chaetocin and HIV-Infections

After entry into the target cell and reverse transcription, HIV-1 genes are integrated into the host genome. It is now well established that the viral promoter activity is directly governed by its chromatin environment. Nuc-1, a nucleosome located immediately downstream of the HIV-1 transcriptional initiation site directly impedes long-terminal repeat (LTR) activity. Epigenetic modifications and disruption of Nuc-1 are a prerequisite to the activation of LTR-driven transcription and viral expression. The compaction of chromatin and its permissiveness for transcription are directly dependent on the post-translational modifications of histones such as acetylation, methylation, phosphorylation and ubiquitination. Understanding the molecular mechanisms underlying HIV-1 transcriptional silencing and activation is thus a major challenge in the fight against AIDS and will certainly lead to new therapeutic tools.

Topics: Azepines; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Viral; Histone Acetyltransferases; Histone Deacetylase Inhibitors; Histone Deacetylases; Histone-Lysine N-Methyltransferase; Histones; HIV Infections; HIV-1; Humans; Nucleosomes; Phorbol Esters; Piperazines; Quinazolines; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic; Virus Integration

HIV infiltrates the brain at early times postinfection and remains latent within astrocytes and macrophages. Because astrocytes are the most abundant cell type in the brain, we evaluated epigenetic regulation of HIV latency in astrocytes. We have shown that class I histone deacetylases (HDACs) and a lysine-specific histone methyltransferase, SU(VAR)3-9, play a significant role in silencing of HIV transcription in astrocytes. Our studies add to a growing body of evidence demonstrating that astrocytes are a reservoir for HIV.

Topics: Astrocytes; Cell Line; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Viral; Histone Deacetylase Inhibitors; Histone Deacetylases; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Leukocytes, Mononuclear; Piperazines; Promoter Regions, Genetic; Transcription, Genetic; Virus Integration; Virus Latency

Reactivation of HIV-1 expression in persistent reservoirs together with an efficient HAART has been proposed as an adjuvant therapy aimed at reaching a functional cure for HIV. Previously, H3K9 methylation was shown to play a major role in chromatin-mediated repression of the HIV-1 promoter. Here, we evaluated the therapeutic potential of histone methyltransferase inhibitors (HMTIs) in reactivating HIV-1 from latency.. We evaluated the reactivation potential of two specific HMTIs (chaetocin and BIX-01294, two specific inhibitors of Suv39H1 and G9a, respectively) in ex-vivo cultures of resting CD4 T cells isolated from HIV-1-infected HAART-treated individuals.. We measured HIV-1 recovery in ex-vivo cultures treated with an HMTI alone or in combination with other HIV-1 inducers (in absence of IL-2 and of allogenic stimulation) of CD8-depleted peripheral blood mononuclear cells (PBMCs) or of resting CD4 T cells isolated from 67 HIV-infected, HAART-treated patients with undetectable viral load.. We demonstrated, for the first time, that chaetocin induced HIV-1 recovery in 50% of CD8-depleted PBMCs cultures and in 86% of resting CD4 T-cell cultures isolated from HIV-1-infected, HAART-treated patients, whereas BIX-01294 reactivated HIV-1 expression in 80% of resting CD4 T-cell cultures isolated from similar patients. Moreover, we showed that combinatory treatments including one HMTI and either the histone deacetylase inhibitor suberoylanilide hydroxamic acid or the non-tumor-promoting NF-κB inducer prostratin had a higher reactivation potential than these compounds alone.. Our results constitute a proof-of-concept for the therapeutic potential of HMTIs in strategies aiming at reducing the pool of latent reservoirs in HIV-infected, HAART-treated patient.

Topics: Antiretroviral Therapy, Highly Active; Azepines; CD4-Positive T-Lymphocytes; Disease Reservoirs; Histocompatibility Antigens; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Methyltransferases; Piperazines; Quinazolines; Repressor Proteins; Virus Latency