Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

English version České info

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology.

Vyšlo v časopise: Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection. PLoS Pathog 9(7): e32767. doi:10.1371/journal.ppat.1003530
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003530

Souhrn

Zdroje

1. SodoraDL, SilvestriG (2008) Immune activation and AIDS pathogenesis. Aids 22: 439–446.

2. ChahroudiA, BosingerSE, VanderfordTH, PaiardiniM, SilvestriG (2012) Natural SIV hosts: showing AIDS the door. Science 335: 1188–1193.

3. LetvinNL, DanielMD, SehgalPK, DesrosiersRC, HuntRD, et al. (1985) Induction of AIDS-like disease in macaque monkeys with T-cell tropic retrovirus STLV-III. Science 230: 71–73.

4. Murphey-CorbM, MartinLN, RanganSR, BaskinGB, GormusBJ, et al. (1986) Isolation of an HTLV-III-related retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys. Nature 321: 435–437.

5. EstaquierJ, IdziorekT, de BelsF, Barre-SinoussiF, HurtrelB, et al. (1994) Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections. Proc Natl Acad Sci U S A 91: 9431–9435.

6. KornfeldC, PloquinMJ, PandreaI, FayeA, OnangaR, et al. (2005) Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J Clin Invest 115: 1082–1091.

7. BrenchleyJM, PriceDA, SchackerTW, AsherTE, SilvestriG, et al. (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12: 1365–1371.

8. SilvestriG, SodoraDL, KoupRA, PaiardiniM, O'NeilSP, et al. (2003) Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 18: 441–452.

9. PandreaI, ApetreiC, DufourJ, DillonN, BarbercheckJ, et al. (2006) Simian immunodeficiency virus SIVagm.sab infection of Caribbean African green monkeys: a new model for the study of SIV pathogenesis in natural hosts. J Virol 80: 4858–4867.

10. PandreaIV, GautamR, RibeiroRM, BrenchleyJM, ButlerIF, et al. (2007) Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. J Immunol 179: 3035–3046.

11. FavreD, LedererS, KanwarB, MaZM, ProllS, et al. (2009) Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog 5: e1000295.

12. EstesJD, GordonSN, ZengM, ChahroudiAM, DunhamRM, et al. (2008) Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques. J Immunol 180: 6798–6807.

13. BosingerSE, LiQ, GordonSN, KlattNR, DuanL, et al. (2009) Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J Clin Invest 119: 3556–3572.

14. JacquelinB, MayauV, TargatB, LiovatAS, KunkelD, et al. (2009) Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest 119: 3544–3555.

15. LedererS, FavreD, WaltersKA, ProllS, KanwarB, et al. (2009) Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog 5: e1000296.

16. Campillo-GimenezL, LaforgeM, FayM, BrusselA, CumontMC, et al. (2010) Non pathogenesis of SIV infection is associated with reduced inflammation and recruitment of plasmacytoid dendritic cells to lymph nodes, not to lack of an interferon type I response, during the acute phase. J Virol 84: 1838–1846.

17. HarrisLD, TabbB, SodoraDL, PaiardiniM, KlattNR, et al. (2010) Downregulation of robust acute type I interferon responses distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts from pathogenic SIV infection of rhesus macaques. J Virol 84: 7886–7891.

18. BosingerSE, SodoraDL, SilvestriG (2011) Generalized immune activation and innate immune responses in simian immunodeficiency virus infection. Curr Opin HIV AIDS 6: 411–418.

19. MirKD, GasperMA, SundaravaradanV, SodoraDL (2011) SIV infection in natural hosts: resolution of immune activation during the acute-to-chronic transition phase. Microbes Infect 13: 14–24.

20. Fitzgerald-BocarslyP, JacobsES (2010) Plasmacytoid dendritic cells in HIV infection: striking a delicate balance. J Leukoc Biol 87: 609–620.

21. FeldmanS, SteinD, AmruteS, DennyT, GarciaZ, et al. (2001) Decreased interferon-alpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors. Clin Immunol 101: 201–210.

22. SoumelisV, ScottI, GheyasF, BouhourD, CozonG, et al. (2001) Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients. Blood 98: 906–912.

23. BrownKN, TrichelA, Barratt-BoyesSM (2007) Parallel loss of myeloid and plasmacytoid dendritic cells from blood and lymphoid tissue in simian AIDS. J Immunol 178: 6958–6967.

