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  10th International Workshop
October 10-11, 2019
New York

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Aging Workshop Report : DNA Methylation : Heart Disease ; Kidney Disease - Christina K. Psomas MD
  Reported by Christina K. Psomas
Department of Infectious Diseases and Internal Medicine
European Hospital Marseille
DNA methylation patterns may be important predictive biomarkers of the development of lung cancer for those aging with HIV.
Individuals with HIV on suppressive therapy are at greater risk for age-related diseases such as cancer, as well as accelerated immunologic aging. DNA methylation is a biomarker for measuring biological age. Chad J. Achenbach from Northwestern University, Chicago, IL, USA presented results on behalf of the CFAR Network of Integrated Clinical Systems (CNICS), in terms of predictive value of HIV-associated epigenetic age acceleration in HIV-associated cancer incidence. Researchers performed two matched case-control pilot studies within 8 CNICS sites. Cases were 24 people living with HIV (PLWH) presenting incident lung cancer, 25 PLWH presenting incident anal cancer, and the same number of matched PLWH (24 and 25 respectively) without cancer selected via incidence density sampling from the CNICS primary study base. Epigenomic profiling was performed on DNA extracted from total PBMCs using the Illumina MethylationEPIC Beadchip (850k sites). Epigenetic age acceleration (EAA) was determined using four measures, namely intrinsic EAA (353 CpG sites derived from many tissue/cell types) and extrinsic EAA (71 CpG sites derived from whole blood) which are two chronologic age predictors, phenoAge acceleration (10 clinical measures) which is a phenotypic age predictor, and GrimAge acceleration (Surrogate DNAm biomarkers of smoking pack-years (172 CpGs) and 7 plasma proteins) which is a time-to-death predictor. Conditional logistic regression, adjusting for race and CD4 T cell count, was used to assess the association between the epigenetic measures and incident cancer. Cases with lung (N=24) and anal cancer (N=25) were matched to control groups of the same number of PLWH regarding all epidemic (age, gender, number of active smokers) and HIV parameters (last value of plasmatic HIV viral load, number of patients on ART). Both cases exhibited lower current CD4 T cell count than their controls, and PLWH with anal cancer seemed to belong more frequently to the black race than their controls. The PBMC sample was obtained 1.7 years (IQR 1.3;2.4) before lung cancer diagnosis, and 1.5 (1.2;2) years before anal cancer diagnosis. Among all measures of EAA only GrimAge acceleration was significantly associated with lung cancer of PLWH after adjustment for race and CD4 T cell count, with 316% greater odds per 5-year increase in age acceleration (OR=3.16 [95% CI:1.06, 9.45]; p=0.04). IEAA, EEAA and PhenoAge acceleration were not associated with lung or anal cancer, and GrimAge acceleration was not associated with anal cancer.


*Adjusting for race and CD4 cell count
These results suggest that GrimAge captures epigenetic markers associated with smoking exposure/oxidative stress and thus, may suggest that accumulation of molecular damage is associated with lung cancer among PLWH independently of immune suppression.
Achenbach C, Zheng Y, Joyce B, et al. Epigenetic age acceleration and non-AIDS defining cancers among HIV infected adults. 10th International Workshop on HIV and Aging, 10-11 October, 2019, New York. Abstract 4.
Lipidome abnormalities in PLWH may contribute to a pro-atherogenic monocyte-derived macrophages (MDMs) phenotype in the aging HIV population.
Persistent immune activation in PLWH may complicate the aging process and accelerate the development of comorbidities, such as cardiovascular disease (CVD). Macrophages accumulate in blood vessel walls and produce factors that contribute to vascular inflammation. The relationship between dyslipidemia [associated to HIV infection and antiretroviral therapy (ART)] and macrophage phenotype in PLWH are not well understood. Emily R. Bowman from the Ohio State University, Columbus, OH, USA and colleagues studied lipidome composition in PLWH by mass spectrometry, as well as coronary artery calcification (CAC) by computed tomography scanning. 40 PLWH (ages 27-67) had significantly increased CAC scores compared to 15 uninfected controls (ages 25-70) both in younger (<55 years old) and older (> 55 years old) groups of participants. Older PLWH (n=17) had an average CAC score of 423, compared to a score of 71 in older people without HIV (n=7). Arterial age estimates (calculation factors: CAC score, age, sex, total cholesterol, HDL, systolic blood pressure, smoking status, use of anti-hypertensive meds) and 10-year Framingham risk score were increased in PLWH compared to uninfected controls. While traditional lipid measurements (TC, LDL, TG) were not significantly different among HIV- and HIV+ groups, 37.1% of all lipidome species were significantly altered in PLWH, including increased serum levels of free fatty acids (FFAs), enrichment of saturated fatty acids (SaFAs) and reduced polyunsaturated fatty acids (PUFAs). Interestingly, lipids classes associated with CVD (ceramides or CERs, diacylglycerols or DAGs, FFAs, and triacylglycerols or TAGs) tended to be increased in older PLWH (over 55 years old) compared to younger ones. Saturated CERs levels, previously linked to CVD in the general population, were directly associated with sCD14 levels in older (r=0.857, p=0.02), but not in younger PLWH. In a cellular level, MDMs from PLWH had an activated phenotype reflected by an increased mean fluorescence index (MFI) in flow cell cytometry for HLA-DR, TLR4 and CD300e expression, as well as an increased percentage of cells that expressed CD163 compared to uninfected controls. MDMs also displayed increased propensity to form foam cells, which was explored by greater lipid intracellular accumulation (bodipy staining) and increased Dil-OxLDL uptake (incubation with labeled oxLDL and measurement of Dil fluorescence). Moreover, MDMs from PLWH and HIV-negative controls displayed differential patterns of transcriptome (811 differentially expressed genes, p<0.05) regarding all possible pathways (innate immune signaling, cell cycle regulation, DNA damage repair, replication complexes, lipid processing pathways and mitochondrial function). Biomarkers (sCD14) associated with morbidity and mortality in HIV infection correlated with unique differential gene expression (DGE) signatures. Additionally, exposure of MDMs from people without HIV to pooled serum from HIV+ donors was sufficient to alter macrophage phenotype of non infected participants (greater intracellular lipid accumulation and DGE than did cells exposed to HIV- pooled serum). Overall, MDMs from PLWH readily form foam cells, have altered transcriptional profiles, and produce mediators of vascular inflammation, which may all enhance CVD risk.
