Publication Abstract Display
Type: Published Abstract
Title: DNA methylation of the HIV LTR is rendered obsolete by chronic suppressive ART.
Authors: LaMere S, Gianella S; Chaillon A, Huynh C, Little S, Smith D
Year:
Publication: CROI 2018
Volume: Issue: Pages:
Abstract:Background Targeting epigenetic mechanisms that influence HIV latency could be important for eradication efforts. Cytosine methylation is one mechanism of interest, as it represses transcription when located in mammalian promoters. Previous work in HIV-1 latency models demonstrated that cytosine methylation accumulates in CpG islands in the 5’ LTR with repeated stimulation. Studies from clinical samples are rare and have produced conflicting results. Methods We compared the frequency of cytosine methylation in 13 HIV-infected persons: 6 who started ART during early HIV infection within 5 months from the estimated date of infection (EDI) and were sampled within 2 years, and 7 from a cohort of chronically suppressed individuals. DNA from PBMCs was extracted and bisulfite converted, and the proximal LTR containing 9-12 CpG residues was amplified and sequenced. Results Short description of cohorts. the % of methylated non-CpG cytosines exceeded the percentage of methylated CpG residues for most (10/13) individuals. The majority of methylated non-CpG cytosines were found in the CTG trinucleotide, which has the highest frequency of all cytosine trinucleotides in the HIV LTR. Second, there was a significantly higher percentage of CpG methylation in individuals treated during early in infection compared to those treated during chronic infection. There was no significant difference in non-CpG cytosine methylation between the two groups. Also, frequency of CpG dinucleotides in the LTR were significantly higher in early treated individuals compared to those treated during chronic infection in the LANL database, while no significant difference was seen in the frequency for CTG trinucleotides. Conclusions Based on these results, we propose that CpG methylation is a host mechanism that attempts to control proviral expression during early infection, while chronic suppression reduces its necessity. Additionally, deamination of methylated cytosines likely accounts for the significantly reduced frequency of CpG residues in the HIV LTR of chronically suppressed individuals. Non-CpG methylation was recently reported in mammalian genes, but this is the first report of its existence in HIV provirus. Non-CpG residues are subject to different methyltransferase preferences than CpG residues, which could account for the frequency differences observed between methylation of these cytosine motifs.

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