Monocyte Activation and Ageing Biomarkers in the Development of Cardiovascular Ischaemic Events or Diabetes in People with HIV

We investigated whether blood telomere length (TL), epigenetic age acceleration (EAA), and soluble inflammatory monocyte cytokines are associated with cardiovascular events or diabetes (DM) in people living with HIV (PLHIV). This was a case–control study nested in the Spanish HIV/AIDS Cohort (CoRIS). Cases with myocardial infarction, stroke, sudden death, or diabetes after starting antiretroviral therapy were included with the available samples and controls matched for sex, age, tobacco use, pre-ART CD4 cell count, viral load, and sample time-point. TL (T/S ratio) was analysed by quantitative PCR and EAA with DNA methylation changes by next-generation sequencing using the Weidner formula. Conditional logistic regression was used to explore the association with cardiometabolic events. In total, 180 participants (94 cases (22 myocardial infarction/sudden death, 12 strokes, and 60 DM) and 94 controls) were included. Of these, 84% were male, median (IQR) age 46 years (40–56), 53% were current smokers, and 22% had CD4 count ≤ 200 cells/mm3 and a median (IQR) log viral load of 4.52 (3.77–5.09). TL and EAA were similar in the cases and controls. There were no significant associations between TL, EAA, and monocyte cytokines with cardiometabolic events. TL and EAA were mildly negatively correlated with sCD14 (rho = −0.23; p = 0.01) and CCL2/MCP-1 (rho = −0.17; p = 0.02). We found no associations between TL, EAA, and monocyte cytokines with cardiovascular events or diabetes. Further studies are needed to elucidate the clinical value of epigenetic biomarkers and TL in PLHIV.

[1]  K. Ley,et al.  How the immune system shapes atherosclerosis: roles of innate and adaptive immunity , 2021, Nature Reviews Immunology.

[2]  B. Rodés,et al.  Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial. , 2021, The lancet. HIV.

[3]  S. Horvath,et al.  The Effects of Anti-retroviral Therapy on Epigenetic Age Acceleration Observed in HIV-1-infected Adults , 2020, Pathogens & immunity.

[4]  S. Horvath,et al.  Accelerated Epigenetic Aging and Methylation Disruptions Occur in Human Immunodeficiency Virus Infection Prior to Antiretroviral Therapy. , 2020, The Journal of infectious diseases.

[5]  Jan A. Roth,et al.  Telomere Length, Traditional Risk Factors, HIV-related Factors and Coronary Artery Disease Events in Swiss Persons Living with HIV. , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  Vicente Andrés,et al.  Biological Versus Chronological Aging: JACC Focus Seminar. , 2020, Journal of the American College of Cardiology.

[7]  Juulia Jylhävä,et al.  Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up , 2020, eLife.

[8]  S. Horvath,et al.  Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. , 2019, Circulation.

[9]  M. Esteller,et al.  DNA methylation biomarkers of myocardial infarction and cardiovascular disease , 2019, bioRxiv.

[10]  Alex P. Reiner,et al.  DNA methylation GrimAge strongly predicts lifespan and healthspan , 2019, Aging.

[11]  K. Ley,et al.  Immunity and Inflammation in Atherosclerosis , 2019, Circulation research.

[12]  T. Nawrot,et al.  Telomere Length as Cardiovascular Aging Biomarker: JACC Review Topic of the Week. , 2018, Journal of the American College of Cardiology.

[13]  B. Rodés,et al.  Blood Telomere Length Changes After Ritonavir-Boosted Darunavir Combined With Raltegravir or Tenofovir-Emtricitabine in Antiretroviral-Naive Adults Infected With HIV-1 , 2018, The Journal of infectious diseases.

[14]  S. Rajagopalan,et al.  Global Burden of Atherosclerotic Cardiovascular Disease in People Living With HIV: Systematic Review and Meta-Analysis , 2018, Circulation.

[15]  M. Lederman,et al.  Changes in Inflammation but Not in T-Cell Activation Precede Non-AIDS-Defining Events in a Case-Control Study of Patients on Long-term Antiretroviral Therapy , 2018, The Journal of infectious diseases.

[16]  B. Rodés,et al.  Impact of Nucleos(t)ide Reverse Transcriptase Inhibitors on Blood Telomere Length Changes in a Prospective Cohort of Aviremic HIV–Infected Adults , 2018, The Journal of infectious diseases.

[17]  M. Levine,et al.  An epigenetic biomarker of aging for lifespan and healthspan , 2018, bioRxiv.

