Combined and IFNα treatment limits inflammation and delay viral rebound in ART-treated, SIV-infected macaques Mirko Paiardini Associate Professor, Emory University School of Medicine Yerkes National Primate Research Center IAS Cure & Cancer Forum Paris, France www.iasociety.org
www.iasociety.org Interleukin-21 treatment in SIV-infected RMs o Th17 cell maintenance is severely impaired in the absence of (Nurieva, Nature 27; Korn, Nature 27; Yang, Nature 28) o Paucity of -producing CD4+ T cells is associated with Th17 depletion in SIVinfected RMs (Micci, Blood 212); o Loss of function of intestinal IL-17 producing cells contributes to inflammation and viral persistence in SIV-infected RMs (Ryan, PLoS Pathogens 216) o treatment in acute SIV infection preserves Th17 cells and reduces microbial translocation (Micci, PLoS Pathogens 214) o treatment in ART-suppressed, SIV-infected RMs reduces residual inflammation and viral persistence (Micci, J Clin Invest 215)
limits intestinal T cell activation and proliferation Treated Treated %CD4 HLA-DR + CD38 + T cells RB 6 4 2 P=.3 P=.11 P<.1 P<.1 P=.2 %CD8 HLA-DR + CD38 + T cells RB 4 3 2 1 P=.21 P=.2477 P<.1 P<.1 P=.12 days on ART pre-art 25 75 2 days on ART pre-art 25 75 2 Average fold change vs day 58 (pre-art).78 1.36.25.54 %CD4 + Ki-67 + T cells RB 5 4 3 o o 2 1 Average fold change vs day 58 (pre-art) P=.3 P=.17 day 58 day 84 day 256 Treated.78 1.36.25.54 P<.1 But modestly reduces plasma P=.19 P=.21 P=.12 viremia upon ART-interruption No differences in timing of rebound No significant differences in viremia at any experimental points Micci L, J Clin Invest 215
Rationale and Study design Phase 1 Gr. 1: ART; #7 RMs Gr. 2: ART+IL21+IFN-α; #14 RMs d35 p.i. r r IFN-α SIVmac239 ART (TDF+FTC+DTG) Weeks Relative to infection 1 2 5 6 7 9 11 15 19 23 26 27 29 31 36 39 47 5 56 LOD: 3 copies/ml A: ART Inflammation Antiviral functions B: ART + + IFNα Inflammation Antiviral functions Time Normalized Read Count 15 1 Time 5 4 3 2 6 4 2 p<.1 + TX IFIT2 MX1 OAS2 MX2 SAMHD1 STAT1 IFIT3 IFI16 GBP1 IFI6 ISG2 ISG15 OAS3 OASL OAS1 IFI27 IRF7 CXCL1 TRIM5 IFIH1 CCL8 APOBEC3G STAT2 IFIT5 IFI44 RTP4 CHMP5 ISG expression by RNAseq in total PBMCs
www.iasociety.org +IFNα treated RMs maintain low levels of activation on ART CD4+ T cells CD8+ T cells PB %CD4 + Mem. HLA-DR + CD38 + T cells PB 3 2 1 * + TX ** ** ** %CD8 + Mem. HLA-DR + CD38 + T cells PB 3 2 1 * + Tx. 14 14 35 77 119 161 217 26 288 339 37 Days Post Infection 14 14 35 77 119 217 26 288 339 37 Days Post Infection RB %CD4 + Mem. HLA-DR + CD38 + T cells RB 3 2 1 14 35 77 161 217 288 37 Days Post Infection + TX %CD8 + Mem. HLA-DR + CD38 + T cells RB 3 2 1 14 35 77 161 217 288 37 Days Post Infection Treated
Infectious units per million (IUPM) In fe c tio u s u n its p e r m ilio n (IU P M ) C D 4 T c e lls (L N ) www.iasociety.org +IFNα treated RMs show reduced viral on ART controls + IFNα + TX RPk11 & RNa12 (PTCs) excluded Rectal biopsies 1 4 1 2 CD4+ T cells from LN c A R T P =. 9 SIVmac 239 DNA copies per 1 6 Tot. CD4 (RB) 1 1 1 1 1 1 pre-art P=.1 P=.6 P=.1 on-art 1 8 6 4 2 1 IF N + IFNα c o n o Longitudinal measurements including post but pre IFNα are pending Additional QVOA analyses in purified CD4+ T cells from LN are pending d35 IL21+ d35 CTRS d37 IL21+ d37 CTRS d 3 7 2 1 a d 3 7 c trs
percent of viremic RMs 1 +IFNα treated RMs show delayed and RPk11 & RNa12 excluded (PTCs) reduced viral rebound after ATI plasma viral load betweem +peg-ifn a vs. Gr. 1: ART; #7 RMs Gr. 2: ART+IL21+IFN-α; #14 RMs 8 6 4 Viral Rebound proportions post-art cessation 5/5 d35 p.i. r r Phase 1 SIVmac239 P=.2 ART (TDF+FTC+DTG) 2/8 + peg- TX IFN-α Phase 2 Viral rebound Phase 3 P=.5 Necropsy Weeks Relative to infection 1 2 5 6 7 9 11 15 19 23 26 27 29 31 36 39 44 46 48 5 51 52 53 55 59 61 65 69 72 cut-off: 2 copies/ml 2 2 Control /8 IL21+peg-IFNα 1 6 9 13 2 3 6 9 13 16 2 44 Days after ART interruption days post-art interruption 7/8 7/8 Plasma SIVmac 239 RNA copies/ml 7 6 5 4 3 d6 peg+ Tx P=.4 for time window from day 6 to 44 ATI; 1.29 log 1 mean difference d6 controls d9 peg+ Tx P<.1 P<.1 peg- P<.1 d9 controls d13 peg+ Tx d13 controls d2 peg+ Tx d2 controls d3 peg- Tx d3 controls d44 peg-infa Tx. 44 d44 controls Kruskal-Wallis test: P=.9-3 groups separated Measures P=.2 - of Tx. vs. viral CTRS persistence post P=.25 - IgFc- Tx. vs. peg- Tx. ATI are pending What is happening after IFNα treatment has been discontinued? day 6 to 44: 1.29 log 1 mean difference
www.iasociety.org Preliminary conclusions + IFNα administration resulted in: Reduced mucosal and systemic immune activation Reduced cell-associated SIV-DNA in GI tract Delayed and reduced viral rebound post ATI (still during IFNα treatment) IFNα treatment was not associated with deleterious effects on T cell levels or immune activation, either on ART or after ATI Multiple immunologic and virologic parameters (including replication competent virus) are pending (longitudinal, blood and tissues) Impact on viral persistence after discontinuation of IFNα needs to be determined
Acknowledgments Paiardini Lab *Luca Micci Justin Harper *Sara Paganini Colin King Hong Wong Maria Pino Kristina Ortiz Emory Genomic Core Steven Bosinger Greg Tharp Nirav Patel NCI/Frederick Jeffrey Lifson Jacob Estes CASE Western Rafick Sekaly Susan Ribeiro Michael Lederman Gilead/ViiV Romas Geleziunas Jim Demarest Support NIH/NIAID amfar Emory CFAR Qura Therapeutics Emory - YNPRC Barbara Cervasi Guido Silvestri Paul Johnson Stephanie Ehnert Sherrie Jean Elizabeth Strobert U. Of Lafayette Francois Villinger *Former members Post doc positions available (mirko.paiardini@emory.edu) www.iasociety.org