Role of inflammation in the pathogenesis of age-related comorbidities Jacqueline Capeau INSERM U938, Université Pierre et Marie Curie Faculté de Médecine, site Saint-Antoine, Hôpital Tenon, Paris, France

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

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

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

Inflammation and the stress response R Medzhitov Cell 2010

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

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

X Chronic low-grade inflammation Not caused by classic inducers: infection and injury Due to tissue stress and malfunction?

« 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

Implication of inflammation in aging processes Salminen Cell Signal 2010

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

Gut-derived inflammation and metabolic risk

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

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

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

Inflammation, immune activation And cardio-vascular risk

Initiation of atherosclerosis : activation of macrophages AM LundbergClinicalImmunology 2010

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

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

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

Role of personal and life-style factors

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

HIV-infected patients 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 Premature aging 23

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

Increased levels of proinflammatory and prothrombotic markers in HIV-infected patients as compared to the general population Biomarkers Levels in SMART Study Participants Receiving Antiretroviral Therapy (ART) Who Had an HIV RNA Level ≤400 Copies/mL and Percentage Differences in Levels Versus CARDIA and MESA Study Participants Participants 33-44 years of age Participants 45-76 years of age Biomarker No. Median level [IQR] % Diff. (P) hsCRP, g/mL 140 2.13 (0.77-5.20) 40.2 (<.001) 293 2.83 (1.07-6.80) 37.8 (<.001) IL-6, pg/mL 139 1.89 (1.15-3.42) 39.0 (<.001) 291 2.64 (1.55-4.14) 60.1 (<.001) D-dimer, g/mL 0.21 (0.15-0.46) NA 0.29 (0.17-0.57) 49.1 (<.001) Cystatin C, mg/dL 86 0.90 (0.78-0.97) 130 1.00 (0.86-1.16) 20.9 (<.001) Data are the median level and (interquartile range [IQR]). CARDIA, Coronary Artery Development in Young Adults; Diff., difference; MESA, Multi-Ethnic Study of Atherosclerosis; NA, not available; SMART, Strategies for Management of Anti-Retroviral Therapy. J Neuhaus CID 2010

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

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

Virus and inflammation

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) IL6 <0.685 IL6 >0.685 CV copies/mL p=0.0408 CRPUS <1 CRPUS: 1-3 CRPUS >3 p=ns JP Bastard Workshop Adverse Drug ReactionComorbidities London 2010

ART and inflammation

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

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

Chronic immune activation and inflammation HIV Infection and replication Anti-HIV immunity Production of viral proteins Intestinal bacterial translocation Reactivation of other viruses Immune activation: Acquired and Innate Immunity Lymphocytes T Differentiation and senescence Proinflammatory cytokines secretion Chronic inflammation Immune depletion and immune senescence Non-AIDS defining morbidity and mortality D’après V Appay J Pathol 2008

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

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

Role of immune activation and inflammation in non-AIDS-defining mortality

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

NG Sandler CID 2011

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

RC Kaplan CID 2011

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

Role of bacterial translocation and immune activation In neurocognitive disorders

 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 increased even in mild forms of impairment, whether symptomatic or not H Carsenti-Dellamonica CROI 404

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Lipodystrophy worsen inflammatory state and metabolic disorders

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

Lipodystrophy and ART predict atherosclerosis lesions in HIV-infected patients OR Confidence interval P-value Male sex 2.8 1.3-6.1 0.009 Age per 1 year 1.12 1.07-1.17 <0.001 BMI 1.09 0.98-1.21 NS Chol T 0.99 0.99-1.01 HDL C 1.00 0.98-1.03 Hypertension 2.09 1.13-3.88 0.018 Exposure to ART, per 1 y 1.21 1.07-1.37 0.002 No lipodystrophy 1 ref Lipoatrophy 3.82 1.11-13.1 0.033 Lipohypertrophy 7.65 1.71-37.17 0.008 Mixed form 4.36 1.26-15.01 0.02 Multivariable logistic analysis for independent predictors of coronary artery calcium G Guaraldi Atherosclerosis 2010

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

TL Stanley AIDS 2011

TL Stanley AIDS 2011

Increased visceral adipose tissue is associated with increased 5-year mortality in the FRAM study R Scherzer AIDS 2011

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

What to do ?

