Why may non-communicable diseases occur more often in those with HIV infection?

1. Why may non-communicable diseases occur more often in those with HIV infection? Suzanne Crowe Co-Head Centre for Virology, Burnet Institute Consultant Infectious Diseases Physician, The Alfred Hospital Melbourne

2. Today’s presentation • What do HIV and healthy ageing have in common? • What is evidenceof prematurely ageing of the immune system by HIV? • What factors increase the risk of non-communicable diseases in HIV infection ? • What roledo monocytes play? • Thelink betweenHIV, monocytes, immune ageing and non-communicable diseases

3. What do HIV infection and healthy ageing have in common?

4. Immunological and clinical manifestations shared by HIV+ and healthy elderly Immunologic characteristics Naïve T cells T cell diversity Memory cells Differentiated, senescent CD8+ T cells (eg CD28-CD57+) Telomere length CD16+ monocytes monocyte function Functional immune defects Replicative capacity Tumour surveillance Pathogen protection Chronic inflammation Clinical manifestations Vaccine responses Infections Age-associated non communicable diseases (eg CVD, non-AIDS cancers, bone/kidney disease, frailty, neurocognitive decline)

5. Similarities between HIV infection and normal ageing Ageing HIV Immunologic changes Chronic immune activation/inflammation • : most relevant Non-communicable diseases

6. Similar comorbidities in HIV infection and normal ageing Ageing HIV Immunologic changes Chronic immune activation/inflammation • Atherosclerosis • Diabetes • Cognitive decline • Osteoporosis • Malignancy • Renal/liver disease • Atherosclerosis • Diabetes • Cognitive decline • Osteoporosis • Malignancy • Renal/liver disease Non-communicable diseases

7. HIV infection and normal ageing: shared immune changes Ageing HIV • Shared characteristics: • ↑ senescent T cells (CD28-/CD57+) • ↓ telomere length • ↑ pro-inflammatory (CD16+) monocytes Immunologic changes Chronic immune activation/inflammation • Shared biomarkers: • ↑ inflammation • Eg CRP, IL-6 • ↑ coagulation • Eg D-dimer Non-communicable diseases • Brenchley, et al Nature Med 2006 ; Jianget al J Infect Dis 2009; Hearps A et al Ageing Cell 2012

8. What evidence do we have that HIV is associated with accelerated ageing?

9. Shortened telomeres in young HIV+ and in healthy elderly Telomere length is shorter in healthy elderly and young HIV+ on cART with VL<50 • Short pieces of DNA (hexonucleotide repeats) at ends of chromosomes • Protect the DNA • Telomeres shorten during each cell division • If telomeres shorten, cells age • Telomere length is a classical marker of immune ageing VL<50 Median age: 28 72 29 years Range (yrs): 20-32 70-82 27-45 Hearps A et al AIDS 2012; 26: 843

10. TERT is inhibited by NRTIs • Telomere length is maintained by telomerase reverse transcriptase (TERT) which “repairs”telomeres • NRTIs inhibit TERT in vivo and in vitro • NRTIs contribute to immune ageing in HIV+ on cART Inhibition of TERT in vitro: TDF > 3TC=FTC=AZT > ABC Leeansyah E et al 2012; slide provided by Sharon Lewin Calado and Young. N Engl J Med 2009:361:2353–65

11. Telomere length is also significantly reduced in cART naïve HIV+ individuals: role of HIV HIV negative HIV positive % telomere length in CD31+ naïve T-cells • Why? • Increased T-cell turnover • Direct inhibition of telomerase RT (TERT) by HIV Young Old cART naïve, within 1-3 yrsof infection Rickabaughet al. Plos One2011; Dagaraget al. J Immunol2004 Slide provided by Sharon Lewin

12. What factors in HIV infection increase risk of non-communicable diseases?

13. Risk for non-communicable diseases in HIV+ individuals and healthy elderly Ageing HIV Immunologic changes Chronic immune activation/inflammation Traditional risk factors CVD, cancer, bone disease, dementia, Traditional risk factors CVD, cancer, bone disease, dementia, Non-communicable diseases

