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 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: βage= 0.007088, p=2.08 x 10-9; βHIV= 0.099574, p=0.0011; Data set 2: βage= 0.008762, p=1.27x 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.
Highlights
Aging is associated with an increasing incidence of chronic, debilitating, diseases
The effects of HIV-1 infection on changes in methylation are additive with the effects of aging
A subset of sites that are hypermethylated with age show a further increase in methylation in individuals infected with HIV-1, while a subset of sites hypomethylated with age was associated with earlier hypomethylation in HIV-1infected individuals in both data sets
Summary
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. There is evidence of telomere shortening within CD8+ T-cells and a significant increase in senescent CD8+ T-cells in HIV-1-infected individuals, similar to that observed in older seronegative individuals [33,34] Together, these findings have led to the suggestion that HIV-1-infection and aging may interact in a mechanistic manner. We show that our systems biologic analysis based on WGCNA leads to more pronounced biological insights than a standard differential methylation analysis that only considers marginal relationships between CpG sites and HIV infection Comparison of this module to our previously found aging module [12] revealed that it can be found in other solid tissues, notably human brain tissue, and may measure organismal aging effects. These unique tools may aid in the elucidation of novel therapeutic targets for aging-related clinical diagnoses in HIV-infected and uninfected individuals
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