Post on 25-Dec-2019
11/18/17
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AlanLanday,PhDProfessor
DepartmentofImmunology/Microbiology
RushUniversityMedicalCenterChicago,Illinois
MechanismofFuncEonalDecline:RoleforFrailtyinHIVandAging
HIV and Aging
• TheintroducEonandsuccessofanEretroviraltherapy(ART)hasledtoanagingHIV+populaEon,alteringthecharacterisEcsoftheHIV/AIDSepidemic
• WithinthisagingpopulaEon,thereisanincreasedriskforandburdenofcomorbidiEestypicallyassociatedwithage
• Examplesincludecardiovasculardisease,chronickidneydisease,osteoporosis,andneurocogniEvedisorders
• Increasesinage-relatedcomorbidiEesmaypredisposeHIV-infectedpersonstoaparEcularlyvulnerablestateknownasfrailty
Frailty • Ingeriatricsliterature,frailtyisdefinedasanincreasedvulnerabilitytostressorsinthefaceoflimitedphysiologicalreserve
• Frailtyhasbeenassociatedwitharangeofaberrant,dynamic,mulEsystemphysiologicalstressresponsesaffecEngneuroendocrine,metabolic,musculoskeletal,cogniEve,andimmunesystems
• DisrupEonofkeystressresponsesystemsdrivenbyunderlyingaging-relatedcellularandmolecularpathogenesisadverselyimpactmusclemassandquality,strength,endurance,andefficiencyofenergyexpenditure
• Friedetaldefinedtheoriginalfrailtyphenotypeinvolvingimpairmentinatleast3offivedomains
• Physicalslownessmeasuredbywalkingspeed,Weaknessmeasuredbygripstrength,FaEgue,LowphysicalacEvity,andUnintenEonalweightloss
• Thefrailtyphenotype(FP)independentlypredictsanumberofadverseoutcomes
• Acuteillness,falls,cogniEvedecline,disability,insEtuEonalizaEon,andmortality
HIV and Frailty
• SimilariEesbetweenfrailty,aging,andHIVinfecEonwererecognizedearlyintheHIVera
• Weightloss,immuneacEvaEon,andhighlevelsofcytokineswerefeaturesofuntreatedHIValsocommoninagingpopulaEons
• AZertheintroducEonofART,focusshiZedtotheeffectofchronictreatedHIVinfecEononhealthandlongevityaslifeexpectancyincreased
• HIV-associatednon-AIDS(HANA)condiEonshavebecomemajorhealthconcerns
• FrailtyisincreasinglybeingrecognizedasanimportantfactortoidenEfyHIV-infectedpersonsathighriskforadversehealthoutcomes
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The role of Inflammation in frailty status in HIV-infected populations
Inflammation
• Theagingimmunesystemischaracterizedbyalowlevelchronicsystemicinflammatorystate,termedinflammaging
• ElevatedcirculaEnglevelsofmarkersofinflammaEon(CRP,IL-6,TNF-α)• Associatedwithincreasedmorbidityandmortalityinolderadults
• ChronicheightenedinflammaEoncontributestothepathogenesisoffrailtyinthegeriatricpopulaEon,directlyorthroughotherintermediatepathophysiologicalprocesses
• FrailtyisassociatedwithincreasedserumlevelsofCRP,IL-6andCXCL-10,TNF-α,andneopterin
Differences in Inflammatory Markers (A), Markers of Immune Activation and Senescence (B), and Markers of Hormonal Regulation (C) by frailty status among HIV-infected Men
B CA
ErlandsonetalJ.InfecDisJan2017
Comparison of T-lymphocyte immune activation (CD38 and HLA-DR expression on CD4+ and CD8+ T cells) between low- and high-functioning
groups
ErlandsonetalJ.InfectDis2013
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Conclusions
• MounEngevidencesupportstheroleofchronicinflammaEonasacontribuEngfactortofrailtyinolderadults,andthisislikelytobetruinpeoplewithchronic,treatedHIVinfecEon,whohavehigherlevelsofsystemicinflammaEon
The role of Cytomegalovirus in physical function impairment of older, HIV-infected
adults
Distribution of CMV IgG (A), HSV 1 and 2 IgG (B), VZV IgG (C), % CMV-Specific CD4+ T cells (D), and % CMV-Specific CD8+ T cells between low and high
physical function groups
Erlandsonetal.AIDSResearchandHumanRetroviruses2015
Correlations between CMV humoral or cell-mediated immune response and baseline characteristics, inflammation, activation, and senescence markers
CorrelaEonsincludingallsubjects(diamond)areshowninthele)panels;correlaEonsseparatedbyhigh(square)andlow(circle)physicalfuncEonareshownintherightpanels
Erlandsonetal.AIDSResearchandHumanRetroviruses2015
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The role of immunometabolism in mechanisms of immune dysfunction and
