1. 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

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 classic inducers: 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 metabolic risk

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-vascular risk

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 Coll Cardiology 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. 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

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

25. 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 years of age
Participants years of age
Biomarker
No.
Median level [IQR]
% Diff. (P)
hsCRP, g/mL
140
2.13 ( )
40.2 (<.001)
293
2.83 ( )
37.8 (<.001)
IL-6, pg/mL
139
1.89 ( )
39.0 (<.001)
291
2.64 ( )
60.1 (<.001)
D-dimer, g/mL
0.21 ( ) NA
0.29 ( )
49.1 (<.001)
Cystatin C, mg/dL 86
0.90 ( )
130
1.00 ( )
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

26. 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

27. 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

28. Virus and inflammation

29. 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

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-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

34. 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

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. Role of 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, 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

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 = ) 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

45. J Lyons CROI 2011 # 405

46. Lipodystrophy worsen inflammatory state and metabolic disorders

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 patientsOR
Confidence interval
P-value
Male sex
2.8
0.009
Age per 1 year
1.12
<0.001
BMI
1.09 NS
Chol T
0.99
HDL C
1.00
Hypertension
2.09
0.018
Exposure to ART, per 1 y
1.21
0.002
No lipodystrophy
1 ref
Lipoatrophy
3.82
0.033
Lipohypertrophy
7.65
0.008
Mixed form
4.36
0.02
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

51. TL Stanley AIDS 2011

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

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

54. What to do ?

55. Statins to decrease immune activation?
JID 2011

56. 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 < for both)
The triglyceride levels fell by respectively 3% and 26% (p = 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

57. 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

59. 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

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

61. 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

62. 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

63. 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

64. 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

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

66. 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

67. 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

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

69. Neurodegenerative diseases , immune activation and inflammation
S Amor Immunology 2010

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

72. 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

73. 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

74. J Lyons CROI 2011 # 405