Role of Innate Immunity in Hepatitis B Virus Infection Adam J. Gehring, Ph.D.

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1 Role of Innate Immunity in Hepatitis B Virus Infection Adam J. Gehring, Ph.D. Biology Lead Toronto Centre for Liver Disease Toronto General Hospital Research Institute University Health Network (UHN)

2 HBV Recognition by Innate Immunity CD14/TLR-4 Historically, HBV seen as a stealth virus Not visible to innate sensing mdc CD14 Mounting evidence for HBV recognition Multiple pattern recognition receptors TLR-2 CD14/TLR-4 RIG-I cgas Cooper, J. Immunol. 175, (2005). Vanlandschoot, J. Gen. Virol (2002). van Montfoort, J. Virol. JVI (2016). Sato. Immunity 42, (2014). Cui. J. Virol. 90, (2015).

3 HBV Recognition by Innate Immunity CD14/TLR-4 mdc CD14 Recognition inflammation Evidence HBV can inhibit signaling HBV polymerase, X Caveat Transfection systems Stimuli was not HBV Restricted to hepatocytes PBMC not infected Infection systems may clarify Cooper, J. Immunol. 175, (2005). Vanlandschoot, J. Gen. Virol (2002). van Montfoort, J. Virol. JVI (2016). Sato. Immunity 42, (2014). Cui. J. Virol. 90, (2015).

4 Innate Immune Response in Chronic HBV Vertical transmission accounts for a majority of chronically infected patients Innate immune system is exposed to HBV before birth No longer any acute response to HBV because virus is always present Hong. Nat Comms 6, 1 12 (2015).

5 Innate Immune Response in Chronic HBV Innate immune system displays a regulatory role during chronic HBV infection Suppress anti-hbv immunity Regulate inflammation Innate immune cells dominate the immune composition of the liver

6 Innate Immune Regulation in Chronic HBV Myeloid-derived suppressor cells (MDSC) Expanded in chronic HBV patients IL-10 & arginase suppress T cells Kupffer cells produce IL-10 in response to HBV core antigen Mouse model Suppression of T cell immunity T cell NK cell TRAIL expression HBV-specific T cells express increased receptor for TRAIL NK-mediated depletion of HBV-specific T cells Pallett. Nat Med 21, (2015). Li. J. Immunol. 195, (2015). Peppa J. Exp Med. 210, (2013).

7 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

8 Blocking NK TRAIL-mediated killing of HBVspecific T cells. NK X TRAIL T Peppa J. Exp Med. 210, (2013).

9 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

10 Inducing presentation of the HBV antigen depot in monocytes CD14 MN GM-CSF + IL-4 6d Co-culture +/- Activation Monocyte-derived DC HBsAg-specific CD8 T cell 8/9 Healthy Chronic HBV HLA-mismatched A0201 Cw0801 Chronic HBV HLA-matched Gehring et al, J Clin Invest. 2013;123(9):

11 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

12 TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 TLR-8 NK & MAIT IL-12/18 IFN-γ NK bright MAIT IFN-γ TNF-α Jo et. al. PLoS Pathog Jun;10(6):e

13 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

14 TLR-7 mediated IFN-alpha production from plasmacytoid DC. GS-9620 TLR-7 IFN-α ISG15 mrna Gane J. Hepatol. 63, (2015).

15 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

16 NKT cell recognition of CD1d on infected hepatocytes. Baron. Immunity 16, (2002).

17 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

18 Blocking MDSC-mediated suppression Pallett. Nat Med 21, (2015).

19 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

20 Direct triggering of RIG-I in infected hepatocytes SB9200: Spring Bank Pharmaceutical RIG-I agonist Chronic Woodchuck Hepatitis Virus Infection model Korolowicz. PLoS ONE 11, e (2016).

21 Opportunities for Innate-targeted Immunotherapy A) Blocking NK TRAIL-mediated killing of HBV-specific T cells. B) Inducing presentation of the HBV antigen depot in monocytes C) TLR-8 activation of intrahepatic monocytes stimulating IL-12 and IL-18 D) TLR-7 mediated IFN-a production from plasmacytoid DC. E) NKT cell recognition of CD1d on infected hepatocytes. F) Blocking MDSC-mediated suppression G) Direct triggering of RIG-I in infected hepatocytes H) CpG induction of imates Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

22 CpG induction of imates TLR-9 TNF-α Huang et. al. Nat Immunol Apr 14;14(6):

23 Opportunities for Innate-targeted Immunotherapy Multiple mechanisms that can potentially be exploited Maini & Gehring. J. Hepatol. 64, S60 S70 (2016).

24 Opportunities for Innate-targeted Immunotherapy Direct antiviral effect & potential environmental effect permit adaptive immunity Concern: Innate immunity is inherently non-specific Identify therapeutic window Effective intrahepatic immune response = inflammation Control/balance systemic toxicity Innate immunity is playing a significant regulatory role in chronic HBV What is regulating the regulators???? Understanding what is controlling the negative regulation by innate immunity may permit an organic immune response vs. therapeutic boosting.