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Laboratoire Immunité & Infection INSERM UMR-S 945 IFR 113 Paris, France

Laboratoire Immunité & Infection INSERM UMR-S 945 IFR 113 Paris, France. Specific phenotypic and functional features of natural killer cells from HIV-infected long-term non progressors and HIV controllers. P DEBRE. PATHOGENESIS. INFECTION. . CD4 non infected cells. Virus. .

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Laboratoire Immunité & Infection INSERM UMR-S 945 IFR 113 Paris, France

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  1. Laboratoire Immunité & Infection INSERM UMR-S 945 IFR 113 Paris, France Specific phenotypic and functional features of natural killer cells from HIV-infected long-term non progressors and HIV controllers P DEBRE

  2. PATHOGENESIS INFECTION  CD4 non infected cells Virus  CD4 infected cells NK ? HIV, CD4 & NK cells

  3. LTNP and HIV-Controllers • HIV seropositive • Antiretroviral untreated • CD4 count (nadir): • LTNP : >600/mm3 • HIV-controllers: Variable • Viral load : • LTNP : Uncontrolled • HIV-controllers: Undetectable The proportion of individuals who become LTNP and HIV- controllers is not known, but is estimated to be ~ 0.5 and 0.1%, respectively.

  4. Characteristics of Healthy donors and HIV-infected patients : ALT cohort

  5. CONT UI PROG LTNP UI PROG LTNP CONT Increased proportion of CD56bright and CD56-CD16+ NK-cell subsets in LTNP and HIV-controllers ** ** ** * 25 25 25 20 20 % CD56bright 15 % CD3-CD56+ 15 10 10 5 5 0 UI PROG LTNP CONT *** *** *** 50 40 30 % CD56-/CD16+ 20 10 0

  6. Specific phenotypic patern of NK-cell markers from LTNP and HIV-controllers PROG10 PROG14 PROG15 PROG12 PROG13 PROG11 PROG4 PROG9 LTNP12 LTNP15 PROG6 PROG8 PROG1 PROG3 LTNP16 LTNP18 LTNP19 PROG7 PROG2 LTNP14 PROG5 LTNP17 LTNP13 LTNP10 CONT2 CONT4 LTNP11 CONT7 CONT1 CONT3 CONT5 CONT8 CONT6 CONT9 LTNP8 LTNP4 LTNP9 LTNP6 LTNP1 LTNP3 LTNP7 LTNP5 LTNP2 UI11 UI10 UI12 UI5 UI4 UI9 UI3 UI2 UI6 UI8 UI1 UI7 CD56bright NKG2A 2B4 NKp30 NKp46 NKp80 DNAM-1 CD16 CRAAC CD161 LAIR-1 CD94 CD158a NKG2D CD158e NKG2C CD158b NKp44 ILT2 CD69 HLA-DR PROG LTNP CONT UI

  7. Increased proportion of IFN-g production in LTNP and HIV-controllers CD56+ CD56-/CD16+ ** * 75 75 50 % IFN-g 50 25 25 0 0 UI LTNP UI LTNP PROG CONT PROG CONT 100 100 *** 75 75 % CD107a 50 50 25 25 0 0 UI LTNP PROG CONT UI LTNP PROG CONT

  8. 40 30 20 10 0 NKp44L expression by CD4+ T cells from HIV-infected patients 40 Kill p=0.002 30 % NKp44L % NKp44L 20 10 CD4 0 4+ 3- 8+ 8+ 4+ 3- 0 250 500 1000 750 CD4 / mm3 Control PBMC HIV+ PBMC 40 40 NKp44L MHC-I 44L+ p=0.005 30 30 NKp44 % NKp44L % NK Lysis - + 20 20 44L- 10 NK 10 0 0.1 10 100 1 1000 0 100/1 50/1 25/1 12.5/1 viral load(x 1000) E/T ratio Vieillard et al Proc Natl Acad Sci USA (2005)

  9. 40 44L+ 30 Autologous NK cells % NK Lysis 20 44L- HIV infected cells 10 0 100/1 50/1 25/1 12.5/1 HIV virion NKp44 E/T ratio NKp44L gp41 Epitope 3S (SWSNKS) CD4+NKp44L+ cell CD4+ T cell CD4+ T cell lysis Anti-3S Ab ex vivo In vitro CD4+ T cell depletion ? HIV1-infected individuals

  10. Low expression of NKp44L by CD4+ T cells from LTNP and HIV-controllers CONT PROG LTNP 30 R2=0.592 p=0.0001 R2=0.862 p=0.0031 R2=0.019 p=0.5235 20 % NKp44L 10 0 0 250 500 750 1000 1250 0 250 500 750 1000 1250 0 250 500 750 1250 1000 CD4 count

  11. 20/1 10/1 5/1 40/1 Low level of cytotoxicity of NK cells from LTNP and HIV-controllers against autologous CD4+ T cells : Relationship with NKp44L expression LTNP PROG CONT UI #1 (<1%) 60 #1 (<1%) #1 (22%) #1 (18%) 40 20 0 60 #2 (<1%) #8 (3%) #9 (13%) #10 (<1%) 40 % NK lysis 20 0 60 #9 (3%) #10 (<1%) #18 (6%) #10 (24%) 40 20 0 20/1 10/1 5/1 20/1 10/1 5/1 20/1 10/1 5/1 40/1 40/1 40/1 E/T ratio

  12. Conclusions • 1 - Different proportion of NK-cell subsets in LTNP and HIV- controllers ✔Specific pattern of NK-cell markers in LTNP and HIV-controllers ✔Higher production of IFN-g in HIV-controllers • ✔ Low expression of NKp44L on CD4+ T cells from LTNP and HIV- controllers • ✔ Low sensitivity of NK cells from LTNP and HIV-controllers against autologous CD4+ T Cells

  13. Conclusions • 2 – Switch of repertoire and function of NK cells during HIV infection ✔Controllers: increase IFN production and no autologouscytotoxicity  control of viral replication ✔Progressor: autologouscytotoxicity and no IFN increase  depletion of CD4 cells • ✔LTNP: intermediate

  14. Partners Pité-Salpêtrière Hospital, Paris Service de Virologie Henri Agut Daniel Candotti Service des Maladies Infectieuses & Tropicales Christine Katlama Unité Immunité & Infection Team-2 Patrice Debré Hugues Fausther Bovendo Vincent Vieillard Team-1 Brigitte Autran Assia Samri Unité Epidémiologie Clinique Dominique Costagliola Grants European program « Gysheal » ANRS Bill & Melinda Gates Foundation

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