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T follicular helper cells in HIV infection

T follicular helper cells in HIV infection. Jan van Lunzen University Medical Center Hamburg-Eppendorf Heinrich-Pette-Institut for Experimental Virology & Immunology Hamburg, Germany. Outline/Questions. Where does HIV replicate in LN? Which cells are preferentially infected?

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T follicular helper cells in HIV infection

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  1. T follicular helper cells in HIV infection Jan van Lunzen University Medical Center Hamburg-Eppendorf Heinrich-Pette-Institut for Experimental Virology & Immunology Hamburg, Germany

  2. Outline/Questions • Where does HIV replicate in LN? • Which cells are preferentially infected? • What effect/limitations does HAART have? • What is the role of T follicular helper cells in HIV infection? • Are TFH cells a viral reservoir? • What are the consequences of dysregulated TFH function? • Can these functions be restored?

  3. Where does HIV replicate in lymph nodes?

  4. Lymph Node Pathology HIV - HIV + Stellbrink & van Lunzen, Curr Opin Infect Dis 2001

  5. Immunopathology of LN CD4+Ki-67+ CD8+ Tenner-Racz K, Stellbrink HJ, van Lunzen J et al., J Exp Med 1998

  6. Which cells are preferentially infected?

  7. Infection rate of CD57+ and CD57- CD4+ T cells in PB and LN LN CD57+CD4+ T cells LN CD57–CD4+ T cells PBL CD57+CD4+ T cells PBL CD57–CD4+ T cells 10 7,5 Infected cells (%) 5 2,5 0 3 Patient no. 1 2 5 7 Ratio of the viral loads: CD57+CD4+ T cells [%]/CD57– CD4+ T cells[%] LN: 10.5 3.3 8.0 9.5 3.0 PBL: 0.3 2.2 <0.1 2.5 2.5 Hufert F, van Lunzen J et al.: AIDS 1997

  8. What effect/limitations does HAART have?

  9. HIV-1 RNA in LN during HAART Day 0 Day 28 HIV-1 RNA p24 Ag Tenner-Racz K, Stellbrink HJ, van Lunzen J et al., J Exp Med 1998 van Lunzen J, Ruiz L et al., AIDS 1998

  10. T cell proliferation in LN during HAART 15% 10% 5% 0 pre-treatment (n = 30) post-treatment (n = 30) normal controls (n = 4) p < 0,0001 p < 0,0001 CD4+Ki-67+ CD8+Ki-67+ van Lunzen J, et al., CROI 1999

  11. What is the role of T follicular helper cells in HIV infection?

  12. CD4 TFH cells are critical for effective antibody responses Plasma cell B cell CD4 TFH cells MHC II TCR PD-1 CXCR5 Memory B cell CD40 CD40L Bcl6 Bcl6 ICOSL ICOS IL-21 IFNγ IL-4 • Within the follicle • Express CXCR5, PD1, ICOS • Bcl6+ • IL-21 (cardinal cytokine) • B cell proliferation • Antibody maturation (SHM) • Class switching (CSR) • Memory development

  13. 5 10 4 10 3 10 2 10 0 3 4 5 0 10 10 10 SIV: Relative Accumulation of TFH in LN SIV- SIV acute SIV chronic (low % of TFH) SIV chronic (high % of TFH) p=0.0008 p<0.0001 % of CM CD4 T cells CCR7 ICOS Petrovas C. et al. JCI 2012 CD150 PD-1

  14. Immune activation rather than direct infection with SIV is associated with in vivo TFH accumulation 5 10 4 10 3 10 2 10 0 3 4 5 0 10 10 10 SIV- SIV chronic (low % of TFH) SIV acute SIV chronic (high % of TFH) Chronic SIV (>2 months) p=0.0004 p=0.0164 p=0.0013 SIV Gag DNA (copies/cell) sCD14 (x106 pg/ml) CCR7 ICOS Petrovas C. et al. JCI 2012 PD-1 CD150 1.5 1.0 0.5 0

  15. Accumulation of TFH is Associated with Increased Frequency of GC-B cells and titers of SIV-specific Antibodies p=0.0286 PNAhighIgGlow PNAhighIgGhigh 10 7.5 SIV-specific IgG (titer, x104) p=0.051 p=0.048 p=0.033 5 2.5 ND ND ND ND ND 0 SIV - SIV + low % TFH SIV + high % TFH gp120 gp130 gp140 p27 p55 SIV acute SIV chronic (low % TFH) SIV chronic (high % TFH) Petrovas C. et al. JCI 2012

