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Dale and Betty Bumpers Vaccine Research Center

Dale and Betty Bumpers Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health. Lymph node structure and HIV-1 infection: T cell immunopathogenesis. Richard A. Koup Vaccine Research Center. Background.

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Dale and Betty Bumpers Vaccine Research Center

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  1. Dale and Betty Bumpers Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Lymph node structure and HIV-1 infection: T cell immunopathogenesis Richard A. Koup Vaccine Research Center

  2. Background • HIV replication is active in lymph nodes throughout the course of HIV infection • HIV leads to an initial hypertrophy, followed by involution of lymphoid tissues (Tim Schacker) • SIV infection in rhesus macaques has a similar pathogenesis to HIV infection in humans (Guido Silvestri) and can be used to study the immuno-pathogenesis of HIV infection in lymph nodes • In this talk I will concentrate on using acute and early SIV infection of rhesus macaques to model HIV pathogenesis in lymph nodes

  3. The Lymph Node has a Complicated Structure Janeway’sImmunobiology (8th Edition)

  4. Simplified LN Structure Lymphoid Follicle (B cells) Light Zone (T/B cell interaction) Germinal Center (B and T cells) Dark Zone (B cell proliferation) Paracortical Area (T cells)

  5. Simplified LN Structure – HIV Infection Uninfected Infected - Early Infected - Late Germinal Center Hypertrophy (increased germinal center T cells) Loss of non-germinal center T cells

  6. Outline • Virus replication in LN during acute/early HIV/SIV infection • Changes in CD4 T cell populations in LNs during acute/early HIV/SIV replication • Underlying mechanisms • Non-T cell consequences

  7. SIV as a model for HIV infection Nature 434:1093-7, 2005

  8. Acute Infection: Plasma Viral Loads Plasma Viral Load (Log10)

  9. Total CD4 Cell Dynamics CD4 T Cells, % of CD3+

  10. J e j u n u m 4 0 I n g u i n a l 6 0 L N 4 0 2 0 2 0 0 0 Memory CD4 T Cell Dynamics M e s e n t e r i c 4 0 4 0 P B M C L N Early expansion at d. 3 2 0 2 0 CD4 Memory, % of CD3+ 0 0 Loss of ~80% of cells by d. 17 0 3 7 1 0 1 4 1 7 0 3 7 1 0 1 4 1 7 D a y s P o s t - i n f e c t i o n

  11. N a i v e C D 4 T C e l l s M e m o r y C D 4 T C e l l s 5 P B M C 2 x 1 0 5 1 x 1 0 0 5 2 x 1 0 I n g u i n a l L N 5 1 x 1 0 Cell-Associated Viral Load (gag Copies / 105 cells) 0 5 2 x 1 0 M e s e n t e r i c L N 5 1 x 1 0 0 5 2 x 1 0 J e j u n u m 5 1 x 1 0 0 3 7 1 0 1 4 1 7 3 7 1 0 1 4 1 7 D a y s P o s t - i n f e c t i o n Cell-Associated Viral Loads

  12. These data do not take into account structural localization within the LN • Where is the virus replicating with respect to the paracortical T cell zone and the light zone of the germinal center? • What is happening to CD4 T cell frequency in these areas during acute and early SIV infection? Light zone of the germinal center Paracortical T cell zone

  13. 5 10 4 10 70.8 3 10 19.5 2 10 0 3 4 5 0 10 10 10 Surface markers can distinguish CD4 T cells from these different areas Light zone of the germinal center FSC-H CD4 CD8 FSC-A CCR7 CD28 Aqua Paracortical T cell zone PD-1 CD3 CD95

  14. 5 10 4 10 3 10 2 10 0 3 4 5 0 10 10 10 5 Where does SIV replicate? 4 3 2 1 Acute SIV (3-21 days) Early SIV (>2 months) 0 p=0.0078 p=0.0156 Light zone of the germinal center SIV Gag DNA (copies/cell) SIV Gag DNA (copies/cell) Paracortical T cell zone Would expect to see depletion of CD4 T cells in germinal centers CCR7 ICOS PD-1 CD150 1.5 1.0 0.5 0