24. MalleretB, ManeglierB, KarlssonI, LebonP, NascimbeniM, et al. (2008) Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression. Blood 112: 4598–4608.

25. BrownKN, WijewardanaV, LiuX, Barratt-BoyesSM (2009) Rapid influx and death of plasmacytoid dendritic cells in lymph nodes mediate depletion in acute simian immunodeficiency virus infection. PLoS Pathog 5: e1000413.

26. KwaS, KannanganatS, NigamP, SiddiquiM, ShettyRD, et al. (2011) Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques. Blood 118: 2763–2773.

27. ReevesRK, EvansTI, GillisJ, WongFE, KangG, et al. (2012) SIV infection induces accumulation of plasmacytoid dendritic cells in the gut mucosa. J Infect Dis 206: 1462–1468.

28. HerbeuvalJP, HardyAW, BoassoA, AndersonSA, DolanMJ, et al. (2005) Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 102: 13974–13979.

29. HerbeuvalJP, NilssonJ, BoassoA, HardyAW, KruhlakMJ, et al. (2006) Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proc Natl Acad Sci U S A 103: 7000–7005.

30. SedaghatAR, GermanJ, TeslovichTM, CofrancescoJJr, JieCC, et al. (2008) Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics. J Virol 82: 1870–1883.

31. BoassoA, RoyleCM, DoumazosS, AquinoVN, BiasinM, et al. (2011) Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis. Blood 118: 5152–5162.

32. O'BrienM, ManchesO, SabadoRL, Jimenez BarandaS, WangY, et al. (2011) Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-alpha-producing and partially matured phenotype. J Clin Invest 121: 1088–1101.

33. BoassoA, ShearerGM (2008) Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol 126: 235–242.

34. EllegardR, ShankarEM, LarssonM (2011) Targeting HIV-1 innate immune responses therapeutically. Curr Opin HIV AIDS 6: 435–443.

35. RiesM, PritschetK, SchmidtB (2012) Blocking type I interferon production: a new therapeutic option to reduce the HIV-1-induced immune activation. Clin Dev Immunol 2012: 534929.

36. BeignonAS, McKennaK, SkoberneM, ManchesO, DaSilvaI, et al. (2005) Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 115: 3265–3275.

37. MandlJN, BarryAP, VanderfordTH, KozyrN, ChavanR, et al. (2008) Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 14: 1077–1087.

38. BarratFJ, MeekerT, GregorioJ, ChanJH, UematsuS, et al. (2005) Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 202: 1131–1139.

39. BarratFJ, MeekerT, ChanJH, GuiducciC, CoffmanRL (2007) Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur J Immunol 37: 3582–3586.

40. GuiducciC, TripodoC, GongM, SangalettiS, ColomboMP, et al. (2010) Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J Exp Med 207: 2931–2942.

41. BrownKN, Barratt-BoyesSM (2009) Surface phenotype and rapid quantification of blood dendritic cell subsets in the rhesus macaque. J Med Primatol 38: 272–278.

42. PichlmairA, Reis e SousaC (2007) Innate recognition of viruses. Immunity 27: 370–383.

43. WonderlichER, WijewardanaV, LiuX, Barratt-BoyesSM (2013) Virus-encoded TLR ligands reveal divergent functional responses of mononuclear phagocytes in pathogenic simian immunodeficiency virus infection. J Immunol 190: 2188–2198.

44. HondaK, et al. (2005) IRF-7 is the master regulator of type-1 interferon-dependent immune responses. Nature 434: 772–777.

45. PickerLJ, HagenSI, LumR, Reed-InderbitzinEF, DalyLM, et al. (2004) Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med 200: 1299–1314.

46. MonceauxV, ViolletL, PetitF, Ho Tsong FangR, CumontMC, et al. (2005) CD8+ T cell dynamics during primary simian immunodeficiency virus infection in macaques: relationship of effector cell differentiation with the extent of viral replication. J Immunol 174: 6898–6908.

47. ShedlockDJ, SilvestriG, WeinerDB (2009) Monkeying around with HIV vaccines: using rhesus macaques to define ‘gatekeepers’ for clinical trials. Nat Rev Immunol 9: 717–728.

48. NascimbeniM, PerieL, ChorroL, DiocouS, KreitmannL, et al. (2009) Plasmacytoid dendritic cells accumulate in spleens from chronically HIV-infected patients but barely participate in interferon-alpha expression. Blood 113: 6112–6119.

