Why may non-communicable diseases occur more often in those

with HIV infection?

Suzanne CroweCo-Head Centre for Virology, Burnet Institute

Consultant Infectious Diseases Physician, The Alfred HospitalMelbourne

Today’s presentation

• What do HIV and healthy ageing have in common?• What is evidence of prematurely ageing of the

immune system by HIV? • What factors increase the risk of non-communicable

diseases in HIV infection ?• What role do monocytes play? • The link between HIV, monocytes, immune ageing

and non-communicable diseases

What do

HIV infection and

healthy ageing have in common?

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)

Ageing HIV

Non-communicable

diseases

Chronic immune activation/inflamm

ation

Immunologic changes

:

Similarities between HIV infection and normal ageing

most relevant

Ageing HIV

Non-communicable

diseases

Chronic immune activation/inflamm

ation

Immunologic changes

• Atherosclerosis• Diabetes• Cognitive decline• Osteoporosis • Malignancy• Renal/liver disease

Similar comorbidities in HIV infection and normal ageing

• Atherosclerosis• Diabetes• Cognitive decline• Osteoporosis • Malignancy• Renal/liver disease

Ageing HIV

Non-communicable

diseases

Chronic immune activation/inflamm

ation

Immunologic changes

Shared characteristics:• ↑ senescent T cells

(CD28-/CD57+) • ↓ telomere length• ↑ pro-inflammatory

(CD16+) monocytes

Brenchley, et al Nature Med 2006 ; Jiang et al J Infect Dis 2009; Hearps A et al Ageing Cell 2012

HIV infection and normal ageing: shared immune changes

Shared biomarkers:• ↑ inflammation

• Eg CRP, IL-6• ↑ coagulation

• Eg D-dimer

What evidence do we have that HIV is associated

with accelerated ageing?

Shortened telomeres in young HIV+ and in healthy elderly

Hearps A et al AIDS 2012; 26: 843

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 ageingMedian age: 28 72 29 yearsRange (yrs): 20-32 70-82 27-45

VL<50

•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

Calado and Young. N Engl J Med 2009:361:2353–65

TERT is inhibited by NRTIs

Inhibition of TERT in vitro: TDF > 3TC=FTC=AZT > ABC

Leeansyah E et al 2012; slide provided by Sharon Lewin

Telomere length is also significantly reduced in cART naïve HIV+ individuals: role of HIV

Rickabaugh et al. Plos One 2011; Dagarag et al. J Immunol 2004

cART naïve, within 1-3 yrs of infection

Young Old

% t

elom

ere

leng

th in

CD

31+

naï

ve T

-cel

ls

HIV negative

HIV positive

Why?• Increased T-cell turnover • Direct inhibition of telomerase

RT (TERT) by HIV

Slide provided by Sharon Lewin

What factors in

HIV infection increase risk of non-communicable diseases?

Ageing HIV

Non-communicable

diseases

Chronic immune activation/inflamm

ation

Immunologic changes

Risk for non-communicable diseases in HIV+ individuals and healthy elderly

Traditional risk factorsCVD, cancer,bone disease, dementia,

Traditional risk factorsCVD, cancer,bone disease, dementia,

Risk of CVD due to HIV is similar to risk from smoking

Yusuf et al., Lancet 2004 364 937Triant et al., JAIDS 2009 51 268

Cardiac events

Smoking

High blood pressure

Diabetes Abdominal obesity

Good diet & exercise

2.83

ModestEtOH

High LDL/HDL

ratio

HIV infection

2.37

3.25

1.62

0.911.91

2.07 0.890.89

Ageing HIV

Non-communicable

diseases

Chronic immune activation/inflamm

ation

Immunologic changes

HIV+: ↑ prevalence of some traditional risk factors for eg CVD SmokingDiabetes mellitusInsulin resistanceDyslipidemia etc

Risk for non-communicable diseases in HIV+ individuals and healthy elderly

Ageing HIV

Non-communicable

diseases

Chronic immune activation/inflamm

ation

Immunologic changes

:

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

Derhovanessian, et al, (2009) Curr Opin Immunol; Linton, et a., (2004) Nat Immunol; Brenchley, et a., (2006) Nature Med; Jiang et al (2009) J Infect Dis

Drivers of NCDs in healthy elderly and HIV are partly similar but differently weighted, some HIV specific

Ageing HIV

Non-communicable

diseases

Chronic immune activation/inflamm

ation

Immunologic changes

:

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

Derhovanessian, et al, (2009) Curr Opin Immunol; Linton, et a., (2004) Nat Immunol; Brenchley, et a., (2006) Nature Med; Jiang et al (2009) J Infect Dis