  15. 5 10 4 10 3 10 2 10 0 2 3 4 5 0 10 10 10 10 SIV: Relative accumulation of CD4 T cells in GCs SIV acute SIV early SIV- CCR7 47.8 29.1 12.9 PD-1 % of CM CD4 T cells TFH CCR7high PD-1low CCR7high/low PD-1dim

  16. Accumulation of GC CD4 T cellsduring SIV infection: Abundant GCs with retained architecture Light zone: T - B cell interaction Dark zone: B cell proliferation CD4PD1Ki-67 Michael Gerner, Ron Germain

  17. Mechanism? Uninfected Infected - Early ?

  18. No correlation between VLs and percent GC T cells during SIV infection Viral Loads Percent GC T cells in LN

  19. Accumulation of GC Tcells is associated with general immune activation (sCD14) SIV- SIV acute SIV early (low % of TFH) SIV early (high % of TFH) p=0.0004 p=0.0164 p=0.0013 sCD14 (x106 pg/ml) % of CM CD4 T cells GC T cells

  20. SIV: Relative accumulation of GC Tcells IL-6 signaling drives the up-regulation of Bcl-6and enhanced T cell responses that are seen during chronic LCMV infection in mice. Does IL-6 production drive the accumulation of GC Tcells during early SIV infection in monkeys?

  21. Increase in the IL-6/IL-6R axis is associated with GC Tcell accumulation during SIV infection p=0.0215 p=0.0136 Plasma IL-6 (pg/ml) IL6Ra on GC T cells (MFI) Percent GC T cells in LN SIV- SIV+ (early)

  22. Mechanism? Uninfected Infected - Early Immune activation 1) IL-6 2) 3) Altered phospho STAT (3>1) 4) GC T cell differentiation Petrovas et al, J. Clin. Invest., 2012

  23. 5 5 10 5 5 10 10 10 4 4 4 10 4 10 10 10 3 3 3 10 3 10 10 10 2 2 10 10 0 0 0 0 3 4 5 3 4 5 0 10 10 10 2 3 4 5 3 4 5 0 10 10 10 0 10 10 10 10 0 10 10 10 GC T cells are TFH that influence B cells differentiation and antibody production LN PBMC Aqua CD3 22.3 6.49 1.87 0.72 28.7 86.1 LN 9.84 61.3 81.5 15.8 SSC CD20 PNA SIV- SIV+ low T SIV+ high T IgG 10 PNAhighIgGlow SIV - SIV chronic (low % GC T cells) 7.5 PNAhighIgGhigh SIV chronic (high % GC T cells) p=0.051 5 SIV-specific IgG (titer, x104) p=0.015 2.5 0 gp120 SIV chronic (low % GC T cells) SIV chronic (high % GC T cells)

  24. Conclusions • HIV/SIV replication is profound during acute infection • This leads to a massive depletion of memory CD4 T cells in the LN and gut • CD4 T cell depletion from the gut leads to microbial translocation and general immune activation (discussed elsewhere) • Immune activation promotes differentiation of T cells in the LN which move to and accumulate in the GCs (lymphoid hypertrophy) • Non-pathogenic SIV controls immune activation • Continued immune activation ultimately leads to fibrosis of the lymph nodes

  25. Simplified LN Structure – HIV Infection Uninfected Infected - Early Infected - Late Germinal Center Hypertrophy (increased germinal center T cells) Immune activation: GC hypertrophy followed by fibrosis Loss of non-germinal center T cells Direct infection: CD4 depletion

  26. Dale and Betty Bumpers Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Immunology Laboratory NIAID/NCI Collaborators Michael Gerner Ron Germain Costas Petrovas Takuya Yamamoto Kristin Boswell Joseph Casazza Rob Paris David Ambrozak Lab Animal Medicine John-Paul Todd Srinivas Rao Human Immunology Section Netanya Sandler Daniel Douek ImmunoTechnology Section Mario Roederer

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