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The role of innate immunity in the pathogenesis of Serious Non-AIDS Events

The role of innate immunity in the pathogenesis of Serious Non-AIDS Events . Suzanne Crowe Associate Director, Burnet Institute Consultant Infectious Diseases Physician, The Alfred Hospital Melbourne. Today’s presentation. HIV, LPS trigger infla mmation. How HIV & inflammation

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The role of innate immunity in the pathogenesis of Serious Non-AIDS Events

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  1. The role of innate immunity in the pathogenesis of Serious Non-AIDS Events Suzanne Crowe Associate Director, Burnet Institute Consultant Infectious Diseases Physician, The Alfred Hospital Melbourne

  2. Today’s presentation HIV, LPS trigger inflammation How HIV & inflammation are linked How breaches in gut mucosa trigger inflammation Contribution of monocyte activation Pro-inflammatory cytokines How monocyte activation Impacts these pathways Involvement of innate immune pathways in Fibrosis Atherosclerotic plaque formation Pro-coagulant activity Metabolic dysregulation Immune senescence Links between monocyte metabolism & inflammation Innate immune senescence & risk of events--- Serious non-AIDS Events

  3. Today’s presentation HIV, LPS trigger inflammation Contribution of monocyte activation Pro-inflammatory cytokines Involvement of innate immune pathways in Fibrosis Atherosclerotic plaque formation Pro-coagulant activity Metabolic dysregulation Immune senescence Serious non-AIDS Events

  4. Chronic inflammation and immune activation • Chronic immune activation & inflammation is central to HIV pathogenesis • In both treated and untreated individuals • Starts during seroconversion • Pro-inflammatory pathways triggered by • HIV replication and viremia • Co-infection eg with CMV • Microbial translocation across the gut mucosa

  5. Intense cytokine storm in acute HIV infection prior to peak viremia Cytokine response in acute HIV Stacey 2009 Changes in plasma cytokine levels Time since HIV infection (days) Stacey et al J Virol 2009 83:3719-3733

  6. T cell immune activationdeclinesduringsuppressive ART Hunt et al, JID, 2003; PLoS One, 2011

  7. But T cellactivationremainselevatedduringsuppressive ART Hunt et al, JID, 2003; PLoS One, 2011

  8. What about Innate immunity and pro-inflammatory pathways?

  9. What is meant by pro-inflammatory pathways? • Activation of cells eg monocytes & mϕ that produce pro-inflammatory cytokines • Pro-inflammatory cytokines include IL-6, TNF-alpha • Chronic inflammation leads to fibrosis and end-organ disease R MedzhitovCell2010; 140:771

  10. Differing pathogenetic roles of T cells & monocytes in HIV infection • T cell activation • Main effect: Central role in T cell decline • Monocyte activation • Main effect: Central role in chronic inflammation • Important in pathogenesis of longer-term, non-AIDS morbidity • CD16+ pro-inflammatory monocytes increased in HIV & only partly normalized by cART Westhorpe C et al Immunol & Cell Biol 2014;92:1338; 2.Tenorio AR et al J Infect Dis 2014; 3. Lederman MM et al AdvImmunol 2013; 119”51; 4. Sandler &SeretiCurrOpin HIV AIDS 2014;9:72

  11. CD16-positive monocytes • increasewithinflammation[pro-inflammatory] CD14+CD16++ non-classical 7-10% CD14++CD16+ intermediate 5-8% • classical CD14++CD16- monocytes 85%

  12. CD16+ monocyte subsets are increased in uncontrolled viremia & may normalize with ART HIV- HIV+ VL<400 HIV+ VL>400 CD14+CD16++ Non classical CD14++CD16- Classical CD14++ CD16+ Intermediate Traditional Inflammatory Patrolling • HIV infection increases the proportions of CD16+ monocytes in blood • cART restores the proportions of monocytes in blood1 • CD16+ monocytes remain elevated in elite controllers2 1. Funderburg NT et al Blood 2012 120: 4599 2. Krishnan S et al J Infect Dis 2014; 209:931

  13. Pro-inflammatory CD14++CD16+ monocytes remain expanded despite cART & virologic suppression HIV- HIV+ Hearps, A, Angelovich T et al unpublished data 2014; Lichtfuss G et al., J Immunol 2012;189:149 ; Hearps A et al AIDS 2012;24:843; Martin G et al PLoSOne 2013;8:e55279l

  14. Elevated levels of intracellular proinflammatory cytokines IL-6 & TNF in monocytes from HIV+ pts Monocyte subsets IL-6 HIV- HIV+ VL<20 HIV- HIV+ VL<20 HIV- HIV+ VL<20 TNF HIV- HIV+ VL<20 HIV- HIV+ VL<20 HIV- HIV+ VL<20 Angelovich T et al 2014 unpublished data 2014 Intermediate Non-Classical Classical