14. Risk of CVD due to HIV is similar to risk from smoking Diabetes Abdominal obesity Smoking 2.37 1.62 2.83 HIV infection Cardiac events 2.07 0.89 0.89 Good diet & exercise 0.91 1.91 3.25 Modest EtOH High blood pressure High LDL/HDL ratio Yusuf et al., Lancet 2004 364 937 Triant et al., JAIDS 2009 51 268

15. Risk for non-communicable diseases in HIV+ individuals and healthy elderly Ageing HIV Immunologic changes HIV+: ↑ prevalence of some traditional risk factors for eg CVD Smoking Diabetes mellitus Insulin resistance Dyslipidemia etc Chronic immune activation/inflammation Non-communicable diseases

16. Drivers of NCDs in healthy elderly and HIV are partly similar but differently weighted, some HIV specific • Potential drivers: • Cumulative effects of lifelong antigenic stress • Thymic involution • Genetic role • Oxidative stress • Chronic endotoxemia • Potential drivers: • HIV viremia • Microbial translocation and endotoxemia • Chronic co-infections • Cumulative effects of life-long antigens • Thymic involution • Oxidative stress Ageing HIV Immunologic changes Chronic immune activation/inflammation • : Non-communicable diseases • Derhovanessian, et al, (2009) CurrOpinImmunol; Linton, et a., (2004) Nat Immunol; • Brenchley, et a., (2006) Nature Med; Jianget al (2009) J Infect Dis

17. Drivers of NCDs in healthy elderly and HIV: similarities and differences • Potential drivers: • Cumulative effects of lifelong antigenic stress • Thymic involution • Genetic role • Oxidative stress • Chronic endotoxemia • Potential drivers: • HIV viremia • Microbial translocation and endotoxemia • Chronic co-infections • Cumulative effects of life-long antigens • Thymic involution • Oxidative stress Ageing HIV Immunologic changes Chronic immune activation/inflammation • : Non-communicable diseases • Derhovanessian, et al, (2009) CurrOpinImmunol; Linton, et a., (2004) Nat Immunol; • Brenchley, et a., (2006) Nature Med; Jianget al (2009) J Infect Dis

18. Chronic endotoxemiapersists during HIV-1 infection • Depletion of CCR5+ CD4+ T cells from gut mucosal tissue • Leakage of microbial products across LP • Guadalupe et al JV 2003, • Brenchley et al Nature Med 2006 Chronic endotoxemia in elderly and HIV+, not reversed by cART HIV- HIV+ Colon lamina propria, acute/early HIV Red=CD4+ T cells Mehandru et al., J Exp Med (2004) (Hearps A et al AIDS 2012

19. HIV viremia is associated with elevated markers of inflammation and coagulation • Veterans Ageing Cohort Study • n = 1525 HIV+ participants • n = 843 HIV- participants (age-matched) • HIV+ VL>500 copies/ml or CD4<200 cells/ul Armah KA Clin Infect Dis 2012 55: 126

20. Residual viremia (VL<50) linked with immune activation and non-communicable diseases? On cART VL<50 • on cART • generally partial reversal of markers of immune activation • Lower levels of activated (CD38+HLA-DR+) CD4+ and CD8+ T cells compared with non-controllers1, 2 • Higher levels of T cell activation and senescent (CD28-CD57+) T cells3,4 • Elevated risk of sub-clinical atherosclerosis compared with HIV uninfected5 HIV elite controllers: VL<50 in absence of ART: conflicting data 1Card CM et al JAIDS 2012 59:427 2Owen RE AIDS 2010 24:1095; 3 Ruiz-Mateos E et al Curr HIV Res 2010 8:471; 4Hsue P AIDS 2006; 5Hsue P et al AIDS 2009 23:1059