Drivers of NCDs in healthy elderly and HIV: similarities and differences

Chronic endotoxemia persists during HIV-1 infection

Mehandru et al., J Exp Med (2004)

HIV-

HIV+

Chronic endotoxemia in elderly and HIV+, not reversed by cART

(Hearps A et al AIDS 2012

•Depletion of CCR5+ CD4+ T cells from gut mucosal tissue•Leakage of microbial products across LP

Colon lamina propria, acute/early HIVRed=CD4+ T cells

Guadalupe et al JV 2003, Brenchley et al Nature Med 2006

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/ulHIV+ (OR, 95% CI) HIV- (OR, 95% CI)

Elevated IL-6 2.25; 1/60-3.16 1.54; 1.14-2.09

Elevated D-dimer 1.97; 1.44-2.71 1.68; 1.22-2.32

Armah KA Clin Infect Dis 2012 55: 126

Residual viremia (VL<50) linked with immune activation and non-communicable diseases?

• 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

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

HIV elite controllers: VL<50 in absence of ART: conflicting data

On cART VL<50

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 IgG titre associated with atherosclerosis in HIV+ women3

1Henson SM et al Curr Opin Immmuol 2012; 2 Van de Berg P et al J Immunol 2010;184:34173 Parrinello CM et al J Infect Dis 2012 205:1788; Hunt et al JID 2011 203: 1474

What role do

monocytesplay with NCD in

HIV+?

Monocyte activation is likely to be central to development of non-communicable diseases

Immune ageing NCD

Inflammation Immune activation Telomere shortening

LPS HIV Co-infection

Monocyte activation

Pro-inflammatory cytokine production

Altered phenotype Reduced

functionAltered

coagulation

fibrosis

HIV accelerates innate immune changes

• HIV induces age-related changes to monocytes

• Some (not all) changes persist despite cART– In HIV+ men1

– In HIV+ women2

• Changes appear approx 10-14 years earlier in HIV+ than HIV- women2.

Increased pro-inflammatory CD16+ monocytes in young HIV+

and the healthy elderly

1. Hearps A et al AIDS 2012; 26: 2. Martin G et al 2012

“Signature of accelerated

immune ageing & risk of NCD”

Emerging “immune signature” to predict immune ageing and risk of age associated diseases

Monocyte activationeg sCD14, CD11b,

neopterinMarkers of microbial

translocation eg LPSMarkers of altered

coagulation eg D-dimer, TF

Markers of T cell senescence

eg CD28-CD57+ CD8+

HIVMonocyte marker of inflammation

eg sCD163

GAP

the link between

monocytes, Immune ageing and non-communicable diseases such as CVD in HIV+

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

LDL

LDLmodification

dyslipidemia

Endothelial activation

Plaque

Monocyte adherence

Systemic inflammation

Monocyte activation

Monocyte maturation & lipid uptake

Foam cell

Monocyte egress

Plaque regression

Pro-inflammatory cytokines

and Tissue factor

Plaque growthdestabilisation

& rupture

Apoptosis, necrosis

MMPs

Atheromatous plaque development: role of monocytes

oxLDL

cholesterol efflux

LDL

LDLmodification

dyslipidemia

Endothelial activation

Plaque

Monocyte adherence

Systemic inflammation

Monocyte activation

Monocyte maturation & lipid uptake

Foam cell

Monocyte egress

Plaque regression

Pro-inflammatory cytokines

and Tissue factor

Plaque growthdestabilisation

& rupture

Apoptosis, necrosis

MMPs

Impact of HIV on atheromatous plaque development

HIV

Microbial translocation endotoxemia

HIV

oxLDL

HIV

HIV

cholesterol efflux

HIV

Why may NCD occur more often in HIV+? multifactorial and complex

Chronic immune activation and inflammation

Certain ARVsAn ageing population

Lifestyle factors

Increased risk of non-communicable age-associated diseases eg CVD

HIV

Anthony JaworowskiAnna HearpsGenevieve MartinClovis PalmerGregor LichtfussTom AngelovichYagmur FarsakogluWan-Jung ChengJingling Zhou

Clare Westhorpe

• Centre for Population HealthTim Spelman

• IDUSharon LewinJenny HoyJulian ElliottKate CherryJanine Trevillyon

• Cardiovascular MedicineAnthony DartLiz DewarSofie Karapanagiotidis

Dmitri Sviridov

Alan Landay

The HaCH Study volunteers

Acknowledgements

“The Ageing Team”

William Muller

Funding from