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Jacques DUTRIEUX PhD .

Jacques DUTRIEUX PhD . Modified IFN- a subtypes production and chemokine networks in the thymus during acute SIV infection, impact on thymopoiesis. DUTRIEUX J. et al. , AIDS Published online march 7th 2014. Institut Cochin INSERM U1016

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Jacques DUTRIEUX PhD .

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  1. Jacques DUTRIEUX PhD. Modified IFN-a subtypes production and chemokine networks in the thymus during acute SIV infection, impact on thymopoiesis DUTRIEUX J. et al., AIDS Published online march 7th 2014 Institut Cochin INSERM U1016 Team « Cytokines and viral infections »Rémi CHEYNIER

  2. HIV infection impacts on thymopoiesis Intra-thymicproliferation From Dion et al. 2004 • Thymopoiesis israpidlyaffectedduringprimary HIV infection (Hatzakiset al. 2000; Richardson et al. 2000; Douek et al. 2001; Dion et al. 2004) • Diminished thymocyte proliferation(Dion et al., 2004) • Consequence of IFN-aresponse ? 2

  3. Acute HIV/SIV infection Human Rhesus macaque VL IFN-a From Stacey et al. 2009 109 60 108 50 • In both humans and macaques :Plasma IFN-a peaks around day 10 post-infection(Stacey et al., 2009; Khatissianet al. 1996; Giavedoniet al. 2000; Abel et al.2002; Bruelet al., 2014, Dutrieux et al. 2014). 107 106 40 105 IFNa (pg/ml) 30 Viral RNA load (copies/ml) 104 103 20 3 102 10 101 100 0 0 4 8 12 16 20 24 28 Days post-infection

  4. Acute SIV infection study SIVmac251 Infection (50AID50)IV Necropsy D0 (3) and in acute phase(D3, D7, D10, D14) 24 rhesus macaques Thymus sampling Blood samplingD0, D3, D5, D7, D10, D12, D14 Plasma IFN-a measurement IFN-a and chemokines mRNA quantifications and identification T-cell subsets analysis Thymic function analysis 4

  5. Thymic modification in vivo 103 102 Intra-thymic proliferation 101 100 * 0 3 7/10 14 17 21 * Days post-infection 70 60 50 40 30 Plasma IFN-a p=0.017 r= -0.67 20 10 • Intra-thymic proliferation decreased at day 10 post-infection • Diminished intra-thymicproliferation correlates with • plasma IFN-a concentration 0 -10 -6 -4 -2 0 2 Intra-thymic proliferation (Fold change) 5

  6. Interferon a diversity 13 IFNa FromWoelket al. 2007 6

  7. 8 7 6 5 4 3 2 1 0 0 3 7 10 14 Days post-infection 103 102 101 100 10-1 Thymic production of IFN-a subtypes Day 3 IFN-a1 IFN-a1 Day 14 Day 0 IFN-a12-15 IFN-a12-15 IFN-a2 IFN-a2 IFN-a14 IFN-a14 IFN-a3 IFN-a3 Number of expressed IFN-a subtypes IFN-a13 IFN-a4-6 IFN-a13 IFN-a4-6 IFN-a5 IFN-a5 IFN-a9 IFN-a9 IFN-a7 IFN-a7 IFN-a8 IFN-a8 IFN-a1 IFN-a12-15 IFN-a2 IFNa mRNA copies / 103 HPRT mRNA copies IFN-a14 IFN-a3 IFN-a13 IFN-a4-6 ** IFN-a5 IFN-a9 IFN-a7 IFN-a8 Diversified thymic IFN-a expression 7

  8. In vitro differentiation of simian thymocytes Simian IFN-asubtypes transfected in CHO Healthy macaque thymus Acidic purification R-sIL-7 12 simian IFN-a Flt3L DN thymocytes OP9-hDL1 14 days Frequency of mature cells Thymocyteproliferation 8

  9. IFN-a subtypes differentially inhibit thymopoiesis 100 Day 5 Day 9 80 Day 12 60 * Divided cells (%) * * 40 * * * * * * 20 # 0 IFN-a7 IFN-a1 IFN-a2 IFN-a3 IFN-a4 IFN-a5 IFN-a6 IFN-a8 IFN-a9 Medium IFN-a13 IFN-a14 IFN-a12/15 IFN-a subtypes differentially inhibit thymocytes proliferation without affecting their differentiation capability 9

  10. IFN-a subtypes differentially inhibit thymopoiesis * * * 100 Day 5 * * Day 9 80 * Day 12 * * * 60 Divided cells (%) 40 20 # 0 IFN-a7 IFN-a1 IFN-a2 IFN-a3 IFN-a4 IFN-a5 IFN-a6 IFN-a8 IFN-a9 Medium IFN-a13 IFN-a14 IFN-a12/15 In vivo-produced IFN-a subtypes demonstrate major anti-proliferative effect 10

  11. Chemokine-driven thymocyte migrations CXCL12 CCL25 CCL19 CCL19 11

  12. CCL25 transcription in the thymus 104 * * 103 CCL25 mRNA copies/ 102 HPRT mRNA copies 102 101 C 100 0 3 7 10 14 Days post-infection M C C 200µm CCL25mRNA DR • Cortical expression • Increased transcription by day 3 12

  13. CCL19 transcription in the thymus 104 * * 103 M CCL19 mRNA copies/ 102 HPRT mRNA copies 102 C C 101 CCL19mRNA 200µm 200µm DR 100 0 3 7 10 14 Days post-infection • Medullar expression • Increased transcription by day 3 13

  14. CXCL12 transcription in the thymus CXCL12 DR • Expressed in subcapsular region • Decreased transcription by day 3 105 C C 104 * C 103 M CXCL12 mRNA copies/ 102 HPRT mRNA copies C 102 14 C 101 200µm 100 0 3 7 10 14 Days post-infection

  15. In the thymus Proliferation CXCL12 • Diversified IFN-a production • Thymic IFN-a subtypes Inhibit thymocytes proliferation • Modified thymic chemokine network CCL25 CCL19 CCL19 15

  16. In the thymus • Accelerated thymopoiesis • Increased thymic function • Increased naive T-cell diversity Proliferation CXCL12 • Diversified IFN-a production • Thymic IFN-a subtypes Inhibit thymocytes proliferation • Modified thymic chemokine network CCL25 Eventually lead to the characteristic HIV-associated thymic exhaustion CCL19 CCL19 16

  17. Acknowledgements Team Antigen presentation by dendritic cells Agnès LEBON Facilities Team Cytokines & Viral Infections Rémi CHEYNIER Véronique FABRE-MERSSEMAN Bénédicte DE MUYLDER Suzanne MORGADO Anne COUEDEL COURTEILLE Isabelle BOURGAULT-VILADA Magali RANCEZ Stéphanie BEQ Sandra ROZLAN Rosalie PONTE Vélislava TERZIEVA Amandine BERNARD Sandrine LOGEROT Raphaëlle PARKER Primate center Institut Pasteur Céline GOMMET Xavier MONTAGUTELLI

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