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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 Naive CD4 T cells Frequency ( 1/n x 10-6) 25-30 years 60-65 years 75-80 years > 20.0 Young memory 20.0 - 5.0 5.0 - 1.0 1.0 - 0.2 0.2 - 0.05 < 0.05 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 T cell receptor b-chains (%) Naylor, K et al. J Immunol. 2005 Jun 1; 174(11):7446-52 80 100 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 are increased 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 length Shortest telomere length at age 60/earlier death Cawthon et al. Lancet,2003 Swedish OCTO study Early 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 progressors Cao et al. J. Acquir Immune Defic Syndr 2009 Telomerase: enzyme that re-elongates telomeres 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 Killer T cells with highest telomerase activity in HIV-1 controllers Lichterfeld et al. Blood, 2008. Immune deficiency • Increased morbidity/mortality from infections • Poor vaccine responses • Cancer Immune Aging Chronic inflammation Autoimmunity • • • • • • • • Coronary artery disease Alzheimer’s disease Osteoporosis Frailty Autoantibody production Polymyalgia rheumatica Giant cell arteritis Rheumatoid arthritis Adapted from Goronzy Bone • Dynamic tissue: undergoes continuous remodeling • Cells responsible for homeostasis: – Osteoclasts – Osteoblasts T lymphocytes secrete factors that regulate bone-destroying osteoclasts T CELLS OPG M-CSF IL-6 TNF IL-1 IFN RANKL Stimulatory Factors Inhibitory Factors TNF OC PRECURSORS Differentiation and activation ACTIVE OC Senescent CD8+ T cells: TNF, IL-6, RANKL; IFN (Modified from SAGE KE/ B.L. Riggs) Increased fractures in HIV+ Torti et al. Endocrine, 2012 Coronary artery disease Initiation, progression, and complication of human coronary atherosclerotic plaque. Libby P Circulation 2001;104:365-372 Copyright © American Heart Association 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 UCLA Collaborators Roy Walford Nancy Perillo Carolyn Spaulding Hector Valenzuela Belle Dagarag Steve Fauce Lucy Graham Stan Parish Jeff Dock Jennifer Chou Margaret Newman Xhoming Zhu Jenny Kim Sarah Choi Jennifer Wu Yukako Kawakatsu Geron Janis Giorgi Otto Yang Beth Jamieson Ron Mitsuyasu Roger Detels Weiwei Cao Nagesh Rao Yin Tintut Farhad Parhami Calvin Harley, Choi-Pik Chiu, Allison Chin 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