 3267
14. LiLMengGGrahamMFShawGMSmithPD 1999 Intestinal macrophages display reduced permissiveness to human immunodeficiency virus 1 and decreased surface CCR5. Gastroenterology 116 1043 1053
15. MengGSellersMMosteller-BarnumMRogersTShawG 2000 Lamina propria lymphocytes, not macrophages, express CCR5 and CXCR4 and are the likely target cell for human immunodeficiency virus type 1 in the intestinal mucosa. J Infect Dis 182 785 791
16. SmythiesLEMaheshwariAClementsRHEckhoffDNovakL 2006 Mucosal IL-8 and TGF-β recruit blood monocytes: Evidence for cross-talk between the lamina propria stroma and myeloid cells. J Leukoc Biol 80 492 499
17. SonzaSMaerzADeaconNMeangerJMillsJ 1996 Human immunodeficiency virus type 1 replication is blocked prior to reverse transcription and integration in freshly isolated peripheral blood monocytes. J Virol 70 3863 3869
18. NaifHMLiSAlaliMChangJMayneC 1999 Definition of the stage of host cell genetic restriction of replication of human immunodeficiency virus type 1 in monocytes and monocyte-derived macrophages by using twins. J Virol 73 4866 4881
19. Smit-McBrideZMattapallilJJMcChesneyMFerrickDDandekarS 1998 Gastrointestinal T lymphocytes retain high potential for cytokine responses but have severe CD4+ T-cell depletion at all stages of simian immunodeficiency virus infection compared to peripheral lymphocytes. J Virol 72 6646 6656
20. VeazeyRSDeMariaMChalifouxLVShvetzDEPauleyDR 1998 Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280 427 431
21. GuadalupeMReayESankaranSPrindivilleTFlammJ 2003 Severe CD4+ T cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 77 11708 11717
22. BrenchleyJMHillBJAmbrozakDRPriceDAGuenagaFJ 2004 T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol 78 1160 1168
23. MehandruSPolesMATenner-RaczKHorowitzAHurleyA 2004 Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200 761 770
24. LiQDuanLEstesJDMaZ-MRourkeT 2005 Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434 1148 1152
25. MattapallilJJDouekDCHillBNishimuraYMartinM 2005 Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434 1093 1097
26. MehandruSPolesMATenner-RaczKManuelliVJean-PierreP 2007 Mechanisms of gastrointestinal CD4+ T-cell depletion during acute and early human immunodeficiency virus type 1 infection. J Virol 81 599 612
27. SmythiesLESellersMClementsRHMosteller-BarnumMMengG 2005 Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 115 66 75
28. SmythiesLEShenRBimczokDNovakLClementsRH 2010 Inflammation anergy in human intestinal macrophages is due to Smad-induced IκBα expression and NF-κB inactivation. J Biol Chem 285 19593 19604
29. SmithPDSmythiesLEMosteller-BarnumMSibleyDARussellMW 2001 Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J Immunol 167 2651 2656
30. SchenkMBouchonABirrerSColonnaMMuellerC 2005 Macrophages expressing triggering receptor expressed on myeloid cells-1 are underrepresented in the human intestine. J Immunol 174 517 524
31. SchenkMBouchonASeiboldFMuellerC 2007 TREM-1-expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. J Clin Invest 117 3097 3106
32. RanaSBessonGCookDGRuckerJSmythRJ 1997 Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of human immunodeficiency virus: resistance to patient-derived and prototype isolates resulting from the deltaccr5 mutation. J Virol 71 3219 3227
33. NaifHMLiSAlaliMSloaneAWuL 1998 CCR5 expression correlates with susceptibility of maturing monocytes to human immunodeficiency virus type 1 infection. J Virol 72 830 836
34. TuttleDLHarrisonJKAndersCSleasmanJWGoodenowMM 1998 Expression of CCR5 increases during monocyte differentiation and directly mediates macrophage susceptibility to infection by human immunodeficiency virus type 1. J Virol 72 4962 4969
35. ZhuTMoHWangNNamDSCaoY 1993 Genotypic and phenotypic characterization of HIV-1 in patients with primary infection. Science 261 1179 1181