development of age-associated comorbidities and functional decline in
HIV infection
Immune Activation reprograms T cell glucose metabolism from oxidative phosphorylation to glycolysis (Warburg Effect)
Macintyreetal.,CellMetabolism2014;Palmeretal…Crowe,JournalofImmunology2016
Palmeretal…Crowe,FrontImmunol.2016;KabatandPearce,Science2017
High Glut1 expression of CD4+ T cells is associated with poor immune recovery in ART-treated HIV+ persons
Palmeretal…Crowe,AIDS,2014;Jesseetal…Palmer,PlosOne(accepted)
H I V - H I V + / n a i v e I R I N R0
2 0
4 0
6 0
8 0
1 0 0
% C
D4
+G
lut1
+T
ce
lls
p < 0 . 0 0 0 1 p < 0 . 0 0 0 1
p < 0 . 0 0 0 1
H I V + / c A R T
n = 4 4 5 8 3 9 2 2
0 5 0 0 1 0 0 0 1 5 0 00
1 0
2 0
3 0
4 0
1 0 0
C D 4 + T c e l l c o u n t
% C
D4
+G
lut1
+ T
ce
lls
r = - 0 . 4 8
p = 0 . 0 0 0 4
n = 5 0
HIV+/cART
Model: metabolic exhaustion drives CD4+ T cell loss in HIV+ Individuals
Palmeretal…Crowe,Ebiomedicine2016
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Recruitment of older HIV+ men for frailty study (Melbourne HIV Silver Aging Study)
Hui-LingYeohetal….Hoy,HIVMed.(accepted)
DrHui-LingMBBS
N o n -F r a il F r a il N o n -F r a il F r a il N o n -F r a il F r a il N o n -F r a il F r a il1 0
1 0 0
1 0 0 0
F ra ilty In d e x
MFI
of G
lut-1
on
mon
ocyt
esu
bpop
ulat
ions
Tota l N o n -c la s s ic a l In te rm e d ia te C la s s ic a l
p= 0 .0 3 7 * p= 0 .0 6 1 p= 0 .1 4 6 p= 0 .0 6 6
MFIofGLUT-1onmonocytesubsetsfromnon-frailandfrailindividuals
≤0.25>0.25
0
5000
10000
15000
Frailty Index
sCD1
4 Ser
um
Conc
entra
tion
(pg/
mL)
0.034
PlasmalevelsofsCD163andsCD14accordingtoFrailtystatus
<0.25=non-frail,>0.25=frail
PlasmalevelsofsCD163andsCD14accordingtoconEnuousFrailtyIndex
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Increased blood monocyte glycolytic activity is associated with frailty and poor quality of life in older HIV+ men
Hui-LingYeohetal….Palmer,Ebiomedicine2017
Conclusions • IncreasedCD4+ T cell glycolyEc acEvity is associatedwith funcEonal decline(metabolicexhaus/on)
• Host-directedtherapiestonormalizeglucosemetabolicacEvityinTcellsandmonocytesmayimprovefuncEonalacEvityandreduceinflammaEon
Microbiome Alterations in HIV :A Possible Driver of Functional Decline • ThemicrobiomehelpsshapetheinnateandadapEveimmunesystemwithadelicatebalanceofpro-andanE-inflammatoryresponses
• Tryptophancatabolites,inparEcularkynurenineandquinolinicacid,areassociatedwithimmuneacEvaEon
• MicrobialdysbiosismaymodulatehealththroughSCFAslikebutyrate,astheyareanimportantenergysourceforcolonocytesandcancontrolbarrierfuncEon
AdaptedFromKoayetal.CurrentOpinionsinHIVandAIDS2017,Bolanetal.EMBOReportsSept2016
RoleofMicrobiomeinAgingandHIVPopulaEons
HIVInfecEon
↑IDO/TDO
↓Butyrate
HealthyMicrobiota
MicrobialDysbiosis
AlteraEonsinSystemic
InflammaEon
Aging
IncreasedriskofComorbidi/esFrailty,CVD,
Cancers,KidneyandLiverDisease,NeurocogniEveImpairment
Frailty
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AdaptedFrom-PalmerandCrowe,AIDSResHumanRetro.2015;Anzingeretal…Palmer,JImmunolRes.2014Freemermanetal.JBiolChem.2014;BuYerfieldetal…Anzinger,AIDS2017
ImmuneAc/va/onandInflamma/on
↑CRP,IL-6,CXCL10MetabolicChanges
↑Glycolysis↑IDO
↓ButyrateComorbidi/es
CVD,Cancers,KidneyandLiverDisease,NeurocogniEveImpairment
CMVInfec/on↓CD4counts
↑CRP,IL-6,TNF-α
Frailty Acknowledgements
Monash University • Clovis Palmer
University of Colorado • Kristine Erlandson
• Aqendancetotheworkshopisfreetocharge.• Search:4thHIVMicrobiomeformoreinformaEon.
JoinustodiscovertheroleMicrobiomeplaysinthepathogenesis,preven/onandtreatmentofHIV/AIDS
HuiLingYeoh,ClovisPalmer,JennyHoy,SuzanneCrowe-Unpublished
SNAEs CVD/FRAILTY
Probio/csRifamyxin,Sulfasalazine
N-acetyl-cysteine
Oxida^vestress
Rosuvasta/nSimvasta/nLifestylemodifica/on
mTORC/PI3KHIF1-αinhibitors
ARTintensifica/on
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Association Between the Microbiome and Clinical Issues Impacting Older Adults
ZapataandQuagliarelloJAmGeriatrSoc.Apr2015