Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults

March Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults Tammy M. Rickabaugh 0 1 2 3 Ruth M. Baxter 0 1 2 3 Mary Sehl 0 1 2 3 Janet S. Sinsheimer 0 1 2 3 Patricia M. Hultin 0 1 2 3 Lance E. Hultin 0 1 2 3 Austin Quach 0 1 2 3 Otoniel Martnez-Maza 0 1 2 3 Steve Horvath 0 1 2 3 Eric Vilain 0 1 2 3 Beth D. Jamieson 0 1 2 3 0 Funding: This study was supported by NIA Grant 1RO1-AG-030327 awarded to B.D. Jamieson , P.I. , and by a UCLA AIDS Institute/CFAR Seed Grant from the National Institutes of Health award AI-28697 given to Dr. Eric Vilain, P.I. Ruth Baxter was supported by a NIH T032 training grant 1 Data Availability Statement: Data are held by the Center for Analysis and Management of Multicenter AIDS Cohort Study (CAMACS). For access to the MACS data, please complete the collaboration concept sheet and identify the article for which the data were used. This form and instructions may be found at: http://statepi.jhsph.edu/macs/forms.html 2 Academic Editor: Karen Conneely, Emory University , UNITED STATES 3 1 Department of Medicine, Division of Hematology/Oncology, AIDS Institute, University of California Los Angeles , Los Angeles , California, United States of America, 2 Department of Human Genetics, University of California Los Angeles , Los Angeles , California, United States of America , 3 Biomathematics , David Geffen School of Medicine, University of California Los Angeles , Los Angeles , California, United States of America, 4 Department of Biostatistics, School of Public Health, University of California Los Angeles , Los Angeles , California, United States of America, 5 Department of Epidemiology, School of Public Health, University of California Los Angeles , Los Angeles , California, United States of America, 6 Departments of Obstetrics and Gynecology , and Microbiology, Immunology and Molecular Genetics , University of California Los Angeles , Los Angeles, California , United States of America Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x10-200 and 0.47, p<1x10-200. Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: age= 0.007088, p=2.08 x 10-9; HIV= 0.099574, p=0.0011; Data set 2: age= 0.008762, p=1.27x 10-5; HIV= 0.128649, p= 0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10-6, odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age-associated patterns and suggest that - #5T32GM008243-25. Janet Sinsheimer is partially funded by NSF grant DMS-1264153. Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) and/or the Women's Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). MACS Principal Investigators are funded by the following sources: Johns Hopkins University Bloomberg School of Public Health (Joseph Margolick), U01-AI35042; Northwestern University (Steven Wolinsky), U01AI35039; University of California, Los Angeles (Roger Detels), U01-AI35040; University of Pittsburgh (Charles Rinaldo), U01-AI35041; the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (Lisa Jacobson), UM1-AI35043. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the National Cancer Institute (NCI). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1TR000424 (JHU CTSA). Research supported in this publication included work performed in the Flow Cytometry Core Facility supported by the National Institutes of Health through the National Cancer Institute under award number P30 CA016042, and through the National Institute of Allergy and Infectious Diseases, Center for AIDS Research award number 5P30 AI028697. Additional support was provided by various donor funds awarded by the David Geffen School of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or donors to the David Geffen School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging. Aging is associated with an increasing incidence of chronic, debilitating, diseases. While cardiovascular, skeletal, and neurodegenerative diseases are widely known and discussed in the general population, there is virtually no organ or tissue system that is not at risk. The mechanisms underlying aging and its deleterious effects are poorly understood, but thought to be multifactorial and to involve epigenetic changes [1]. Epigenetics is the alteration of DNA through modifications that do not change the underlying nucleotide sequence [2], yet are important in controlling (...truncated)