36. van't WoutABKootstraNAMulder-KampingaGAAlbrecht-van LentNScherpbierHJ 1994 Macrophage-tropic variants initiate human immunodeficiency virus type I infection after sexual, parenteral, and vertical transmission. J Clin Invest 94 2060 2067
37. KeeleBFGiorgiEESalazar-GonzalezJFDeckerJMPhamKT 2008 Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA 105 7552 7557
38. LeeSHStarkeyPMGordonS 1985 Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J Exp Med 161 475 489
39. PetersPJBhattacharyaJHibbittsSDittmarMTSimmonsG 2004 Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages. J Virol 78 6915 6926
40. MengGWeiXWuXSellersMTDeckerJM 2002 Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat Med 8 150 156
41. NabelGBaltimoreD 1987 An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326 711 713
42. PoliGKinterALJustementJSBresslerPKehrlJH 1991 Transforming growth factor beta suppresses human immunodeficiency virus expression and replication in infected cells of the monocyte/macrophage lineage. J Exp Med 173 589 597
43. PoliGKinterALJustementJSBresslerPKehrlJH 1992 Retinoic acid mimics transforming growth factor beta in the regulation of human immunodeficiency virus expression in monocytic cells. Proc Natl Acad Sci USA 89 2689 2693
44. LazdinsJKKlimkaitTWoods-CookKWalkerMAlteriE 1991 In vitro effect of transforming growth factor-β on progression of HIV-1 infection in primary mononuclear phagocytes. J Immunol 147 1201 1207
45. GriffinGELeungKFolksTMKunkelSNabelGJ 1989 Activation of HIV gene expression during monocyte differentiation by induction of NF-κB. Nature 339 70 73
46. MosesAVIbanezCGaynorRGhazalPNelsonJA 1994 Differential role of long terminal repeat control elements for the regulation of basal and Tat-mediated transcription of the human immunodeficiency virus in stimulated and unstimulated primary human macrophages. J Virol 68 298 307
47. RittnerKChurcherMJGaitMJKarnJ 1995 The human immunodeficiency virus long terminal repeat includes a specialised initiator element which is required for Tat-responsive transcription. J Mol Biol 248 562 580
48. LiJMShenXHuPPWangXF 1998 Transforming growth factor β stimulates the human immunodeficiency virus 1 enhancer and requires NF-κB activity. Mol Cell Biol 18 110 121
49. WestMJLoweADKarnJ 2001 Activation of human immunodeficiency virus transcription in T cells revisited: NF-κB p65 stimulates transcriptional elongation. J Virol 75 8524 8537
50. DreikhausenUHiebenthal-MillowKBartelsMReschKNourbakhshM 2005 NF-κB-repressing factor inhibits elongation of human immunodeficiency virus type 1 transcription by DRB sensitivity-inducing factor. Mol Cell Biol 25 7473 7483
51. RoulstonALinRBeauparlantPWainbergMAHiscottJ 1995 Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-κB/Rel transcription factors. Microbiol Rev 59 481 505
52. DeLucaCPetropoulosLZmeureanuDHiscottJ 1999 Nuclear IκBβ maintains persistent NF-κB activation in HIV-1-infected myeloid cells. J Biol Chem 274 13010 13016
53. AsinSTaylorJATrushinSBrenGPayaCV 1999 Iκκ mediates NF-κB activation in human immunodeficiency virus-infected cells. J Virol 73 3893 3903
54. HiscottJKwonHGeninP 2001 Hostile takeovers: viral appropriation of the NF-κB pathway. J Clin Invest 107 143 151
55. SmithPDOchsenbauer-JamborCSmythiesLE 2005 Intestinal macrophages: unique effector cells of the innate immune system. Immunol Rev 206 149 159
56. SmithPDSmythiesLEShenRGreenwell-WildTGliozziM 2011 Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4 31 42
57. SmithPDFoxCHMasurHWinterHSAllingDW 1994 Quantitative analysis of mononuclear cells expressing human immunodeficiency virus type 1 RNA in esophageal mucosa. J Exp Med 180 1541 1546
58. MaheshwariASmythiesLEWuXNovakLClementsR 2006 Cytomegalovirus blocks intestinal stroma-induced down-regulation of macrophage HIV-1 infection. J Leuk Biol 80 1111 1117
