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
Dec 26, 2015
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