Epigenetic Modification of FOXP3 in Patients With Chronic HIV Infection

Abdel-hameed, Enass A.; Ji, Hong; Sherman, Kenneth E.; Shata, Mohamed T.

doi:10.1097/qai.0b013e3182a1bca4

Cited by 17 publications

(25 citation statements)

References 41 publications

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“…For example, Abdel-Hameed, et al recently reported that chronic HIV infection is associated with alterations in expression of methylation machinery including suppression of DNMT-1 activity, leading to increased FoxP3 promoter demethylation (60). However, others have demonstrated that HIV may enhance the activity of DNMTs, leading to hypermethylation and inactivation of genes important for anti-viral function, such as IFNγ (61).…”

Section: Discussionmentioning

confidence: 99%

Modulating DNA Methylation in Activated CD8+ T Cells Inhibits Regulatory T Cell–Induced Binding of Foxp3 to the CD8+ T Cell IL-2 Promoter

Miller

Akaronu

et al. 2015

The Journal of Immunology

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We have previously demonstrated that CD4+CD25+ Treg cells activated during the course of FIV infection suppress CD8+ CTL function in a TGFβ-dependent fashion, inhibiting IFNγ and IL2 production, and inducing G1 cell cycle arrest. Here, we describe the molecular events occurring at the IL2 promoter leading to suppression of IL2 production. These experiments demonstrate that FoxP3 induced by lentivirus-activated Treg cells in the CD8+ target cells binds to the IL2 promoter, actively repressing IL2 transcription. We further demonstrate that the chronic activation of CD8+ T cells during FIV infection results in chromatin remodeling at the IL2 promoter, specifically, demethylation of CpG residues. These DNA modifications occur during active transcription and translation of IL2; however, these changes render the IL2 promoter permissive to FoxP3-induced transcriptional repression. These data help explain, in part, the seemingly paradoxical observations that CD8+ T cells displaying an activation phenotype exhibit altered antiviral function. Further, we demonstrate that blocking demethylation of CpG residues at the IL2 promoter inhibits FoxP3 binding, suggesting a potential mechanism for rescue and / or reactivation of CD8+ T cells. Using the FIV model for lentiviral persistence, these studies provide a framework for understanding how immune activation combined with Treg cell-mediated suppression may affect CD8+ T cell IL2 transcription, maturation, and anti-viral function.

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Section: Discussionmentioning

confidence: 99%

Modulating DNA Methylation in Activated CD8+ T Cells Inhibits Regulatory T Cell–Induced Binding of Foxp3 to the CD8+ T Cell IL-2 Promoter

Miller

Akaronu

et al. 2015

The Journal of Immunology

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“…The HIV-1-induced epigenetic modulations were also demonstrated in the CD4 + FoxP3 + regulatory T cells (Treg) [ 14 ]. Recent study showed that Treg cells suffered demethylation in the FOXP3 promoter after HIV-1 infection.…”

Section: Introductionmentioning

confidence: 99%

“…Recent study showed that Treg cells suffered demethylation in the FOXP3 promoter after HIV-1 infection. Furthermore, an elevated frequency of Treg cells was found in the gut mucosa of HIV-1 infected patients due to possible aberrant methylation processes [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Modulations in Activated Cells Early after HIV-1 Infection and Their Possible Functional Consequences