59. HuffKRAkhtarLNFoxALCannonJASmithPD 2011 Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa. Mucosal Immunol epub 10.1038/mi.2010.1086
60. Salazar-GonzalezJFSalazarMGKeeleBFLearnGHGiorgiEE 2009 Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med 206 1273 1289
61. LiHBarKJWangSDeckerJMChenY 2010 High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men. PLoS Pathog 6 e1000890
62. PengGLeiKJJinWGreenwell-WildTWahlSM 2006 Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti-HIV-1 activity. J Exp Med 203 41 46
63. PionMGranelli-PipernoAMangeatBStalderRCorreaR 2006 APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection. J Exp Med 203 2887 2893
64. WangXYeLHouWZhouYWangYJ 2009 Cellular microRNA expression correlates with susceptibility of monocytes/macrophages to HIV-1 infection. Blood 113 671 674
65. SungTLRiceAP 2009 miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1. PLoS Pathog 5 e1000263
66. CullenBR 2006 Is RNA interference involved in intrinsic antiviral immunity in mammals? Nat Immunol 7 563 567
67. SwaminathanSZaundersJWilkinsonJSuzukiKKelleherAD 2009 Does the presence of anti-HIV miRNAs in monocytes explain their resistance to HIV-1 infection? Blood 113 5029 5030
68. KaushikRZhuXStranskaRWuYStevensonM 2009 A cellular restriction dictates the permissivity of nondividing monocytes/macrophages to lentivirus and gammaretrovirus infection. Cell Host Microbe 6 68 80
69. BergamaschiADavidALe RouzicENisoleSBarre-SinoussiF 2009 The CDK inhibitor p21Cip1/WAF1 is induced by FcγR activation and restricts the replication of human immunodeficiency virus type 1 and related primate lentiviruses in human macrophages. J Virol 83 12253 12265
70. ZhangJScaddenDTCrumpackerCS 2007 Primitive hematopoietic cells resist HIV-1 infection via p21. J Clin Invest 117 473 481
71. HondaYRogersLNakataKZhaoBYPineR 1998 Type I interferon induces inhibitory 16-kD CCAAT/enhancer binding protein (C/EBP)β, repressing the HIV-1 long terminal repeat in macrophages: pulmonary tuberculosis alters C/EBP expression, enhancing HIV-1 replication. J Exp Med 188 1255 1265
72. HoshinoYNakataKHoshinoSHondaYTseDB 2002 Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines. J Exp Med 195 495 505
73. SmithPDJanoffENMosteller-BarnumMMergerMOrensteinJM 1997 Isolation and purification of CD14-negative mucosal macrophages from normal human small intestine. J Immunol Meth 202 1 11
74. SmythiesLEWahlLMSmithPD 2006 Isolation and purification of human intestinal macrophages. Curr Protocol Immunol 7.6B 1 9
75. WahlLMWahlSMSmythiesLESmithPD 2006 Isolation of human monocyte populations. Curr Protocol Immunol 7.6A 1 10
76. ShenRSmythiesLEClementsRHNovakLSmithPD 2010 Dendritic cells transmit HIV-1 through human small intestinal mucosa. J Leukoc Biol 87 663 670
77. ShenRDrelichmanERBimczokDOchsenbauerCKappesJC 2010 GP41-specific antibody blocks cell-free HIV type 1 transcytosis through human rectal mucosa and model colonic epithelium. J Immunol 184 3648 3655
78. WeiXDeckerJMLiuHMZhangZAraniRB 2002 Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46 1896 1905
79. KutschOBenvenisteENShawGMLevyDN 2002 Direct and quantitative single-cell analysis of human immunodeficiency virus type 1 reactivation from latency. J Virol 76 8776 8786
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2011 Číslo 5
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Crystal Structure and Functional Analysis of the SARS-Coronavirus RNA Cap 2′-O-Methyltransferase nsp10/nsp16 Complex
- The OXI1 Kinase Pathway Mediates -Induced Growth Promotion in Arabidopsis
- The Hexamer Structure of the Rift Valley Fever Virus Nucleoprotein Suggests a Mechanism for its Assembly into Ribonucleoprotein Complexes
- Acquisition of Human-Type Receptor Binding Specificity by New H5N1 Influenza Virus Sublineages during Their Emergence in Birds in Egypt