1 / 12

Differential impact of IL-7 and IL-15 on HIV reservoir persistence

Differential impact of IL-7 and IL-15 on HIV reservoir persistence. Claire Vandergeeten, PhD. IAS, Rome, July 18th 2011. Why are we interested in the study of the role of IL-7 and IL-15 on HIV reservoir persistence?.

ocean
Download Presentation

Differential impact of IL-7 and IL-15 on HIV reservoir persistence

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Differential impact of IL-7 and IL-15 on HIV reservoir persistence Claire Vandergeeten, PhD IAS, Rome, July 18th 2011

  2. Why are we interested in the study of the role of IL-7 and IL-15 on HIV reservoir persistence? • HIV persists in memory T cells (Chun, Proc Natl Acad Sci U S A, 1997; Wong, Science, 1997; Finzi, Nat Med, 1999) • Persistence by homeostatic proliferation(Chomont, Nat Med, 2009) • IL-7 and IL-15 are involved in the maintenance of memory CD4 T-cells (Kondrack, J Exp Med, 2003; Lenz, Proc Natl Acad Sci U S A, 2004) • What are the role of IL-7 and IL-15 on HIV persistence?

  3. IL-7 placebo 75 50 25 0 0 10 20 30 Impact of IL-7 therapy on the HIV reservoir size (1) • ACTG5214 clinical trial (10 virally suppressed subjects) • A single injection of 4 rhIL-7 doses (3, 10, 30 or 60 µg/kg) or placebo PBMCs PBMCs PBMCs % CD4+ Ki67+ Day 0 Day 4 Day 28 IL-7 injection Days IL-7 induces proliferation of CD4 T cells

  4. p=0.03 Int HIV DNA per mL of blood Int HIV DNA per 106 CD4 T cells 800 2000 600 1500 400 1000 200 500 0 Day 0 Day 28 0 Day 0 Day 28 Impact of IL-7 therapy on the HIV reservoir size (2) • Integrated HIV DNA was measured by a semi-nested Real Time PCR (Alu PCR) IL-7 does not increase the frequency of reservoir cells within the CD4 compartment IL-7 increases the absolute number of CD4 T cells harboring HIV DNA

  5. Impact of IL-7 on HIV reservoir diversity • CD4 T-cells from successfully treated subjects were stimulated with IL-7 (1 or 10 ng/mL) • HIV reservoir diversity was evaluated by sequence of the env gene after 8 days. P = NS P = NS P = NS P = NS P = 0.0002 P < 0.0001 4 8 3 6 Genetic diversity (%) Genetic diversity (%) Subject 1 Subject 2 2 4 1 2 0 0 Baseline CD3/ CD28 IL-7 1ng ml–1 IL-7 10ng ml–1 Baseline CD3/ CD28 IL-7 1ng ml–1 IL-7 10ng ml–1 Day 0 Day 8 Day 0 Day 8 IL-7 maintains HIV reservoir diversity in vitro

  6. Although IL-7 restores CD4 T cell count through cell proliferation (Sereti, Blood, 2009; Levy, JCI, 2009) it also increases the number of CD4 T cells harboring HIV integrated DNA IL-15 is another c cytokine involved in the maintenance of T cell memory • Evaluation of the effect of IL-15 and IL-7 on: • Viability of CD4 T cells • Activation and proliferation of CD4 T cells • Viral production from latently infected CD4 T cells

  7. Impact of IL-7 and IL-15 on viability of CD4 T cells • CD4 T-cells were stimulated with IL-7 or IL-15 at 10 ng/mL. • Viability was measured by flow cytometry after 6 days. 100 95 % viability 90 85 80 NS IL-7 10 ng/mL IL-15 10 ng/mL Both IL-7 and IL-15 promote survival of CD4 T cells

  8. 8 6 4 2 0 IL-15 10 ng/mL NS IL-7 10 ng/mL Impact of IL-7 and IL-15 on activation and proliferation of CD4 T cells • CD4 T-cells were stimulated with IL-7 or IL-15 at 10 ng/mL. • Proliferation and activation were measured by flow cytometry after 6 days. p=0.004 % CD4+ Ki67+ % CD4+ PD-1+ % CD4+ HLA-DR+ 20 12 9 15 6 10 3 5 0 0 IL-7 10 ng/mL IL-15 10 ng/mL NS NS IL-7 10 ng/mL IL-15 10 ng/mL IL-7 induces higher levels of cell proliferation than IL-15 IL-7 and IL-15 induce similar levels of activation markers

  9. #1 #2 #3 #4 #5 #6 Impact of IL-7 and IL-15 on HIV reservoir reactivation • CD4 T-cells from successfully treated subjects were stimulated with IL-7 or IL-15 at 10 ng/mL in the presence of ARV. • Viral production was measured by a sensitive real time PCR after 6 days. p = 0.04 Viral RNA copy 12000 9000 6000 3000 0 NS CD3/ CD28 IL-7 10 ng/mL IL-15 10 ng/mL IL-15 reactivates HIV production from latently infected cells in vitro IL-15 induced viral production in latently infected cells very efficiently when compared to IL-7 ( 4 fold increase)

  10. Conclusion • IL-7 increases the absolute number of CD4 T cells harboring integrated HIV DNA in vivo and maintain the genetic diversity of the reservoir in vitro • IL-7 and IL-15 induce proliferation, activation and survival of CD4 T cells • IL-15 induce viral production very efficiently when compared to IL-7 IL-15 should be considered as a possible candidate to achieve HIV eradication

  11. Differential impact of IL-7 and IL-15 on HIV reservoir CD4 T cells Integrated HIV DNA HIV viral particles IL-7 IL-15 ARV

  12. Acknowledgments ACTG5214 study : Michael Lederman Irini Sereti VGTI Florida: Nicolas Chomont Rafick-Pierre Sekaly Sandrina DaFonseca Rémi Fromentin

More Related