Abstract
We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12 years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01 years) of the participants was higher than their mean chronological age (10.77 years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+
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Funding
This study was funded primarily by R21MH107327-01 (AJL and JH). Funding for CTAAC was provided by R01-HD074051 (HJZ) and SA MRC. HJZ and DJS are supported by the South African Medical Research Council.
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AJL, JH, DJS, and SH conceived of the study. AJL and JH are the PIs of the R21 which primarily funded this study. HZ is PI of the CTAAC study, from which most of the data were derived. SJH and SE carried out the statistical analysis. JF extracted the brain imaging data. JH wrote the first draft of the article. The remaining authors conceived of and aided with the CTAAC study, including collection of the DNA samples and phenotypic data. All authors helped in the interpretation of the findings and the write up of the article.
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Hoare, J., Stein, D.J., Heany, S.J. et al. Accelerated epigenetic aging in adolescents living with HIV is associated with altered development of brain structures. J. Neurovirol. 28, 208–216 (2022). https://doi.org/10.1007/s13365-021-00947-3
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DOI: https://doi.org/10.1007/s13365-021-00947-3