Statins to decrease immune activation? JID 2011

Statins to decrease systemic inflammation VIHSTATINE: effect of statins 45 days (pravastatine and rosuvastatine) on CRP levels After 45 days of statin therapy the median change in the hsCRP concentration was -20% overall (-0.6 mg/l, p<0.001) respectively -22% and -16% in the pravastatin and rosuvastatin groups (p = 0.932). The LDL-c level fell by a median of 19% in the pravastatin group and 37% in the rosuvastatin group (P < 0.001 for both) The triglyceride levels fell by respectively 3% and 26% (p = 0.008 for both) There was no correlation between the change in the hsCRP level and changes in the markers of lipid, endothelial and inflammatory status E Aslangul AIDS 2011

Chronic immune activation and inflammation HIV Infection and replication Immune activation: Acquired and Innate Immunity Chronic inflammation Immune depletion and immune senescence Lipodystrophy Age Personal factors Treatment Non-AIDS defining morbidity and mortality D’après V Appay J Pathol 2008

Prelamin A : a senescence protein Involved in progeria 11-year children Other syndromes of premature aging linked to defects in the enzyme that maturates prelamin A to lamin A 59

Accumulation of farnesylated prelamin A results in accelerated aging From Liu, Nature Medicine 2005 60

Prelamin A a biomarker of vascular aging in human subjects Aged vascular smooth muscle cells accumulate prelamin A and exhibit nuclear morphology defects and senescence markers CD Ragnauth Circulation 2010

Some PIs induce prelamin A accumulation and cellular senescence in endothelial cells IL-6 secretion C Lefèvre ATVB, 2010 Some PIs inhibit ZMPSTE24 and lead to prelamin A accumulation (M Caron AIDS 2003, M Caron Cell Death Diff 2007, C Coffinier PNAS 2007) 62

PBMC from HIV-infected patients under PI/r express prelamin A and senescence markers HIV+ patients under NRTI without PI HIV+ patients under PI/r

The process of prelamin A maturation into lamin A: effect of statins and farnesyl-transferase inhibitors (FTI) statin FTI C Navarro Hum Mol Gen 2006

Decreased expression of senescence markers in PBMC from HIV-infected patients under PI/r and a statin

Hypothetical mechanisms of RTV-boosted PI toxicity in endothelial cells Drugs Inhibition of ZMP-STE24 Accumulation of farnesylated prelamin A Increased ROS Cellular senescence Activation of NFkB Increased IL6, IL8, MCP-1 Systemic low grade inflammation

Hypothetical mechanisms of RTV-boosted PI toxicity in endothelial cells: beneficial effect of statins Drugs Inhibition of ZMP-STE24 Statins Accumulation of farnesylated prelamin A Increased ROS Cellular senescence Activation of NFkB Increased IL6, IL8, MCP-1 Systemic low grade inflammation

Accelerated aging model in HIV infection role of immune activation/senescence S Desai and A Landay Curr HIV/AIDS Res 2010

Neurodegenerative diseases , immune activation and inflammation S Amor Immunology 2010

Inflammation and activation of stress signals induces insulin resistance NFkB G Hotamisligil Cell 2010

Inflammation and aging Chronic low-grade inflammation, « inflammaging » Low-grade Controlled Asymptomatic Chronic Systemic  cytokines (IL6, IL8) and coagulation factors Subclinical infection with common viruses (CMV) Genetic components  ROS  adaptative immunity « released » innate immunity: increased pro-inflammatory responses Frailty, age-related diseases Acute inflammation Redness Swelling Heat Pain Local Resolutive Giunta B J Neuroinflammation, 2008

High-fat food, antibiotics, dietary fibers (prebiotics) and bacterial additives (probiotics) can change the intestinal microflora ecology, leading to an unbalanced Firmicutes –Bacteroidetes ratio. Diabetes, Obesity M Serino Diabetes Metab 2009

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