49. LonghiMP, TrumpfhellerC, IdoyagaJ, CaskeyM, MatosI, et al. (2009) Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 206: 1589–1602.

50. SwieckiM, GilfillanS, VermiW, WangY, ColonnaM (2010) Plasmacytoid dendritic cell ablation impacts early interferon responses and antiviral NK and CD8(+) T cell accrual. Immunity 33: 955–966.

51. LevyDE, MarieIJ, DurbinJE (2011) Induction and function of type I and III interferon in response to viral infection. Curr Opin Virol 1: 476–486.

52. VanderfordTH, SlichterC, RogersKA, LawsonBO, ObaedeR, et al. (2012) Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation. Blood 119: 5750–5757.

53. TavelJA, HuangCY, ShenJ, MetcalfJA, DewarR, et al. (2010) Interferon-alpha produces significant decreases in HIV load. J Interferon Cytokine Res 30: 461–464.

54. ManionM, RodriguezB, MedvikK, HardyG, HardingCV, et al. (2012) Interferon-alpha administration enhances CD8+ T cell activation in HIV infection. PLoS One 7: e30306.

55. EstesJD, HarrisLD, KlattNR, TabbB, PittalugaS, et al. (2010) Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog 6: e1001052.

56. DutertreCA, AmraouiS, DerosaA, JourdainJP, VimeuxL, et al. (2012) Pivotal role of M-DC8+ monocytes from viremic HIV-infected patients in TNFalpha overproduction in response to microbial products. Blood 120: 2259–2268.

57. BiancottoA, GrivelJC, IglehartSJ, VanpouilleC, LiscoA, et al. (2007) Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood 109: 4272–4279.

58. EstesJD, LiQ, ReynoldsMR, WietgrefeS, DuanL, et al. (2006) Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J Infect Dis 193: 703–712.

59. KatsikisPD, MuellerYM, VillingerF (2011) The cytokine network of acute HIV infection: a promising target for vaccines and therapy to reduce viral set-point? PLoS Pathog 7: e1002055.

60. GearyRS, LeedsJM, HenrySP, MonteithDK, LevinAA (1997) Antisense oligonucleotide inhibitors for the treatment of cancer: 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des 12: 383–393.

61. GearyRS, YuRZ, WatanabeT, HenrySP, HardeeGE, et al. (2003) Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 31: 1419–1428.

62. MonteithDK, HornerMJ, GillettNA, ButlerM, GearyR, et al. (1999) Evaluation of the renal effects of an antisense phosphorothioate oligodeoxynucleotide in monkeys. Toxicol Pathol 27: 307–317.

63. MonteithDK, LevinAA (1999) Synthetic oligonucleotides: the development of antisense therapeutics. Toxicol Pathol 27: 8–13.

64. PhillipsJA, CraigSJ, BayleyD, ChristianRA, GearyR, et al. (1997) Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration. Biochem Pharmacol 54: 657–668.

65. HardyAW, GrahamDR, ShearerGM, HerbeuvalJP (2007) HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha. Proc Natl Acad Sci U S A 104: 17453–17458.

66. FiorentiniS, RiboldiE, FacchettiF, AvolioM, FabbriM, et al. (2008) HIV-1 matrix protein p17 induces human plasmacytoid dendritic cells to acquire a migratory immature cell phenotype. Proc Natl Acad Sci U S A 105: 3867–3872.

67. OrendiJM, BloemAC, BorleffsJC, WijnholdsFJ, de VosNM, et al. (1998) Activation and cell cycle antigens in CD4+ and CD8+ T cells correlate with plasma human immunodeficiency virus (HIV-1) RNA level in HIV-1 infection. J Infect Dis 178: 1279–1287.

68. SachsenbergN, PerelsonAS, YerlyS, SchockmelGA, LeducD, et al. (1998) Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J Exp Med 187: 1295–1303.

69. HacklD, LoschkoJ, SparwasserT, ReindlW, KrugAB (2011) Activation of dendritic cells via TLR7 reduces Foxp3 expression and suppressive function in induced Tregs. Eur J Immunol 41: 1334–1343.

70. PasareC, MedzhitovR (2004) Toll-dependent control mechanisms of CD4 T cell activation. Immunity 21: 733–741.

71. HirotsuC, SrivastavaM (2000) Simultaneous confidence intervals based on one-sided max t test. Stat Prob Letters 49: 25–37.