Inflammation Chronic inflammation and aging Why? Inflammation, immune activation and HIV infection

1. Role of inflammation in the pathogenesis of age-related comorbiditiesJacqueline CapeauINSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site Saint-Antoine, Hôpital Tenon, Paris, France

2. Inflammation Chronic inflammation and aging Why? Inflammation, immune activation and HIV infection Consequences on morbidity/mortality in HIV-infected patients Anti-inflammatory treatment: Statins?

3. Acute inflammation « Rubor et tumor cum calore et dolore » Redness and swelling with heat and pain Corneluis Celsius 1rst century AD

4. Inflammation pathways components Infection Injury Host defense Tissue repair Inflammation R Medzhitov Cell 2010

5. Inflammation and the stress response R Medzhitov Cell 2010

6. Inflammation Chronic inflammation and aging Why? Inflammation, immune activation and HIV infection Consequences on morbidity/mortality in HIV-infected patients Anti-inflammatory treatment: Statins?

7. Chronic low-grade inflammation is associated with most age-related diseases Hs-CRP< 10mg/l Hs-IL6 A Freund Trends Molecular Med 2010

8. X Chronic low-grade inflammation Not caused by classicinducers: infection and injury Due to tissue stress and malfunction?

9. « Inflammaging » « Immune activation  » Proinflammatory cytokines produced by immune cells: monocytes/macrophages and T lymphocytes but also endothelial cells, adipocytes, epithelial cells HY Chung Aging Research Reviews 2008,9;8:18

10. Implication of inflammation in aging processes Salminen Cell Signal 2010

11. Inflammation Chronic inflammation and aging Why? Inflammation, immune activation and HIV infection Consequences on morbidity/mortality in HIV-infected patients Anti-inflammatory treatment: Statins?

12. Gut-derived inflammation and metabolicrisk

13. Intestinal Microbiota 1014 bacteria and archaea Large diversity: 1100species 150 more gene than our own genome From Burcelin London 2010

14. Role of food composition in systemic inflammation and metabolic consequences sCD14 M Serino Diabetes Metab 2009

15. Role of adipose tissue in inflammaging GUT LPS, sCD14 From VD Dixit J Leukoc Biol 2008

16. Inflammation, immune activation And cardio-vascularrisk

17. Initiation of atherosclerosis : activation of macrophages AM LundbergClinicalImmunology 2010

18. Role of innate and acquired immunity in atherosclerosis progression TLR stimulation of macrophages results in the release of proinflammatory cytokines, TNFa, IL-1 and IL-6, that can have both local and systemic effects. AM LundbergClinicalImmunology2010

19. Role of immune activation in plaque inflammation and risk of rupture and thrombosis J Andersson ClinicalImmunology 2010

20. Increased levels of CRP and LDL-c decrease the probability of cardiovascular event-free survival EY Yang J Am CollCardiology 2009

21. Role of personal and life-style factors

22. Inflammation Chronic inflammation and aging Why? Inflammation, immune activation and HIV infection Consequences on morbidity/mortality in HIV-infected patients Anti-inflammatory treatment: Statins?

23. Early occurrence of age-related comorbidities Osteoporosis Neurocognitive dysfunction Sarcopenia Frailty Cardio-vascular risk and hypertension Fat redistribution and lipodystrophy Insulin resistance, diabetes et dyslipidemia Non-AIDS related Cancers HIV-infected patients Premature aging

24. Non-AIDS defining comorbidities HIV- HIV+ INCIDENCE 10-15years AGE From J Campisi

25. Increased levels of proinflammatory and prothrombotic markers in HIV-infected patients as compared to the general population J Neuhaus CID 2010

26. Why ? HIV- HIV+ Inflammation, Immune Activation, thromboticrisk HIV, ART Immune depletion/senescence INCIDENCE AGE 10-15 years From J Campisi

27. Inflammaging in HIV-infected patients Virus Role of chronic infection Role of treatment Role of inflammation/immune activation Role of immune deficiency/senescence Role des personal factors : age, tobacco, coinfections Earlyaging Immunity ART