et al. 2015

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Epigenetic modifications refer to a number of biological processes which alter the structure of chromatin and its transcriptional activity such as DNA methylation and histone post-translational processing. Studies have tried to elucidate how the viral genome and its products are affected by epigenetic modifications imposed by cell machinery and how it affects the ability of the virus to either, replicate and produce a viable progeny or be driven to latency. The purpose of this study was to evaluate epigenetic modifications in PBMCs and CD4+ cells after HIV-1 infection analyzing three approaches: (i) global DNA- methylation; (ii) qPCR array and (iii) western blot. HIV-1 infection led to methylation increases in the cellular DNA regardless the activation status of PBMCs. The analysis of H3K9me3 and H3K27me3 suggested a trend towards transcriptional repression in activated cells after HIV-1 infection. Using a qPCR array, we detected genes related to epigenetic processes highly modulated in activated HIV-1 infected cells. SETDB2 and RSK2 transcripts showed highest up-regulation levels. SETDB2 signaling is related to transcriptional silencing while RSK2 is related to either silencing or activation of gene expression depending on the signaling pathway triggered down-stream. In addition, activated cells infected by HIV-1 showed lower CD69 expression and a decrease of IL-2, IFN-γ and metabolism-related factors transcripts indicating a possible functional consequence towards global transcriptional repression found in HIV-1 infected cells. Conversely, based on epigenetic markers studied here, non-stimulated cells infected by HIV-1, showed signs of global transcriptional activation. Our results suggest that HIV-1 infection exerts epigenetic modulations in activated cells that may lead these cells to transcriptional repression with important functional consequences. Moreover, non-stimulated cells seem to increase gene transcription after HIV-1 infection. Based on these observations, it is possible to speculate that the outcome of viral infections may be influenced by the cellular activation status at the moment of infection.

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“…The same group found the CpG sites in the Foxp3 locus to be hypermethylated due to increased expression of DNMT3b [ 105 ]. Another report, however, showed increased frequency of Treg cells in the gut mucosa of HIV-1 infected patients due to decreased methylation of Foxp3 promoters in the gut associated T cells, causing the induction of iTreg cells [ 160 ]. They also reported that the Foxp3 promoter was significantly de-methylated possibly due to the downregulation of key DNMT enzymes in HIV patients when compared to uninfected control subjects [ 160 ].…”

Section: Epigenetic Modulation Of Immune Cells As a Results Of Hiv mentioning

confidence: 99%

Epigenetic Modulation of CD8+ T Cell Function in Lentivirus Infections: A Review

Nag

Paris

Fogle

2018

Viruses

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CD8+ T cells are critical for controlling viremia during human immunodeficiency virus (HIV) infection. These cells produce cytolytic factors and antiviral cytokines that eliminate virally- infected cells. During the chronic phase of HIV infection, CD8+ T cells progressively lose their proliferative capacity and antiviral functions. These dysfunctional cells are unable to clear the productively infected and reactivated cells, representing a roadblock in HIV cure. Therefore, mechanisms to understand CD8+ T cell dysfunction and strategies to boost CD8+ T cell function need to be investigated. Using the feline immunodeficiency virus (FIV) model for lentiviral persistence, we have demonstrated that CD8+ T cells exhibit epigenetic changes such as DNA demethylation during the course of infection as compared to uninfected cats. We have also demonstrated that lentivirus-activated CD4+CD25+ T regulatory cells induce forkhead box P3 (Foxp3) expression in virus-specific CD8+ T cell targets, which binds the interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ promoters in these CD8+ T cells. Finally, we have reported that epigenetic modulation reduces Foxp3 binding to these promoter regions. This review compares and contrasts our current understanding of CD8+ T cell epigenetics and mechanisms of lymphocyte suppression during the course of lentiviral infection for two animal models, FIV and simian immunodeficiency virus (SIV).

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Epigenetic Modification of FOXP3 in Patients With Chronic HIV Infection

Cited by 17 publications

References 41 publications

Modulating DNA Methylation in Activated CD8+ T Cells Inhibits Regulatory T Cell–Induced Binding of Foxp3 to the CD8+ T Cell IL-2 Promoter

Modulating DNA Methylation in Activated CD8+ T Cells Inhibits Regulatory T Cell–Induced Binding of Foxp3 to the CD8+ T Cell IL-2 Promoter

Epigenetic Modulations in Activated Cells Early after HIV-1 Infection and Their Possible Functional Consequences

Epigenetic Modulation of CD8+ T Cell Function in Lentivirus Infections: A Review

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