Immune Activation/Inflammation and HIV Disease
Prof. Georg BehrensDepartment for Clinical Immunology and RheumatologyHannover Medical SchoolGermany
Inflammation and metabolic complications in HIV disease
What comes first?
Inflammation + metabolism + HIV
3. Some experimental evidence
1. Metabolism and HIV
2. Current concepts outside HIV
Lipodystrophy No Lipodystrophy
A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.Carr A, Samaras K, Burton S, Law, M, Freund J, Chisholm DJ, Cooper DAAIDS 12 (7): F51-F58, 1998
Background
HAART and cardiovascular disease
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
Peripheral fat lossCentral obesity
HAARTCVD
Age, genetics, diet, hypertension, sedentery life style, renal disease…
Inflammation
Inflammation and lipoatrophy
Pro-inflammatory mediators• Macrophage infiltration2,3
• Increased IL-6 and TNF- expression3
Mitochondrial dysfunction• Altered mitochondrial
morphology2
Compromised adipocyte life cycle
• Decreased adipocyte size1-3
• Increased apoptosis4
X 400
Control1
Patient3
X 400
Increased number of macrophages3
1. Bastard, JP et al. Lancet. 2002; 2. Nolan D et al. AIDS. 2003; 3. Veronique J & Cervera P, et al. Antivir Ther. 2004; 4. Domingo, P et al. AIDS. 1999
Pontes-Cardoso L et al. Lipodystrophy Conference 2007
Serum cytokine levels in patients with HIV lipodystrophy
200 400 600 800 1000
IFN-γ (µg/ml)
200
400
600
800TN
F-R
2α (µ
g/m
l)
Patients with lipodystrophyPatients without lipodystrophy
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
HAART
HAART and cardiovascular disease
CVD
?Inflammation
Peripheral fat lossCentral obesity
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
HAART
HAART and cardiovascular disease
CVD
HIV ?Inflammation
Peripheral fat lossCentral obesity
Atherosclerosis and immune cells
Modified from Hansson & Libby, Nat Rev Immunol 2006
oxLDL
LPSoxLDL
Foam cells
Macrophages• Inflammation• Coagulation• Apoptosis
Inflammation + metabolism + HIV
3. Some experimental evidence
1. Metabolism and HIV
2. Current concepts outside HIV
Modified from Hotamisligil GS, Erbay E Nat Rev Immunol 2008
Macrophages
Adipocytes
Pre-adipocytes
CCL2IL-1IL-6IL-8
TNF-
TLR2TLR4iNOSPAI 1TGF
Similarities of macrophages and adipocytes
~6,000Genes
~1,500
~1,400
~1,450
Adipocyte
Macrophage (M2)
CD4+T cell
……
Lean with normal metabolic function
……
Necrotic adipocyte
Crown-like structure
Obese with full metabolic dysfunction
Proinflammatory cytokinesLeptin CCL2 TNFCXCL5 IL-6 IL-18
Modified from Ouchi N et al., Nat Rev Immunol 2011
Obesity + inflammatory infiltration of fat tissue
TH2
(IL-4, IL13)
Anti-inflammatory
M2 Macrophages
(↓TNF, ↓ IL6, ↓ IL12)
TH1
(IFN-, LPS)
Pro-inflammatory
M1 Macrophages
(↑TNF, ↑IL6, ↑IL12)
Macrophages: M1 and M2
Modiefied from Tilg & Hotamisligil, Gastroenterology 2006
Ubiquitin-mediateddegradation
Lipids
ROS
FABP
TLR
LPSlipids
MyD88
Inflammation and insulin resistance
Inflammation + metabolism + HIV
3. Some experimental evidence
1. Metabolism and HIV
2. Current concepts outside HIV
Macrophages only?
Adipose tissue inflammation in obesity
What about adaptive immunity (CD8 and CD4 T cells)or other immune cells?
Feuerer M et al. Nat Med 2009
Foxp3
Lean, but not obese, fat is enriched for Tregs
Expansion of Tregs in the fat improves insulin resistance!
Lepob/ob
Lepob/+
Normal mice
Obese mice
RegulatoryT cells (CD4+)
Modified from Lumeng CN, Nat Med 2009
↓Tregs
Resident (M2)Macrophages
InflammatoryMacrophages
(M1)
Lean Obese
Obesity + inflammatory infiltration of fat tissue
Nishimura S et al. Nat Med 2009
CD8+ T cells recruit macrophages into fat tissue1
CD8 T cells
Normal chow
1Epididymal fat tissue of mice
High fat
Nishimura S et al. Nat Med 2009
DIO: Diet-induce obesity
CD8 Ab depletion
Insulin tolerance
CD8+ T cell interact with adipocytes, recruit monocytes and induce macrophage differentitaion and activation
CD8+ T cells recruit macrophages into fat tissue1
RegulatoryT cells (CD4+)
Modified from Lumeng CN, Nat Med 2009
↓Tregs EffectorT cells (CD8+)
Resident (M2)Macrophages
InflammatoryMacrophages
(M1)
CCL2?
Lean Obese
Obesity + inflammatory infiltration of fat tissue
RegulatoryT cells (CD4+)
Modified from Lumeng CN, Nat Med 2009
Resident (M2)Macrophages
Lean Eosinphils1
IL-4
Immune cells maintain lipid homeostasis
1Wu D et al. Science 2011;332:243-247
Zu L et al. J Biol Chem 2009
Bacterial endotoxins stimulate lipolysis via TLR4
Mice
WT TLR4 -/-
Inflammation + metabolism + HIV
3. Some experimental evidence
1. Metabolism and HIV
4. Summary
2. Current concepts outside HIV
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
HAART
Inflammatory/metabolic organ damage
CVD
HIV ?Inflammation
Peripheral fat lossCentral obesity
NASHNASH
Microbial translocation
