1. Immune Activation/Inflammation and HIV Disease Prof. Georg Behrens Department for Clinical Immunology and Rheumatology Hannover Medical School Germany Inflammation and metabolic complications in HIV disease

3. What comes first?

4. Inflammation + metabolism + HIV 3. Some experimental evidence 1. Metabolism and HIV 2. Current concepts outside HIV

5. 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 DA AIDS 12 (7): F51-F58, 1998 Background

6. HAART and cardiovascular disease Insulin resistance Type 2 diabetes Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG Dyslipidemia High FFA Small dense LDL Low HDL High TG Peripheral fat loss Central obesity Peripheral fat loss Central obesity HAART CVD Age, genetics, diet, hypertension, sedentery life style, renal disease… Inflammation

7. Inflammation and lipoatrophy Pro-inflammatory mediators Macrophage infiltration 2,3 Increased IL-6 and TNF-  expression 3 Mitochondrial dysfunction Altered mitochondrial morphology 2 Compromised adipocyte life cycle Decreased adipocyte size 1-3 Increased apoptosis 4 X 400 Control 1 Patient 3 X 400 Increased number of macrophages 3 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

8. Pontes-Cardoso L et al. Lipodystrophy Conference 2007 Serum cytokine levels in patients with HIV lipodystrophy 2004006008001000 IFN- γ (µg/ml) 200 400 600 800 TNF-R2 α (µg/ml) Patients with lipodystrophy Patients without lipodystrophy

9. Insulin resistance Type 2 diabetes Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG Dyslipidemia High FFA Small dense LDL Low HDL High TG HAART HAART and cardiovascular disease CVD ? Inflammation Peripheral fat loss Central obesity Peripheral fat loss Central obesity

10. Insulin resistance Type 2 diabetes Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG Dyslipidemia High FFA Small dense LDL Low HDL High TG HAART HAART and cardiovascular disease CVD HIV ? Inflammation Peripheral fat loss Central obesity Peripheral fat loss Central obesity

11. Atherosclerosis and immune cells Modified from Hansson & Libby, Nat Rev Immunol 2006 oxLDL LPS oxLDL Foam cells Macrophages Inflammation Coagulation Apoptosis

12. Inflammation + metabolism + HIV 3. Some experimental evidence 1. Metabolism and HIV 2. Current concepts outside HIV

13. Modified from Hotamisligil GS, Erbay E Nat Rev Immunol 2008 Macrophages Adipocytes Pre-adipocytes CCL2 IL-1  IL-6 IL-8 TNF-  TLR2 TLR4 iNOS PAI 1 TGF Similarities of macrophages and adipocytes ~6,000 Genes ~1,500 ~1,400 ~1,450

14. Adipocyte Macrophage (M2) CD4 + T cell …… Lean with normal metabolic function …… Necrotic adipocyte Crown-like structure Obese with full metabolic dysfunction Proinflammatory cytokines LeptinCCL2TNF CXCL5IL-6IL-18 Modified from Ouchi N et al., Nat Rev Immunol 2011 Obesity + inflammatory infiltration of fat tissue

15. T H 2 (IL-4, IL13) Anti-inflammatory M2 Macrophages (↓TNF, ↓ IL6, ↓ IL12) T H 1 (IFN- , LPS) Pro-inflammatory M1 Macrophages (↑TNF, ↑IL6, ↑IL12) Macrophages: M1 and M2

16. Modiefied from Tilg & Hotamisligil, Gastroenterology 2006 Ubiquitin-mediated degradation Lipids ROS FABP TLR LPS lipids MyD88 Inflammation and insulin resistance

17. Inflammation + metabolism + HIV 3. Some experimental evidence 1. Metabolism and HIV 2. Current concepts outside HIV

18. Macrophages only? Adipose tissue inflammation in obesity What about adaptive immunity (CD8 and CD4 T cells) or other immune cells?

19. Feuerer M et al. Nat Med 2009 Foxp3 Lean, but not obese, fat is enriched for T regs Expansion of T regs in the fat improves insulin resistance! Lep ob/ob Lep ob/+ Normal mice Obese mice

20. Regulatory T cells (CD4 + ) Modified from Lumeng CN, Nat Med 2009 ↓T regs Resident (M2) Macrophages Inflammatory Macrophages (M1) LeanObese Obesity + inflammatory infiltration of fat tissue

21. Nishimura S et al. Nat Med 2009 CD8 + T cells recruit macrophages into fat tissue 1 CD8 T cells Normal chow 1 Epididymal fat tissue of mice High fat

22. 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 tissue 1

23. Regulatory T cells (CD4 + ) Modified from Lumeng CN, Nat Med 2009 ↓T regs Effector T cells (CD8 + ) Resident (M2) Macrophages Inflammatory Macrophages (M1) CCL2? LeanObese Obesity + inflammatory infiltration of fat tissue

24. Regulatory T cells (CD4 + ) Modified from Lumeng CN, Nat Med 2009 Resident (M2) Macrophages Lean Eosinphils 1 IL-4 Immune cells maintain lipid homeostasis 1 Wu D et al. Science 2011;332:243-247

25. Zu L et al. J Biol Chem 2009 Bacterial endotoxins stimulate lipolysis via TLR4 Mice WTTLR4 -/-

26. Inflammation + metabolism + HIV 3. Some experimental evidence 1. Metabolism and HIV 4. Summary 2. Current concepts outside HIV

27. Insulin resistance Type 2 diabetes Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG Dyslipidemia High FFA Small dense LDL Low HDL High TG HAART Inflammatory/metabolic organ damage CVD HIV ? Inflammation Peripheral fat loss Central obesity Peripheral fat loss Central obesity NASH Microbial translocation