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Immune Activation/Inflammation and HIV Disease Inflammation and metabolic complications in HIV disease Prof. Georg Behrens Department for Clinical Immunology and Rheumatology Hannover Medical School Germany What comes first? Inflammation + metabolism + HIV 1. Metabolism and HIV 2. Current concepts outside HIV 3. Some experimental evidence Background 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 DA AIDS 12 (7): F51-F58, 1998 Lipodystrophy No Lipodystrophy HAART and cardiovascular disease Insulin resistance Type 2 diabetes HAART Dyslipidemia High FFA Small dense LDL Low HDL High TG CVD Peripheral fat loss Central obesity Inflammation Age, genetics, diet, hypertension, sedentery life style, renal disease… Inflammation and lipoatrophy Pro-inflammatory mediators • Macrophage infiltration2,3 Patient3 Increased number of macrophages3 • Increased IL-6 and TNF- expression3 Mitochondrial dysfunction X 400 • Altered mitochondrial morphology2 Control1 Compromised adipocyte life cycle • Decreased adipocyte size1-3 • Increased apoptosis4 X 400 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 Serum cytokine levels in patients with HIV lipodystrophy TNF-R2α (µg/ml) Patients with lipodystrophy Patients without lipodystrophy 800 600 400 200 200 400 600 800 1000 IFN-γ (µg/ml) Pontes-Cardoso L et al. Lipodystrophy Conference 2007 HAART and cardiovascular disease Insulin resistance Type 2 diabetes HAART Dyslipidemia High FFA Small dense LDL Low HDL High TG CVD Peripheral fat loss Central obesity ? Inflammation HAART and cardiovascular disease Insulin resistance Type 2 diabetes HAART Dyslipidemia High FFA Small dense LDL Low HDL High TG CVD Peripheral fat loss Central obesity ? HIV Inflammation Atherosclerosis and immune cells LPS oxLDL oxLDL Macrophages • Inflammation • Coagulation • Apoptosis Foam cells Modified from Hansson & Libby, Nat Rev Immunol 2006 Inflammation + metabolism + HIV 1. Metabolism and HIV 2. Current concepts outside HIV 3. Some experimental evidence Similarities of macrophages and adipocytes Pre-adipocytes ~1,500 ~1,400 ~6,000 Genes ~1,450 Adipocytes CCL2 IL-1 IL-6 IL-8 TNF- TLR2 TLR4 iNOS PAI 1 TGF Macrophages Modified from Hotamisligil GS, Erbay E Nat Rev Immunol 2008 Obesity + inflammatory infiltration of fat tissue Lean with normal metabolic function …… Obese with full metabolic dysfunction Necrotic adipocyte Adipocyte …… CD4+T cell Macrophage (M2) Crown-like structure Proinflammatory cytokines Leptin CCL2 TNF CXCL5 IL-6 IL-18 Modified from Ouchi N et al., Nat Rev Immunol 2011 Macrophages: M1 and M2 Anti-inflammatory TH2 (IL-4, IL13) M2 Macrophages (↓TNF, ↓ IL6, ↓ IL12) Pro-inflammatory TH1 (IFN-, LPS) M1 Macrophages (↑TNF, ↑IL6, ↑IL12) Inflammation and insulin resistance LPS lipids TLR MyD88 ROS Ubiquitin-mediated degradation FABP Lipids Modiefied from Tilg & Hotamisligil, Gastroenterology 2006 Inflammation + metabolism + HIV 1. Metabolism and HIV 2. Current concepts outside HIV 3. Some experimental evidence Adipose tissue inflammation in obesity Macrophages only? What about adaptive immunity (CD8 and CD4 T cells) or other immune cells? Lean, but not obese, fat is enriched for Tregs Normal mice Foxp3 Obese mice Lepob/+ Lepob/ob Expansion of Tregs in the fat improves insulin resistance! Feuerer M et al. Nat Med 2009 Obesity + inflammatory infiltration of fat tissue Lean Obese Inflammatory Macrophages (M1) Resident (M2) Macrophages Regulatory T cells (CD4+) ↓Tregs Modified from Lumeng CN, Nat Med 2009 CD8+ T cells recruit macrophages into fat tissue1 Normal chow High fat CD8 T cells 1Epididymal fat tissue of mice Nishimura S et al. Nat Med 2009 CD8+ T cells recruit macrophages into fat tissue1 Insulin tolerance CD8 Ab depletion DIO: Diet-induce obesity CD8+ T cell interact with adipocytes, recruit monocytes and induce macrophage differentitaion and activation Nishimura S et al. Nat Med 2009 Obesity + inflammatory infiltration of fat tissue Lean Obese Inflammatory Macrophages (M1) Resident (M2) Macrophages CCL2? Regulatory T cells (CD4+) ↓Tregs Effector T cells (CD8+) Modified from Lumeng CN, Nat Med 2009 Immune cells maintain lipid homeostasis Lean Resident (M2) Macrophages Eosinphils1 IL-4 Regulatory T cells (CD4+) Modified from Lumeng CN, Nat Med 2009 1Wu D et al. Science 2011;332:243-247 Bacterial endotoxins stimulate lipolysis via TLR4 Mice WT TLR4 -/- Zu L et al. J Biol Chem 2009 Inflammation + metabolism + HIV 1. Metabolism and HIV 2. Current concepts outside HIV 3. Some experimental evidence 4. Summary Inflammatory/metabolic organ damage Insulin resistance Type 2 diabetes HAART Dyslipidemia High FFA Small dense LDL Low HDL High TG CVD Peripheral fat loss Central obesity ? HIV Inflammation Microbial translocation NASH
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