[18]  R. Perona,et al.  Impact of Antiretroviral Treatment Containing Tenofovir Difumarate on the Telomere Length of Aviremic HIV-Infected Patients , 2017, Journal of Acquired Immune Deficiency Syndromes.

[19]  A. Aviv,et al.  Short Telomeres, but Not Telomere Attrition Rates, Are Associated With Carotid Atherosclerosis , 2017, Hypertension.

[20]  Yan V. Sun,et al.  Identification of HIV infection-related DNA methylation sites and advanced epigenetic aging in HIV-positive, treatment-naive U.S. veterans , 2017, AIDS.

[21]  M. Levine,et al.  DNA methylation-based measures of biological age: meta-analysis predicting time to death , 2016, Aging.

[22]  Trey Ideker,et al.  Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. , 2016, Molecular cell.

[23]  S. Yusuf,et al.  Telomere Length and Risk of Myocardial Infarction in a MultiEthnic Population: The INTERHEART Study. , 2016, Journal of the American College of Cardiology.

[24]  E. Bahiru,et al.  Patterns of Cardiovascular Mortality for HIV-Infected Adults in the United States: 1999 to 2013. , 2016, The American journal of cardiology.

[25]  N. Iwai,et al.  Establishment of the MethyLight Assay for Assessing Aging, Cigarette Smoking, and Alcohol Consumption , 2015, BioMed research international.

[26]  S. Horvath,et al.  HIV-1 Infection Accelerates Age According to the Epigenetic Clock , 2015, The Journal of infectious diseases.

[27]  J. Margolick,et al.  Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection. , 2015, The Journal of infectious diseases.

[28]  S. Horvath,et al.  Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults , 2015, PloS one.

[29]  H. Gerstein,et al.  Association Between Shortened Leukocyte Telomere Length and Cardiometabolic Outcomes: Systematic Review and Meta-Analysis , 2015, Circulation. Cardiovascular genetics.

[30]  S. Horvath,et al.  DNA methylation age of blood predicts all-cause mortality in later life , 2015, Genome Biology.

[31]  M. Lederman,et al.  Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. , 2014, The Journal of infectious diseases.

[32]  L. Hurley,et al.  HIV infection and incidence of ischemic stroke , 2014, AIDS.

[33]  Stephen Kaptoge,et al.  Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis , 2014, BMJ : British Medical Journal.

[34]  J. Singer,et al.  Association between short leukocyte telomere length and HIV infection in a cohort study: No evidence of a relationship with antiretroviral therapy. , 2014, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[35]  Thomas W. Mühleisen,et al.  Aging of blood can be tracked by DNA methylation changes at just three CpG sites , 2014, Genome Biology.

[36]  S. Horvath DNA methylation age of human tissues and cell types , 2013, Genome Biology.

[37]  Manuel Serrano,et al.  The Hallmarks of Aging , 2013, Cell.

[38]  M. Budoff,et al.  HIV infection and the risk of acute myocardial infarction. , 2013, JAMA internal medicine.

[39]  Hermann Brenner,et al.  A systematic review of leukocyte telomere length and age in adults , 2013, Ageing Research Reviews.

[40]  T. Ideker,et al.  Genome-wide methylation profiles reveal quantitative views of human aging rates. , 2013, Molecular cell.

[41]  C. Tural,et al.  Risk, predictors, and mortality associated with non-AIDS events in newly diagnosed HIV-infected patients: role of antiretroviral therapy , 2013, AIDS.

[42]  D. Fliser,et al.  CD14 CD16 Monocytes Independently Predict Cardiovascular Events , 2012 .

[43]  L. Kuller,et al.  Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals , 2012, PloS one.

[44]  J. McCune,et al.  Immunosenescence and HIV. , 2012, Current opinion in immunology.

[45]  Raquel Lorente,et al.  The Spanish HIV BioBank: a model of cooperative HIV research , 2009, Retrovirology.

[46]  Nancy E. Adler,et al.  The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men , 2008, Aging.

[47]  G. De Backer,et al.  Telomere length and cardiovascular risk factors in a middle‐aged population free of overt cardiovascular disease , 2007, Aging cell.

[48]  R. Kronmal,et al.  Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. , 2006, American journal of epidemiology.

[49]  F. Pulido,et al.  Cohorte RIS de pacientes con infección por VIH sin tratamiento antirretroviral previo (CoRIS): metodología y primeros resultados , 2007 .