Why may non-communicable diseases occur more often in those with HIV infection?
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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
% te
lom
ere
leng
th in
CD
31+
naïv
e T-
cells
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
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