11/18/17. HIV and Aging. HIV and Frailty. Frailty. Mechanism of FuncEonal Decline: Role for Frailty in HIV and Aging

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1 Mechanism of FuncEonal Decline: Role for Frailty in HIV and Aging Alan Landay, PhD Professor Department of Immunology/ Microbiology Rush University Medical Center Chicago, Illinois HIV and Aging The introduceon and success of aneretroviral therapy(art) has led to an aging HIV+ populaeon, altering the characterisecs of the HIV/AIDS epidemic Within this aging populaeon, there is an increased risk for and burden of comorbidiees typically associated with age Examples include cardiovascular disease, chronic kidney disease, osteoporosis, and neurocognieve disorders Increases in age-related comorbidiees may predispose HIV-infected persons to a parecularly vulnerable state known as frailty Frailty In geriatrics literature, frailty is defined as an increased vulnerability to stressors in the face of limited physiological reserve Frailty has been associated with a range of aberrant, dynamic, mulesystem physiological stress responses affeceng neuroendocrine, metabolic, musculoskeletal, cognieve, and immune systems DisrupEon of key stress response systems driven by underlying aging-related cellular and molecular pathogenesis adversely impact muscle mass and quality, strength, endurance, and efficiency of energy expenditure Fried et al defined the original frailty phenotype involving impairment in at least 3 of five domains Physical slowness measured by walking speed, Weakness measured by grip strength, FaEgue, Low physical acevity, and UnintenEonal weight loss The frailty phenotype (FP) independently predicts a number of adverse outcomes Acute illness, falls, cognieve decline, disability, insetueonalizaeon, and mortality HIV and Frailty SimilariEes between frailty, aging, and HIV infeceon were recognized early in the HIV era Weight loss, immune acevaeon, and high levels of cytokines were features of untreated HIV also common in aging populaeons AZer the introduceon of ART, focus shized to the effect of chronic treated HIV infeceon on health and longevity as life expectancy increased HIV-associated non-aids (HANA) condieons have become major health concerns Frailty is increasingly being recognized as an important factor to idenefy HIVinfected persons at high risk for adverse health outcomes 1

2 Inflammation The role of Inflammation in frailty status in HIV-infected populations The aging immune system is characterized by a low level chronic systemic inflammatory state, termed inflammaging Elevated circulaeng levels of markers of inflammaeon (CRP, IL-6, TNF-α) Associated with increased morbidity and mortality in older adults Chronic heightened inflammaeon contributes to the pathogenesis of frailty in the geriatric populaeon, directly or through other intermediate pathophysiological processes Frailty is associated with increased serum levels of CRP, IL-6 and CXCL-10, TNF-α, and neopterin 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 Comparison of T-lymphocyte immune activation (CD38 and HLA-DR expression on CD4 + and CD8 + T cells) between low- and high-functioning groups A B C Erlandson et al J. Infec Dis Jan 2017 Erlandson et al J. Infect Dis

3 Conclusions MounEng evidence supports the role of chronic inflammaeon as a contribueng factor to frailty in older adults, and this is likely to be tru in people with chronic, treated HIV infeceon, who have higher levels of systemic inflammaeon 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 Correlations between CMV humoral or cell-mediated immune response and baseline characteristics, inflammation, activation, and senescence markers Erlandson et al. AIDS Research and Human Retroviruses 2015 CorrelaEons including all subjects (diamond) are shown in the le) panels; correlaeons separated by high (square) and low (circle) physical funceon are shown in the right panels Erlandson et al. AIDS Research and Human Retroviruses

