2014 “Towards an HIV Cure” Symposium Melbourne
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Transcript of 2014 “Towards an HIV Cure” Symposium Melbourne
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2014 “Towards an HIV Cure” SymposiumMelbourne
IL-21 reduces residual inflammation and virus persistence in ART-treated SIV-
infected rhesus macaquesMirko Paiardini, PhD
Yerkes National Primate Research Center Emory University
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Implications of residual chronic immune activation in HIV-treated patients
Residual Inflammation
Inflammation in treated HIV disease is: • Higher than expected
• Stable over time
Currier J.S. AIDS conference 2012
• Strong prognostic importance
HIV persistence and replication
• Associated with HIV persistence
non-AIDS-related overall morbidity
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Contributors to chronic immune activation
Paiardini & Muller-Trutwin, Immunol Rev 2013
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oImportant for anti-bacterial/fungal immunity and epithelial integrity Neutrophil recruitment Proliferation of GI enterocytes Production of tight junction proteins Production of anti-bacterial defensins
oIf not properly regulated, Th17 pro-inflammatory activity may result in tissue damage
Laurence et al. Nat Med 2008
IL-17 and IL-22 producing cells are critical for the mucosal immune functions
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Depletion of intestinal Th17 cells is associated with progression to AIDS
o Th17 & Th22 cells are preferentially depleted in pathogenic HIV and SIV infections (Brenchley, 2008; Cecchinato, 2008; Raffatellu, 2008; Campillo-Gimenez, 2010; Li, 2011; Singh, 2012; Klatt, 2012; Kim, 2012)
o Th17 cells are preserved in nonpathogenic SIV infection of natural hosts as well as in HIV Elite controllers and LTNP (Brenchley, 2008; Favre, 2009; Brandt, 2011; Salgado, 2011; Ciccone, 2011)
o Depletion of Th17 cells is associated with microbial translocation, chronic immune activation, and disease progression (Raffatellu, 2008; Cecchinato, 2008; Gordon, 2010)
o Effective CD4 T cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with increased Th17 cells (Macal, 2008)
o SIV replication in rhesus macaque is limited by the size of the preexisting Th17 cell compartment (Hartigan-O'Connor, 2012)
Can we modulate the levels of intestinal Th17 cells in vivo?
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Interleukin (IL)-21 functions
• Th17 cell generation is severely impaired in the absence of IL-21 (Nurieva, Nature 2007; Korn, Nature 2007; Yang, Nature 2008)
• Plasma levels of IL-21 are reduced in progressive HIV-infection (Iannello A., Viral Immunol 2008; Chevalier M., J Virol 2010; Williams L., J Virol 2010)
• IL-21 shows promise in multiple myeloma and renal cell carcinoma trials to improve CD8 and NK cell functions (Davis, Clin Cancer Res 2009; Rasmussen, Br J Clin Pharmacol 2010; Steele, Br J Cancer 2012).
Rationale
Further rationale comes from our previous studies
H. Søndergaard, Tissue Antigens, 2009
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16 RMs, 8 ART+IL-21 & 8 ART alone; age/sex matched; 8 A01+, all B08- & B17-
Study design
Does IL-21 improve the partial reconstitution of intestinal Th17 and Th22 cells achieved with ART?
Does it limit residual immune activation/inflammation?
Would this impact on residual viremia and/or size of the latent SIV reservoir?
Weeks p.i. -2 9 15 19
IL-21
5
SIVmac239 (i.v.)
2 29 380
BloodLymph Node
Rectal biopsy
2310 12
cART (PMPA, FTC, Raltegravir, Ritonavir boosted Darunavir)
34 39 40 42 454136 47
Rhesus IL-21-Fc-IgG fusion protein; 100ug/kg; s.c. (Francois Villinger, YNPRC)
IL-21
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cART is very effective in suppressing SIV replication in RMs
Limit of detection 60 copies/mL; undetectable values plotted at half LOD
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Improved homeostasis of Intestinal IL-17 and IL-22 producing cells
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CD4 T cells
IL-21 limits intestinal T cell activation
CD8 T cells
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IL-21 limits intestinal T cell proliferation
Similar reduction found in CD4 and CD8 T cell activation in blood
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Repeated measures analyses: percentages of RMs with undetectable viremia over time is significantly higher in IL-21 treated animals than controls (P=0.03)
IL-21 limits plasma residual viremia
d200d105on ART: d75
28.5% vs. 37.5% 42.8% vs. 25% 85.7% vs. 37.5%% N.D.
Limit of detection: 3 copies/mL (Jeff Lifson)
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IL-21 reduces cell associated SIV DNA in rectal tissues
Jeff Lifson
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ConclusionsIL-21 administration in ART-treated, SIV-infected RMs:
Is safe and significantly improves reconstitution of intestinal IL-17 and IL-22 producing CD4 T cells
Results in a more rapid and pronounced reduction of residual activation in blood and intestinal T cells
Limits residual viremia in plasma and cell associated SIV-DNA in rectal tissues
To explore IL-21 as a potential immunotherapeutic agent for HIV infection
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OPEN QUESTIONS – WORK IN PROGRESS
Did IL-21 reduce the levels of soluble markers of inflammation?
Did IL-21 reduce the size of the latent SIV reservoir?
How the achieved results impact on viral rebound following ART interruption?
How the achieved results impact on immune activation following ART interruption?
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Acknowledgments
Emory - YNPRCFrancois VillingerGuido SilvestriStephanie EhnertChristopher SouderSherrie Jean
Support – NIHR01-AI084836R21-AI104278
NIH/NIAIDDaniel DouekJason Brenchley
ART DrugsDaria Hazuda (Merck)Romas Geleziunas (Gilead)Guenter Kraus (Janssen)
Paiardini LabLuca MicciEmily RyanColleen McGarySara PaganiniZachary Ende*
NCIJeff LifsonMichael PiatakJake Estes
Case WesternMichael Lederman Flow core EVC
Barbara Cervasi*
CFAR Virology core Thomas VanderfordBenton LawsonMelon Nega
* Former lab members
VGTI - FloridaNicolas Chomont
DARE Steven DeeksMike McCuneRafick Sekaly