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Publication Abstract Display
Type: Published Abstract
Title: DNA methylation correlates with neurological decline in HIV-infected individuals.
Authors: Perez-Santiago J, Plongthongkum N, Letendre S, Ellis R, Gouaux B, Moore D, LeBlanc S, Rajagopal N, Zhang K, Woelk C
Year: 2012
Publication: 19th Conference on Retroviruses and Opportunistic Infections
Volume: Issue: Pages:
Abstract:Introduction HIV invasion of the central nervous system may result in impairment of neurocognitive function. Even with successful antiretroviral therapy, some HIV-infected individuals can experience further neurocognitive decline, for which no biomarkers exist. We hypothesize that levels of DNA methylation, which regulate gene expression, could be used for prediction and diagnosis of neurocognitive decline. Methods HIV-infected participants (N=17) enrolled in a longitudinal cohort at the HIV Neurobehavioral Research Center with neuropsychological performance (NP) test scores at 2 consecutive visits (T1 and T2) were analyzed retrospectively. Raw NP test scores from a comprehensive battery were converted to practice effect corrected mean scaled scores. Genomic DNA was extracted from PBMC samples taken at T1 and T2 (QIAamp DNA Blood Midi Kit). Padlock probes were used to target genomic regions in the human genome (hg18) for methylation analysis. Bisulfite conversion was performed using Zymo DNA Methylation Gold Kit and sequenced using Illumina Hi-Seq 2000. Statistical analyses were performed using R statistical software. Results For each participant, the change in mean neuropsychological scaled score (ΔNP) was calculated between timepoints and methylation profiles (MP) were generated at each time point. Spearman rank correlation analysis between ΔNP and MP at T1 identified 26 highly correlated autosomal sites (|ρ|>0.8 and p < 0.0001). Ten of these methylation sites lie in the promoter region of known genes. Correlation analysis using the MP at T2 showed 48 highly correlated autosomal sites with ΔNP (|ρ|>0.8 and p < 0.0001) with 24 methylation sites in promoter regions of known genes. A total of 18 and 26 methylation sites showed negative correlations with ΔNP at T1 and at T2, respectively. A positive correlation suggests that repression of a gene regulated by a methylation site leads to improvement in NP whereas a negative correlation suggests that de-repression of a gene is associated with improvement. Conclusions This study identified MP associated with the decline in NP performance both prior to (T1) and after (T2) the change. This result suggests that MP could be used as a prognostic as well as a diagnostic tool for neurocognitive decline in HIV infection. DNA methylation may provide a rich source for biomarker development since, in addition to the repression of promoter activity, methylation can also indicate the repression of distal regulatory elements.

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