Premature Aging and Functional Decline Associated with HIV Disease:

Mechanisms and Triggers

Rita B. Effros, Ph.D.Department of Pathology & Laboratory Medicine

UCLA AIDS Institute

David Geffen School of Medicine at UCLA

Take Home Message• In persons infected with HIV, specific components of the

immune system show signs of accelerated aging

• Chronically activated T cells contribute to pro-inflammatory milieu in persons who are old and/or HIV-infected

• Abundance of “senescent” T cells correlates with multiple deleterious outcomes in aging and HIV disease

• Cross-fertilization between HIV research and other areas of medicine involving chronic inflammation

• Critical to validate biomarkers of disease across multiple geographical areas/populations

• The human immune system pervades the entire body

• Its total mass is as large as that of the human brain

skin

Chronological aging is associated with multiple changes in the immune system

Age-dependent decline in T cell output from thymus

Naylor, K et al. J Immunol. 2005

Aging: reduced T cell diversity

Young memory

0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100

T cell receptor b-chains (%)

75-80 years60-65 years25-30 years

< 0.05

> 20.0

0.2 - 0.05

1.0 - 0.2

5.0 - 1.0

20.0 - 5.0

Fre

qu

ency

( 1

/n x

10-6

)

Naive CD4 T cells

Naylor, K et al. J Immunol. 2005 Jun 1; 174(11):7446-52

in senescent “CD8” T cells• Irreversible state of growth arrest

• Consequence of extensive cell division

• Altered function and gene expression

• Proinflammatory cytokines (TNF, IL-6)

• Shortened telomeres

CD8 (cytotoxic) T cells with these same features areincreased in younger persons who are HIV+

HIV: Premature telomere shortening in chronically activated, senescent T cells

X

Shorter telomeres even in naïve T cells(ART-treated)

Rickabaugh et al. PLoS One, 2011

Telomeres: biomarkers of health status

• Atherosclerosis (Samani et al., Lancet 2001)

• Premature myocardial infarction(Brouilette et al., Arterioscler. Thromb. Vasc. Biol., 2002)

• Insulin resistance(Demissie et al., Aging Cell, 2006)

• Type 2 diabetes and microalbuminuria(Tentolaouris et al., Diabetes Care, 2007)

• Alzheimer’s disease(Panossian et al., Neurobiol. of Aging, 2004)

• Psychological stress( Epel et al., PNAS, 2005; Weng et al., J.Immunol. 2006)

Senescent T cells & mortality

Lymphocyte telomere lengthShortest telomere length at age 60/earlier deathCawthon et al. Lancet,2003

Swedish OCTO studyEarly mortality correlates with “immune risk profile”( CD8+CD28- T cells, reversal of CD4:CD8 ratio, CMV seropositivity)Wikby et al. Exp Gerontol., 2002

HIV disease: progression to AIDS ↑CD8+CD28-T cells in fast progressorsCao et al. J. Acquir Immune Defic Syndr 2009

Present in germ cells, stem cells, and activated immune cells

Telomerase: enzyme that re-elongates telomeres

Present in germ cells, stem cells, and activated immune cells

Telomerase: enzyme that re-elongates telomeres

Killer T cells with highest telomerase activity in HIV-1 controllersLichterfeld et al. Blood, 2008.

Immune deficiency• Increased morbidity/mortality from

infections• Poor vaccine responses• Cancer

Autoimmunity• Autoantibody production• Polymyalgia rheumatica• Giant cell arteritis• Rheumatoid arthritis

Chronic inflammation• Coronary artery disease• Alzheimer’s disease• Osteoporosis• Frailty

Immune Aging

Adapted from Goronzy

Bone• Dynamic tissue: undergoes continuous remodeling• Cells responsible for homeostasis:

– Osteoclasts– Osteoblasts

(Modified from SAGE KE/ B.L. Riggs)

T lymphocytes secrete factors that regulate bone-destroying osteoclasts

T CELLS

ACTIVE OC

TNFaIL-6

OC PRECURSORS

TNFa

Differentiationand activation

Stimulatory Factors

Inhibitory Factors

IL-1

RANKLIFN

OPGM-CSF

Senescent CD8+ T cells: TNF, IL-6, RANKL; IFN

Increased fractures in HIV+

Torti et al. Endocrine, 2012

Initiation, progression, and complication of human coronary atherosclerotic plaque.

Libby P Circulation 2001;104:365-372

Copyright © American Heart Association

Coronary artery disease

T cells and atherosclerosis

Activated T cells

Senescent T cells

Kaplan et al, JID 2011

International perspective

Global cooperation is essential in both research and treatment

Confirmatory studies required for many biomarkers: Swedish Immune Risk Profile differs even among different populations within Europe

Cannot assume that all aging and/or HIV-related biomarkers will be common worldwide

Acknowledgments

Roy WalfordNancy PerilloCarolyn SpauldingHector ValenzuelaBelle DagaragSteve FauceLucy GrahamStan Parish

Janis GiorgiOtto YangBeth JamiesonRon MitsuyasuRoger DetelsWeiwei CaoNagesh RaoYin TintutFarhad Parhami

UCLA

Calvin Harley, Choi-Pik Chiu, Allison Chin

Geron

THANKS TO….NIA, NIAID, UC Discovery/GeronCorp., TA Therapeutics,Ltd.

Frank Jernigan Fdn. Plott Endowment, UCLA Center on Aging

Blood donors : UCLA CARE CENTER, UCLA MACS

Jeff DockJennifer ChouMargaret Newman Xhoming ZhuJenny KimSarah ChoiJennifer WuYukako Kawakatsu

Collaborators