title: Acceleration of age-associated methylation patterns in HIV-1-infected adults.
abstract: 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 x 10(-200) and 0.47, p<1 x 10(-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: βage=0.007088, p=2.08 x 10(-9); βHIV=0.099574, p=0.0011; Data set 2: βage=0.008762, p=1.27 x 10(-5); βHIV=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 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.
authors: Department of Medicine, Division of Hematology/Oncology, AIDS Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Tammy M
authors: TM
authors: Rickabaugh
authors: Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Ruth M
authors: RM
authors: Baxter
authors: Department of Medicine, Division of Hematology/Oncology, AIDS Institute, University of California Los Angeles, Los Angeles, California, United States of America; Biomathematics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Mary
authors: M
authors: Sehl
authors: Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America; Biomathematics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Department of Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Janet S
authors: JS
authors: Sinsheimer
authors: Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Patricia M
authors: PM
authors: Hultin
authors: Department of Medicine, Division of Hematology/Oncology, AIDS Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Lance E
authors: LE
authors: Hultin
authors: Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Austin
authors: A
authors: Quach
authors: Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America; Departments of Obstetrics and Gynecology, and Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Otoniel
authors: O
authors: Martínez-Maza
authors: Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Steve
authors: S
authors: Horvath
authors: Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Eric
authors: E
authors: Vilain
authors: Department of Medicine, Division of Hematology/Oncology, AIDS Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Beth D
authors: BD
authors: Jamieson
mesh_terms: D000328:Adult; D000367:Age Factors; D000375:Aging / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015658:HIV Infections / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D055815:Young Adult