bix-01294 and HIV-Infections

Despite the advances in Human Immunodeficiency Virus (HIV) treatment, the cure for all HIV patients still poses a major challenge, which needs to be surpassed in the coming years. Among the strategies pursuing this aim, the 'kick-and-kill' approach, which involves the reactivation and elimination of a latent HIV reservoir that resides in some CD4

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Histone Deacetylase Inhibitors; HIV Infections; HIV-1; Humans; Molecular Structure; Virus Latency

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

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