21. CMV linked with immune activation and NCD • CMV induces CD8+ T cell activation that is suppressed by valganciclovir in HIV+4 • Activation of senescence signaling pathways in elderly patients with CMV1 • Shortened telomere length of leukocytes in CMV infection2 • Increased CMV IgGtitre associated with atherosclerosis in HIV+ women3 1Henson SM et al CurrOpinImmmuol 2012; 2 Van de Berg P et al J Immunol 2010;184:3417 3Parrinello CM et al J Infect Dis 2012 205:1788; Hunt et al JID 2011 203: 1474

22. What role do monocytes play with NCD in HIV+?

23. Monocyte activation is likely to be central to development of non-communicable diseases LPS HIV Co-infection Monocyte activation Pro-inflammatory cytokine production Altered phenotype Reduced function Altered coagulation Telomere shortening fibrosis Inflammation Immune activation Immune ageing NCD

24. HIV accelerates innate immune changes Increased pro-inflammatory CD16+ monocytes in young HIV+ and the healthy elderly • HIV induces age-related changes to monocytes • Some (not all) changes persist despite cART • In HIV+ men1 • In HIV+ women2 • Changes appear approx10-14 years earlier in HIV+ than HIV- women2. • 1. HearpsA et al AIDS 2012; 26: • 2. Martin G et al 2012

25. Emerging “immune signature” to predict immune ageing and risk of age associated diseases HIV Monocyte activation eg sCD14, CD11b, neopterin Monocyte marker of inflammation eg sCD163 Markers of microbial translocation egLPS Markers of altered coagulation egD-dimer, TF Markers of T cell senescence eg CD28-CD57+ CD8+ GAP “Signature of accelerated immune ageing & risk of NCD”

26. the linkbetweenmonocytes, Immune ageing and non-communicable diseases such as CVD in HIV+

27. Monocytes are central to pathogenesis of atherosclerosis • Foam cells are lipid laden macrophages • Accumulate in intima • Key feature of atherosclerotic plaques • Foam cells secrete inflammatory mediators • that recruit more monocytes, promote plaque progression Westhorpe, Dufour, Maisa, Jaworowski, Crowe, Muller: 2012 in press

28. Atheromatousplaque development:role of monocytes Plaque regression Systemic inflammation Monocyte egress Pro-inflammatory cytokines and Tissue factor Monocyte activation dyslipidemia Monocyte adherence Plaque growth destabilisation & rupture LDL Endothelial activation MMPs Foam cell Monocyte maturation & lipid uptake oxLDL LDL modification Apoptosis, necrosis cholesterol efflux Plaque

29. Impact of HIV on atheromatous plaque development Microbial translocation endotoxemia Plaque regression Systemic inflammation HIV Monocyte egress HIV Pro-inflammatory cytokines and Tissue factor Monocyte activation HIV dyslipidemia Monocyte adherence Plaque growth destabilisation & rupture HIV LDL Endothelial activation MMPs Foam cell Monocyte maturation & lipid uptake oxLDL LDL modification HIV Apoptosis, necrosis cholesterol efflux Plaque

30. Why may NCD occur more often in HIV+? multifactorial and complex HIV Certain ARVs An ageing population Chronic immune activation and inflammation Lifestyle factors Increased risk of non-communicable age-associated diseases eg CVD

31. Acknowledgements Dmitri Sviridov • IDU • Sharon Lewin • Jenny Hoy • Julian Elliott • Kate Cherry • Janine Trevillyon Anthony Jaworowski Anna Hearps Genevieve Martin Clovis Palmer GregorLichtfuss Tom Angelovich YagmurFarsakoglu Wan-Jung Cheng Jingling Zhou Clare Westhorpe Alan Landay • Cardiovascular Medicine • Anthony Dart • Liz Dewar • SofieKarapanagiotidis William Muller The HaCH Study volunteers Funding from • Centre for Population Health • Tim Spelman “The Ageing Team”