Memory loss: T cell subsets associated with mortality in HIV+ and HIV veterans
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1 Memory loss: T cell subsets associated with mortality in HIV+ and HIV veterans Wyatt J. McDonnell 1, Meredith S. Duncan 1, John R. Koethe 1, Margaret Doyle 2, Simon Mallal 1, Amy Justice 3, Matthew S. Freiberg 1 1 Vanderbilt University Medical Center, Nashville, TN, USA 2 University of Vermont, Burlington, VT, USA 3 Yale University, New Haven, CT, USA 9 th International Workshop on HIV & Aging New York, NY, 2018 Title slide 13 September 2018
2 Today, we ll discuss: Some background: HIV and immune activation, T cells, inflammaging Study design/sample collection in VACS (Veterans Aging Cohort Study) Preliminary analyses of T cell subsets and mortality in HIV+ and HIV veterans Outline 13 September 2018
3 HIV and immune activation HIV replication Immune activation A little background: HIV and chronic immune activation 13 September 2018
4 HIV and immune activation HIV replication Immune activation A little background: HIV and chronic immune activation 13 September 2018
5 HIV and immune activation HIV replication Immune activation Vascular damage A little background: HIV and chronic immune activation 13 September 2018
6 HIV and immune activation HIV replication Immune activation Vascular damage Microbial translocation A little background: HIV and chronic immune activation 13 September 2018
7 HIV and immune activation HIV replication ARV therapy Immune activation Vascular damage Microbial translocation A little background: HIV and chronic immune activation 13 September 2018
8 HIV and immune activation Co-infection (HCV, CMV, etc.) HIV replication ARV therapy Immune activation Vascular damage Microbial translocation A little background: HIV and chronic immune activation 13 September 2018
9 T cells: from naïve to memory Naïve T cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
10 T cells: from naïve to memory Naïve T cells Effector T cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
11 T cells: from naïve to memory Naïve T cells Effector T cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
12 T cells: from naïve to memory Naïve T cells Effector T cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
13 T cells: from naïve to memory Naïve T cells Long-lived classical memory Effector T cells T EM cells T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
14 T cells: from naïve to memory Naïve T cells Effector T cells T EM and T EMRA cells Long-lived classical memory T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
15 T cells: from naïve to memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T effector memory CD45RA+ T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
16 T cells: from naïve to memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T effector memory CD45RA+ T effector memory revertant T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
17 T cells: from naïve to memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
18 T cells: from naïve to memory Long-lived non-classical memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
19 T cells: from naïve to memory Transcription T-bet hi Eomes low Long-lived non-classical memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
20 T cells: from naïve to memory Transcription T-bet hi Eomes low Co-stimulation 4-1BB hi (CD137) CD27 low CD28 low IL-7R low Long-lived non-classical memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