4 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) Macintyre et al., Cell Metabolism 2014; Palmer et al Crowe, Journal of Immunology 2016 Palmer et al Crowe, Front Immunol. 2016; Kabat and Pearce, Science 2017 High Glut1 expression of CD4+ T cells is associated with poor immune recovery in ART-treated HIV+ persons Model: metabolic exhaustion drives CD4+ T cell loss in HIV+ Individuals p < HIV+/cART % C D 4 + G l u t 1 + T c e l l s p < p < H I V - H I V + / n a i v e I R I N R % C D 4 + G l u t 1 + T c e l l s r = p = n = H I V + / c A R T n = C D 4 + T c e l l c o u n t Palmer et al Crowe, AIDS, 2014; Jesse et al Palmer, Plos One (accepted) Palmer et al Crowe, Ebiomedicine

5 Recruitment of older HIV+ men for frailty study (Melbourne HIV Silver Aging Study) MFI of GLUT-1 on monocyte subsets from non-frail and frail individuals Dr Hui-Ling MBBS M FI of G lut-1 on m onocyte s u b p o p u la t io n s p = * p = p = p = 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 il Total N on-classical Interm ediate C lassical F r a ilty In d e x Hui-Ling Yeoh et al.hoy, HIV Med. (accepted) Plasma levels of scd163 and scd14 according to Frailty status Plasma levels of scd163 and scd14 according to conenuous Frailty Index scd14 Serum Concentration (pg/ml) >0.25 Frailty Index <0.25 = non-frail, >0.25 = frail 5

6 Increased blood monocyte glycolytic activity is associated with frailty and poor quality of life in older HIV+ men Conclusions Increased CD4+ T cell glycolyec acevity is associated with funceonal decline (metabolic exhaus/on) Host-directed therapies to normalize glucose metabolic acevity in T cells and monocytes may improve funceonal acevity and reduce inflammaeon Hui-Ling Yeoh et al.palmer, Ebiomedicine 2017 Microbiome Alterations in HIV :A Possible Driver of Functional Decline The microbiome helps shape the innate and adapeve immune system with a delicate balance of pro- and ane-inflammatory responses Tryptophan catabolites, in parecular kynurenine and quinolinic acid, are associated with immune acevaeon Microbial dysbiosis may modulate health through SCFAs like butyrate, as they are an important energy source for colonocytes and can control barrier funceon Healthy Microbiota Role of Microbiome in Aging and HIV PopulaEons Aging HIV InfecEon Microbial Dysbiosis IDO/TDO Butyrate AlteraEons in Systemic InflammaEon Increased risk of Comorbidi/es Frailty, CVD, Cancers, Kidney and Liver Disease, NeurocogniEve Impairment Frailty Adapted From Koay et al. Current Opinions in HIV and AIDS 2017, Bolan et al. EMBO Reports Sept

7 Frailty Immune Ac/va/on and Inflamma/on CRP, IL-6, CXCL10 Metabolic Changes Glycolysis IDO Butyrate Comorbidi/es CVD, Cancers, Kidney and Liver Disease, NeurocogniEve CD4 Impairment counts CRP, CMV IL-6, Infec/on TNF-α Monash University Clovis Palmer Acknowledgements University of Colorado Kristine Erlandson Adapted From - Palmer and Crowe, AIDS Res Human Retro. 2015; Anzinger et al Palmer, J Immunol Res Freemerman et al. J Biol Chem. 2014; BuYerfield et al Anzinger, AIDS 2017 ART intensifica/on N-acetyl-cysteine Oxida^ve stress Join us to discover the role Microbiome plays in the pathogenesis, preven/on and treatment of HIV/AIDS Probio/cs Rifamyxin, Sulfasalazine mtorc/pi3k HIF1-α inhibitors Aqendance to the workshop is free to charge. Search: 4th HIV Microbiome for more informaeon. Rosuvasta/n Simvasta/n Lifestyle modifica/on SNAEs CVD/FRAILTY Hui Ling Yeoh, Clovis Palmer, Jenny Hoy, Suzanne Crowe - Unpublished 7

8 Association Between the Microbiome and Clinical Issues Impacting Older Adults Zapata and Quagliarello J Am Geriatr Soc. Apr