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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