21 T cells: from naïve to memory Transcription T-bet hi Eomes low Co-stimulation 4-1BB hi (CD137) CD27 low CD28 low IL-7R low Functionality Granzyme B hi Perforin hi PD-1 low Long-lived non-classical memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
22 T cells: from naïve to memory Transcription T-bet hi Eomes low Co-stimulation 4-1BB hi (CD137) CD27 low CD28 low IL-7R low Functionality Granzyme B hi Perforin hi PD-1 low Tissue homing CX 3 CR1 hi CD62L low CCR7 low Long-lived non-classical memory Naïve T cells Long-lived classical memory Effector T cells T EM and T EMRA cells T CM cells Modified from Klenerman & Oxenius. Nat Rev Immunol Jun;16(6): doi: /nri A little background: T cell differentiation 13 September 2018
23 The main question 2337 veterans from VACS: 1518 HIV+ 819 HIV Methods: cohort design 13 September 2018
24 The main question 2337 veterans from VACS: 1518 HIV+ 819 HIV : PBMCs banked : 80 immune cell subsets via FACS Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory T EMRA CD45RO+CCR7 CD45RA+CCR7 CD57+ Methods: cohort design 13 September 2018
25 The main question 2337 veterans from VACS: 1518 HIV+ 819 HIV : PBMCs banked : 80 immune cell subsets via FACS Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory T EMRA CD45RO+CCR7 CD45RA+CCR7 CD57+ Methods: cohort design 13 September 2018
26 The main question 2337 veterans from VACS: 1518 HIV+ 819 HIV : PBMCs banked : 80 immune cell subsets via FACS Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory T EMRA CD45RO+CCR7 CD45RA+CCR7 CD57+ Methods: cohort design 13 September 2018
27 CD27 & cardiovascular mortality in HIV populations Lowest quartile of CD27 / CD28- cells (blue) Newcastle 85+ study: 749 individuals 641 CMV+ No differences in gender, CVD risk factors, age-related disease HR 1.78 [ ] Spyridopolous et al. Nat Immunol Apr;15(2): doi: /acel Also of note September 2018
28 The main question Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory CD45RO+CCR7 T EMRA CD45RA+CCR7 CD57+ September 2015 Alive Dead HIV+ HIV HIV+ HIV Cox model: Age Sex Race ART Methods: cohort design 13 September 2018
29 The main question Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory CD45RO+CCR7 T EMRA CD45RA+CCR7 CD57+ September 2015 Alive Dead HIV+ HIV HIV+ HIV Cox model: Age Sex Race ART Methods: cohort design 13 September 2018
30 The main question Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory CD45RO+CCR7 T EMRA CD45RA+CCR7 CD57+ September 2015 Alive Dead HIV+ HIV HIV+ HIV Cox model: Age Sex Race ART Methods: cohort design 13 September 2018
31 The main question Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory CD45RO+CCR7 T EMRA CD45RA+CCR7 CD57+ September 2015 Alive Dead HIV+ HIV HIV+ HIV Cox model: Age Sex Race ART Methods: cohort design 13 September 2018
32 The main question Naive CD45RA+CCR7+ Activated CD38+ Memory CD45RO+CCR7+ Effector memory CD45RO+CCR7 T EMRA CD45RA+CCR7 CD57+ September 2015 Alive Dead HIV+ HIV HIV+ HIV Cox model: Age Sex Race ART Methods: cohort design 13 September 2018
33 Cohort characteristics by HIV status at baseline HIV+ n=1518 HIVn=819 Age, mean years Male sex, % African American race, % Diabetes, % Hypertension, % High LDL cholesterol ( 160 mg/dl), % 5 7 Smoking, % Hepatitis C, % Hazardous drinking, % CD4 cell count/mm 3 (median) 392 HIV-1 RNA copies/ml (median) 75 Results 13 September 2018