28. Virus and inflammation

29. p=0.0408 p=ns CV copies/mL IL6 <0.685 IL6 >0.685 CRPUS <1 CRPUS: 1-3 CRPUS >3 The level of IL-6 is related to viral load in HIV-infected patients with a controlled VL • 122 patients, ART-treated, VL: 1 to 500 copies/ml, • IL-6 values were positively related to HIV-RNA levels (rho=0.217 p=0.017) JP Bastard Workshop Adverse Drug ReactionComorbidities London 2010

30. ART and inflammation

31. Effect of different antiretrovirals on human adipocytes : PI and NRTI C Lagathu Antiviral Ther 2007

32. Some PI induce oxidative stress and inflammation in endothelial cells: Beneficial effect of statins Lefèvre ATVB 2010

33. Chronic immune activation and inflammation HIV Infection and replication Anti-HIVimmunity Reactivation of otherviruses Intestinal bacterial translocation Production of viral proteins Immune activation: Acquired and InnateImmunity Lymphocytes T Differentiation and senescence Proinflammatory cytokines secretion Chronic inflammation Immune depletion and immune senescence Non-AIDSdefiningmorbidity and mortality D’après V Appay J Pathol 2008

34. Relations between bacterial translocation, immune activation and chronic inflammation  Bacterial translocation in naïve and treated patients LPS, 16S rDNA sCD14, innateimmunity activation IL-6 acquiredimmunity activation, CD4, CD8 CRP immune depletion/senescence JM Brenchley Nat Med 2006 W Jiang JID 2009 R Rajasuriar JID 2010

35. Inflammation Chronic inflammation and aging Why? Inflammation, immune activation and HIV infection Consequences on morbidity/mortality in HIV-infected patients Anti-inflammatory treatment: Statins?

36. Roleof immune activation and inflammation in non-AIDS-defining mortality

38. Fibrinogen and CRP are independent risk factors for mortality in the FRAM study Even in patients with preserved CD4 count >500 cells per microliter, inflammation remains an important factor for mortality P Tien JAIDS 2010

39. NG Sandler CID 2011

40. Relations between bacterial translocation, immune activation and cardio-vascular risk  Bacterial translocation naïve and treated patients LPS, 16S rDNA sCD14, innateimmunity activation IL-6 acquiredimmunityactivation, CD4, CD8 CRP immune depletion/senescence JM Brenchley Nat Med 2006 W Jiang JID 2009 Cardio-vascularrisk R Rajasuriar JID 2010 RC Kaplan Atherosclerosis, CID 2011

41. RC Kaplan CID 2011

42. IMT is associated with CRP and insulin resistance AC Ross CID 2009

43. Role of bacterial translocation and immune activation In neurocognitive disorders

44. 179 subjects, median age 48 years, • 14 (8%) patients with neuropsychological deficit (ND), 22 (12%) with asymptomatic neurocognitive impairment (ANI), 14 (8%) with mild cognitive impairment (MCD), and 5 (3%) with HIV-associated dementia (HAD) : 31% affected. • Mean LPS values for NT were 94±47 pg/mL, ND: 131±37 pg/mL, ANI: 122±61 pg/mL, MCD: 131±8 pg/mL, HAD: 129±45 pg/mL (p = 0.002). • In multivariate analysis, plasma LPS >120 pg/mL (p = 0.0001) and pDNA (p = 0.032) were independent risk factors for NI. Plasma LPS increasedeven in mildforms of impairment, whethersymptomatic or not H Carsenti-Dellamonica CROI 404

45. J Lyons CROI 2011 # 405

46. Lipodystrophy worseninflammatory state and metabolicdisorders

47. Lipodystrophic HIV-infected patients have increased CRP and decreased adiponectin levels K Samaras Obesity 2009

48. Lipodystrophy and ART predict atherosclerosis lesions in HIV-infected patients Multivariable logistic analysis for independent predictors of coronary artery calcium G Guaraldi Atherosclerosis 2010

49. The inflammatory status 48 weeks after cART initiation is associated with an increased incidence of diabetes TT Brown Diabetes Care 2010

50. TL Stanley AIDS 2011