  15. Markers of inflammation and coagulation, but not T-cell activation, predict non-AIDS events • Case-control study in virologically suppressed patients • Cases:non-AIDS events (AMI, CVA, non-AIDS cancers, bacterial infection, death) • Controls: well matched (age, sex, pre-ART CD4, ART regimen) • Blood taken for inflammatory markers • at baseline, 1 yr post ART initiation, pre-event • Conditional logistic regression analysis Tenorio AR et al J Infect Dis 2014 May;

  16. Markers of inflammation & coagulation, but notT-cell activation, predict non-AIDS events Pre-event marker Odds ratio 1 IQR increase p value OR at baseline for Death CaAMI/stroke IL-6 ** ** IP-10 ** ** sTNFR-I ** ** sTNFR-II ** ** sCD14 ** ** D-dimer ** ** CD38+DR+CD8 Tenorio AR et al J Infect Dis 2014 May ahead of print

  17. Increased innate immune inflammatory markers are strongly associated with non-AIDS morbidity • T cell activation is less related to non-AIDS morbidity Tenorio AR et al J Infect Dis 2014 May

  18. So where does this inflammation come from? (HIV,co-pathogens, and…)

  19. Early loss of CD4+ cells in gut-associated lymphoid tissue results in systemic inflammation HIV- • Mϕ accumulate in gut mucosa * in untreated HIV • Further drive pro-inflammatory cytokine production • Loss of CD4+ T cells in GALT • Not in elite controllers • Starts in acute HIV infection • Permanently damages gut mucosa • Microbial translocation • Systemic inflammation • Incompletely restored by ART HIV+ Guadalupe M et al J Virol 2003 77:11708; Ciccone E et al J Virol 2011;85:5880 Brenchley et al Nat Med 2006 12:1365;. Allers K et al JID 2014 209:739-48

  20. Gut-derived bacterial products translocate to the systemic circulation Increased gut permeability & microbial translocation Altered gut microbiome + Gut- derived bacterial products LPS peptidoglycan lipo-techoic acid unmethylatedCpG DNA ribosomal DNA Portal vein Liver Innate immune activation & systemic inflammation (monocytes, mϕ) End organ disease Data from multiple sources &reviews including Deeks SG et al; Immunity; 2013: 39 :633

  21. Activation of Kynurenine/IDO pathway may be involved in the pathogenesis of non-AIDS events Increased gut permeability & microbial translocation Altered gut microbiome (dysbiosis) + LPS activation of IDO pathway Pro-inflammatory cytokine production (TNF, IL-6) Tryptophan Innate immune activation & inflammation (monocytes, mϕ) End organ disease Quinolinic acid Data from multi[le sources including HeyesMP et al J Neuroimmunol 1992;40:71; Vujkovic-Cvijin et al AciTransl Med 2013;5:193;

  22. Activation of the IDO pathway is also linked to premature mortality Byakwaga H, et al J infect Dis 2014 August

  23. Multi-pronged liver attack by HIV, co-pathogens and gut-derived bacterial products Increased gut permeability & microbial translocation Gut- derived bacterial products LPS peptidoglycan lipo-techoic acid unmethylatedCpG DNA ribosomal DNA Portal vein Liver damage clearance LPS Kupffermϕ & hepatic stellate cell activation Activation of innate pro-inflammatory & pro-fibrotic pathways End organ disease Including liver fibrosis Tacke F& Zimmerman H J Hepatol 2014;60:1090; Balagopal A et al Gastroenterology 2008 135:226

  24. Multi-pronged liver attack via HIV, co-pathogens, gut-derived bacterial products, etc Increased gut permeability & microbial translocation Gut- derived bacterial products LPS peptidoglycan lipo-techoic acid unmethylatedCpG DNA ribosomal DNA Portal vein Impaired hepatic function clearance LPS, etc Coinfection Eg HCV Kupffermϕ Hepatic stellate cell activation Activation of innate pro-inflammatory & pro-fibrotic pathways End organ disease eg liver fibrosis Tacke F& Zimmerman H J Hepatol 2014;60:1090; Balagopal A et al Gastroenterology 2008 135:226

  25. Monocyte activation is associated with liver fibrosis in HIV+ patients in Uganda • Retrospective Case/Control study • in RakaiUganda • HIV+ & HIV- subjects with liver fibrosis (transient elastography >9.3kPa) • Cases n = 133 • Controls n =133 • matched for age, gender, HIV, ART • Less than 5% infected with HBV Redd AD et al AIDS Res Hum Retroviruses 2013:29:1026

  26. Patients with monocyte activation had higher odds of liver fibrosis • Higher sCD14 levels were associated with • 19% increased odds of having liver fibrosis (adj OR 1.19 p 0.002) • In HIV+ higher sCD14 was associated with • 54% increased odds of having liver fibrosis (adj OR 1.54, p <0.001) Redd AD et al AIDS Res Hum Retroviruses 2013:29:1026

  27. How do monocytes contribute to the development of cardiovascular disease in HIV+?

  28. Contributing factors to CVD in HIV+ patients Traditional risk factors cART toxicity Co-infection with eg CMV monocyte & mϕ activation other pro-inflammatory & pro-coagulant pathways chronic inflammation Cardiovascular disease