  16. High frequency of CXCR5+PD-1high CD4 T cell subset in the lymph node Lindqvist M et al., JCI 2012

  17. IL-21 preferentially produced by TFH cells Lindqvist M et al., JCI 2012

  18. Expansion of TFH cells correlated with skewing of B cell subsets GC B cells Plasma B cells Late memory B cells Lindqvist M et al., JCI 2012

  19. Hypersecretion of IgG was associated with BCL6 expression in TFH cells Lindqvist M et al., JCI 2012

  20. Are TFH cells a viral reservoir?

  21. TFH Cells and CXCR5-PD-1+ CD4 T-Cells Are Enriched in HIV-Specific CD4 T-Cells PTEs (Gag, Pol, Env)+α-CD28 Brefeldin A Perreau M et al JEM 2012

  22. TFH Cells and CXCR5-PD-1+ CD4 T-Cells Are Enriched in CD4 T-Cells Containing HIV DNA Perreau M et al JEM 2012

  23. TFH Cells and CXCR5-PD-1+ CD4 T-Cells Are the Most Efficient in Supporting Production of HIV Anti-CD3/CD28 Collection of SNs p24 detection D0 D2 D5 High viremia (>15000 HIV RNA copies/mL) Perreau M et al JEM 2012

  24. HIV Isolation from Patients with Low (<1000 HIV RNA copies/mL of plasma) in Different CD4 T-Cell Populations Collection of SNs CD8-depleted PBMCs + p24 detection Coated CD3/28 D0 D3 D7 Low viremia (<1000 HIV RNA copies/mL) • TFH and CXCR5-PD-1+ but not CXCR5-PD-1- and CXCR5+PD-1- CD4 T-cells efficiently support virus isolation and production in patients with low viremia levels

  25. What are the consequences of dysregulated TFH function?

  26. PD-L1 expression in GC B cells Cubas RA et al. Nature Med. 2013

  27. PD-1 ligand and TFH proliferation, activation and cytokine secretion PD1-L Cubas RA et al. Nature Med. 2013

  28. PD-1 Triggering affects TFH function P = 0.01 P = 0.03 ICOS MFI P = 0.009 P = 0.025 IL-21 pg/ml Absolute number ICOS+ Tfh cells Cubas RA et al. Nature Med. 2013

  29. Can these functions be restored?

  30. Exogenous IL-21 enhances TFH function P < 0.03 P < 0.03 IgG (ng/ml) IgG (ng/ml) -IL-21 +IL21 HIV- LN HIV+ LN P < 0.02 P < 0.02 P < 0.02 CD27 MFI (B cells) CD27 MFI (B cells) -IL-21 +IL21 -IL21 +IL21 +IL21 (10ng/ml) (40ng/ml) HIV+ LN

  31. Enhancing HIV-specific TFH function by interfering with PD-1/IL-21 axis Total IgG (ng/ml) Total IgG (ng/ml) Isotype αPD-L1/L2 -IL-21 +IL21 HIV+ LN (Gag-Env stimulation) HIV+ LN (Gag-Env stimulation) Cubas RA et al. Nature Med. 2013

  32. Hypothesis model Germinal center Memory B cell Germinal center B cell HIV viremia IL-21 Plasma cell TFH B cell follicle Lymph node

  33. Summary I • HIV-specific TFH cells are expanded in chronic infection • Expansion of TFH cells correlated with skewing of B cell subsets in chronic HIV infection • Hypersecretion of IgG1 was associated with BCL6 expression in TFH cells • TFH serve as a viral reservoir and promote HIV replication

  34. Summary II • B memory cell responses are skewed in HIV infection • PD-L1 is overexpressed on B cells in HIV infection and down regulates TFH function • TFH and B cell function can be restored by anti-PD-1 and/or exogenous II-21 • TFH cells may represent the primary obstacle for achieving functional HIV cure

  35. Pathogenesis Model Vinuesa CG, JCI 2012

  36. O. Degen S. Hertling A. Hüfner S. Schmiedel J. Schulze zur Wiesch I. Toth P. Hartjen S. Kummer

  37. O. Degen S. Hertling A. Hüfner S. Schmiedel J. Schulze zur Wiesch I. Toth P. Hartjen S. Kummer Slides and data provided by: C. Petrovas, R. Koup (VRC, NIH, USA) M. Lindqvist, H. Streeck (Ragon Inst., MGH, Boston, USA) M. Perreau, G. Pantaleo (Univ. of Lausanne, Switzerland) R. Cubas, E. Haddad (VGTI, Florida, USA)

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