Immune Activation/Inflammation and HIV Disease

1. 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

3. What comes first?

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

5. Lipodystrophy No Lipodystrophy 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

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

7. 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 Inflammation and lipoatrophy Patient3 Increased number of macrophages3 X 400 Control1 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

8. Patients with lipodystrophy Patients without lipodystrophy Serum cytokine levels in patients with HIV lipodystrophy 800 TNF-R2α(µg/ml) 600 400 200 200 400 600 800 1000 IFN-γ(µg/ml) Pontes-Cardoso L et al. Lipodystrophy Conference 2007

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

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

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

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

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

14. Obese with full metabolic dysfunction Necrotic adipocyte Crown-like structure Proinflammatory cytokines Leptin CCL2 TNF CXCL5 IL-6 IL-18 Obesity + inflammatory infiltration of fat tissue Lean with normal metabolic function …… Adipocyte …… CD4+T cell Macrophage (M2) Modified from Ouchi N et al., Nat Rev Immunol 2011

15. 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)

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

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

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

19. 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

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

21. 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

22. 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

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

24. Immune cells maintain lipid homeostasis Lean Eosinphils1 Resident (M2) Macrophages IL-4 Regulatory T cells (CD4+) Modified from Lumeng CN, Nat Med 2009 1Wu D et al. Science 2011;332:243-247

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

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

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