  29. Role of monocytes in atheromatous plaque development Adhesion m’cules Slide produced by G Martin • HIV activates monocytes & endothelial cells (in conjunction with proatherogenic lipids), • Increase monocyte transmigration • Increase uptake of oxLDL • Promote differentiation into foam cells • And contribute to atherosclerotic plaque formation Campbell J et al AIDS 2014 in press

  30. HIV promotes monocyte foam cell formation in vitro • Sub-endothelial monocytes take up ox LDL via CD36 and develop into foam cells after migrating across TNF-activated endothelial cells1 • Endothelial activation is critical for this process1 • Foam cell formation by activated monocytes from HIV+2 monocyte macrophage Foam cell 1. Westhorpe C et al ExpMolPathol 2012;93:220 2. Maisa A et al submitted 2014

  31. How does monocyte metabolism augment inflammation in HIV+ patients?

  32. Glucose metabolism in monocytes • Glucose is important substrate for ATP production • Glut1 is major glucose transporter • Activated monocytes dramatically increase Glut1 expression & glucose uptake • Change from oxidative to glycolytic metabolism Palmer CS & Crowe SM AIDS Res Human Retro 2014 30:335

  33. Glucose uptake is linked to pro-inflammatory responses of mΦ • Glut1 is rate-limiting transporter in mΦ • (murine & human) Fold expression Murine MΦ with high Glut1 expression express high levels of pro-inflammatory cytokines Glut1 Glut2 Glut3 Glut4 IL-6 TNF p = .018 p = .006 Glut1 LOW Glut1 HIGH Glut1 LOW Glut1 HIGH Freemerman AJ et al J BiolChem 2014 289:7884

  34. HIV increases glucose metabolic activity in monocytes, linked to inflammation • The increased Glut1 expression is on intermediate and non-classical (NC) monocytes in HIV+ • Not restored by ART • Increase in proportion of Glut1+ monocytes in HIV+ • Not restored by ART • Correlates with monocyte activation & D-dimer expression % Glut1+ monocytes % Glut1+ monocytes NC I C NC I C NC I C HIV-HIV+ naïve HIV+cART+ HIV-HIV+ naïve HIV+cART+ N = 18 17 11 Palmer C , Anzinger J et al submitted, 2014 See POSTER MOPE-006 & TODAY WEPE-009

  35. Does premature Innate immune senescence contribute to premature risk of non-AIDS morbidities ?

  36. Shared immunologic features between HIV infection & ageing Ageing HIV Immunologic changes Chronic immune activation/inflammation • : Immune senescence CVD, cancers, kidney, bone & liver disease, neurocognitive impairment

  37. Shortened telomeres in young HIV+ and in healthy elderly Telomere length is shorter in healthy elderly and young HIV+ on cART with VL<50 • Telomeres shorten during each cell division • As telomeres shorten, cells age • Telomere length is a classical marker of immune ageing Classical monocytes CD16+ monocytes Young Aged Young HIV+ Young Aged Young HIV+ Median age: 28 72 29 28 72 29 yrs Range (yrs): 20-32 70-82 27-45 Hearps A et al AIDS 2012; 26: 843

  38. HIV accelerates innate immune changes • HIV induces age-related changes in monocytes • In HIV+ men1 • In HIV+ women2 • Changes appear approx 10-14 years earlier in HIV+ compared with HIV- women2. • Does the clinical phenotype of ageing emerge earlier in HIV+ patients with innate senescence? • No clear evidence • Hearps A et al AIDS. 2012;24:843-53 • Martin G et al 2013;8(1):e55279;

  39. Summary • Pathogenesis of SNAEs is complex & multifactorial • Chronic endotoxemia activates innate immune cells • Pro-inflammatory environment with associated coagulation, fibrotic & immune metabolic changes • Heightened risk of serious non-AIDS events Palmer CS & Crowe SM AIDS Res Human Retro 2014 30:335

  40. Conclusions: Strong role of innate immune pathways in pathogenesis of Serious Non-AIDS Events • Most innate immune changes in HIV+ only partly reversed by ART • Residual immune dysregulationsyndrome • Persistent immune activation, inflammation & coagulation • Circulating biomarkers of inflammation are strongest predictors of non-AIDS events • Less evidence for T cell involvement • Innate immune senescence occurs earlier in HIV+ • Not clear whether this translates into premature risk of SNAEs

  41. Acknowledgements Dmitri Sviridov Infectious Diseases Sharon Lewin Jenny Hoy Julian Elliott Kate Cherry Janine Trevillyon Anthony Jaworowski Anna Hearps Genevieve Martin Clovis Palmer Tom Angelovich Anna Maisa GregorLichtfuss Wan-Jung Cheng Jingling Zhou Tim Spelman M Gouillou Alan Landay Cardiovascular Medicine Anthony Dart Liz Dewar SofieKarapanagiotidis William Muller Univ West indies, Jamaica The HaCH Study volunteers Josh Anzinger Funding Clare Westhorpe Mike McCune Also with grateful thanks to colleagues who contributed slides for this presentation, some not included because of time limitations “The Ageing Team”

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