Bowman E, Kulkarni M, Gabriel J, et al. Lipidome abnormalities and altered macrophage phenotype may contribute to cardiovascular disease risk in the aging HIV population.
10th International Workshop on HIV and Aging,
10-11 October, 2019, New York. Abstract 5.
Older PLWH had a remarkably elevated risk of cardiovascular disease using the atherosclerotic cardiovascular disease (ASCVD) risk score of the American College of Cardiology calculator, and this risk was correlated with moderate-severely elevated albuminuria, suggesting common metabolic and inflammatory pathophysiologic mechanisms.
Chronic non-communicable disease burden (such as kidney dysfunction and cardiovascular disease) is increased in older PLWH and can be respectively assessed by estimated glomerular filtration rate/measurement of albuminuria, and calculation of the 10-year ASCVD Risk Score. Carrie Johnston from NYP-Weill Cornell Medical Center, New York, United States, examined association of albuminuria with elevated ASCVD in a cross-sectional analysis of older PLWH participating in the Research on Older Adults with HIV (ROAH) 2.0 Survey that was undertaken at a single urban medical center. The researchers recruited a random sample of 164 PLWH over age 55, who underwent a ROAH 2.0 substudy with a clinical visit (BP Measurement, Waist Circumference, Psychosocial Survey, Frailty testing and MoCA), a body composition analysis, and a blood/urine collection. Characteristics of participants were rather common with other cohorts of older PLWH, namely a mean age of 61+/- 6 years, a median time since HIV diagnosis of 25 years (IQR 22-29), 34% were female, 50% were African-American, 93% were virologically suppressed at the cut-off value of 200 copies of HIV ARN/mL de plasma, and median value of current CD4 T cells was 582/mm3 (IQR 402-795). GFR was relatively preserved in this population [median estimation by CKD-Epi Equation of 75 mL/min per 1.73 m2 (IQR 60-91)], but they observed a notable albuminuria, with 28 (18%) participants having moderately increased albuminuria ("microalbuminuria" as defined by 30-300 mg albumin/g urine creatinine) and 8 (5%) participants having > 300 mg albumin/g urine creatinine ("macroalbuminuria"). Albuminuria was inversely correlated with eGFR (p=0.002), but there was no significant relationship between presence of moderate-severe elevation in albuminuria by medication use [Tenofovir Disoproxil Fumarate (TDF), Tenofovir Alafenamide (TAF), Angiotensin Converting Enzyme (ACEi) or Angiotensin II receptor blockers (ARB)] by Ficher's Exact test.
The median ASVCD score was 9.8% (IQR 6.4-15.2). Median ASCVD score was greater in those with moderate-severe albuminuriaby two-sample Wilcoxon rank-sum (p=0.002), with similar findings in the sensitivity analysis restricted to non-diabetics (p=0.052). It is important to highlight that among participants with elevated ASCVD score (>7.5%) only 52% were on statin therapy [PLWH over 65 years old or had a diabetes history were more likely to be on statin (p<0.001 and p=0.002 respectively)], and 19% were currently on abacavir. Globally, nearly a quarter (23%) of this population had moderate-severely elevated albuminuria, and over half (53%) presented elevated ASCVD Score (>7.5%), suggesting the interest of a parallel follow-up of cardiac and renal parameters, in order to optimise cardiovascular and renal disease prevention.
Johnston C, Ifeagwu K, Siegler E, et al. Elevated cardiac risk score by ASCVD calculation is associated with albuminuria in older people living with HIV. 10th International Workshop on HIV and Aging, 10-11 October, 2019, New York. Abstract 6.