Abstract
BackgroundHuman immunodeficiency virus type 1 (HIV-1) latency represents the major barrier to virus eradication in infected individuals because cells harboring latent HIV-1 provirus are not affected by current antiretroviral therapy (ART). We previously demonstrated that DNA methylation of HIV-1 long terminal repeat (5’ LTR) restricts HIV-1 reactivation and, together with chromatin conformation, represents an important mechanism of HIV-1 latency maintenance. Here, we explored the new issue of temporal development of DNA methylation in latent HIV-1 5’ LTR.ResultsIn the Jurkat CD4+ T cell model of latency, we showed that the stimulation of host cells contributed to de novo DNA methylation of the latent HIV-1 5’ LTR sequences. Consecutive stimulations of model CD4+ T cell line with TNF-α and PMA or with SAHA contributed to the progressive accumulation of 5’ LTR DNA methylation. Further, we showed that once established, the high DNA methylation level of the latent 5’ LTR in the cell line model was a stable epigenetic mark. Finally, we explored the development of 5’ LTR DNA methylation in the latent reservoir of HIV-1-infected individuals who were treated with ART. We detected low levels of 5’ LTR DNA methylation in the resting CD4+ T cells of the group of patients who were treated for up to 3 years. However, after long-term ART, we observed an accumulation of 5’ LTR DNA methylation in the latent reservoir. Importantly, within the latent reservoir of some long-term-treated individuals, we uncovered populations of proviral molecules with a high density of 5’ LTR CpG methylation.ConclusionsOur data showed the presence of 5’ LTR DNA methylation in the long-term reservoir of HIV-1-infected individuals and implied that the transient stimulation of cells harboring latent proviruses may contribute, at least in part, to the methylation of the HIV-1 promoter.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0185-6) contains supplementary material, which is available to authorized users.
Highlights
Human immunodeficiency virus type 1 (HIV-1) latency represents the major barrier to virus eradication in infected individuals because cells harboring latent HIV-1 provirus are not affected by current antiretroviral therapy (ART)
Cellular stimulation contributed to de novo DNA methylation of the proviral 5’ long terminal repeat (LTR) in the cell line model The accumulation of highly methylated latent proviral copies observed during consecutive cycles of provirus reactivation and negative selection could be explained either by the selection of preexisting non-reactivated methylated proviruses or by de novo proviral 5’ LTR DNA methylation induced in the process of tumor necrosis factor-α (TNF-α) and PMA-mediated cell stimulations
Hypermethylation of 5’ LTR DNA in the HIV-1 latency model cell line is maintained by DNA methyltransferase 1 (DNMT1) Assuming the role of provirus 5’ LTR DNA methylation in the maintenance of HIV-1 latency, we explored the stability of HIV-1 5’ LTR hypermethylation in the 2D12 cell line
Summary
Human immunodeficiency virus type 1 (HIV-1) latency represents the major barrier to virus eradication in infected individuals because cells harboring latent HIV-1 provirus are not affected by current antiretroviral therapy (ART). We explored the development of 5’ LTR DNA methylation in the latent reservoir of HIV-1-infected individuals who were treated with ART. It was demonstrated that HDAC inhibitors, including VPA and SAHA, do not induce HIV production in the latent viral reservoir of aviremic individuals in ex vivo system [32]. The results of clinical trials have demonstrated that the latent reservoir in vivo is reactivated only partially, and the latency maintenance mechanisms are crucial targets for HIV-1-therapeutic strategies (reviewed in [36])
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