34 Baseline CD4 subsets and risk of mortality T Cell HIV+ (n=1055) Hazard Ratio [95% CI] p-value HIV-neg (n=578) Hazard Ratio [95% CI] p-value CD4+ Naïve 0.71 [0.56, 0.91] [0.47, 1.01] 0.05 CD4+CD38+ (activated) CD4+CD45RO+ (memory) 1.47 [1.24, 1.75] < [0.56, 1.06] [0.74, 1.05] [0.91, 1.50] 0.24 Hazard ratios refer to one interquartile range increase in T cell subset Results 13 September 2018
35 Baseline CD4 subsets and risk of mortality T Cell HIV+ (n=1055) Hazard Ratio [95% CI] p-value HIV-neg (n=578) Hazard Ratio [95% CI] p-value CD4+ Naïve 0.71 [0.56, 0.91] [0.47, 1.01] 0.05 CD4+CD38+ (activated) CD4+CD45RO+ (memory) 1.47 [1.24, 1.75] < [0.56, 1.06] [0.74, 1.05] [0.91, 1.50] 0.24 CD4+ T EM 1.05 [0.91, 1.22] [0.96, 1.57] 0.10 CD4+ T EMRA * 1.12 [1.04, 1.22] [0.95, 1.40] 0.14 CD4+ T EMRA 1.17 [1.10, 1.24] < [0.99, 1.29] 0.08 Hazard ratios refer to one interquartile range increase in T cell subset * CD4+ T EMRA cells defined as CD45RA + CD28 CD57 + CD4+ T EMRA cells alternately defined as CD45RA + CD27 Results 13 September 2018
36 Baseline CD8 subsets and risk of mortality T Cell HIV+ (n=1238) Hazard Ratio [95% CI] p-value HIV-neg (n=700) Hazard Ratio [95% CI] p-value CD8+ naϊve 0.75 [0.56, 0.99] [0.61, 1.23] 0.42 CD8+CD38+ (activated) CD8+CD45RO+ (memory) 1.32 [1.10, 1.59] [0.59, 1.07] [1.07, 1.45] [0.96, 1.58] 0.09 Hazard ratios refer to one interquartile range increase in T cell subset Results 13 September 2018
37 Baseline CD8 subsets and risk of mortality T Cell HIV+ (n=1238) Hazard Ratio [95% CI] p-value HIV-neg (n=700) Hazard Ratio [95% CI] p-value CD8+ naϊve 0.75 [0.56, 0.99] [0.61, 1.23] 0.42 CD8+CD38+ (activated) CD8+CD45RO+ (memory) 1.32 [1.10, 1.59] [0.59, 1.07] [1.07, 1.45] [0.96, 1.58] 0.09 CD8+ T EM 1.13 [0.96, 1.32] [0.73, 1.44] 0.88 CD8+ T EMRA * 0.85 [0.72, 1.01] [0.74, 1.11] 0.34 CD8+ T EMRA 0.97 [0.83, 1.14] [0.76, 1.13] 0.44 Hazard ratios refer to one interquartile range increase in T cell subset * CD8+ T EMRA cells defined as CD45RA + CD28 CD57 + CD8+ T EMRA cells alternately defined as CD45RA + CD27 Results 13 September 2018
38 T EMRA and HIV status In the HIV+ subjects, higher CD4+ T EMRA cells defined by two different surface markers were associated with increased risk of death These T EMRA cells were 2-fold higher in the HIV+ Age < >55 CD4+CD45RA+CD28-CD57+ T EMRA CD4+CD45RA+CD27- T EMRA HIV+ HIV-neg p-value HIV+ HIV-neg p-value 5.4% 2.0% < % 2.3% < < < < < Results 13 September 2018
39 CD4 + CD45RA + CD28 - CD57 + as % CD4 T EMRA and HIV status CD4 T EMRA (CD28-CD57+) by suppression and age groups 100 HIV- HIV+ suppressed HIV+ viremic <45 yo yo >55 yo <45 yo yo >55 yo <45 yo yo >55 yo Group Results 13 September 2018
40 CD4 + CD45RA + CD28 - CD57 + as % CD4 T EMRA and HIV status CD4 T EMRA (CD28-CD57+) by suppression and age groups 100 HIV- HIV+ suppressed HIV+ viremic <45 yo yo >55 yo <45 yo yo >55 yo <45 yo yo >55 yo Group Results 13 September 2018
41 CMV and T EMRA cells Patin et al. Nat Immunol Feb;19(3): doi: /s Also of note September 2018
42 Acknowledgments John Koethe, MD Simon Mallal, MBBS Matthew Freiberg, MD Meredith Duncan, MS Jeffrey Blume, PhD Melissa Wellons, MD Sarah Felter Loch, BA Acknowledgments 13 September 2018
43 Acknowledgments Amy Justice, MD, PhD Kathleen McGinnis, PhD Margaret Doyle, PhD Russell Tracy, PhD NIAAA U10 AA NIAAA U24 AA NIAAA U01 AA NHLBI R01 HL NIDDK R56 DK Acknowledgments 13 September 2018
44 Thank you for your attention! Questions? 13 September 2018
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