A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

Abstract

Approximately 70% of the HIV-1 latent reservoir originates from infections of CD4 T cells that occur in the months near the time of ART initiation, raising the possibility that interventions during this period might prevent reservoir seeding and reduce reservoir size. We identify class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to striking changes in the memory phenotype of infected cells. Proviral silencing is accomplished through distinct activities of HDAC1/2 and HDAC3. Thus HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus.

The histone methyltransferase SETD2 regulates HIV expression and latency through a post-transcriptional mechanism

“…We then infected the EPZ-719 exposed cells or control vehicle exposed cells with a GFP expressing clone of HIV (HIV-drEGFP). This specific clone contains a short half-life GFP (dreGFP) within the envelope open reading frame, allowing dynamic analysis of LTR-driven HIV expression [17]. When we measured productive HIV infection (%GFP+) by flow cytometry at 3dpi, we observed similar levels of overall infection (29% vs 26%) for EPZ-719 treated cells and cells treated with control vehicle (DMSO) respectively ( Figure 2B, 2C ).…”

“…HIV latency is a stable and heritable phenomenon, consistent with the notion of an epigenetic program that regulates HIV latency [16]. In particular, removal of activating marks such as H3K9ac and H3K27ac by class 1 histone deacetylases (HDACs) and the addition of repressive H3K9me3 and H3K27me3 marks by histone methyltransferases have been shown to contribute to HIV latency [17–19]. ATACseq analysis has also shown that latent proviruses exhibit a “closed” chromatin conformation that likely restricts access by key TFs and RNA Polymerase II (RNAPol2) [16].…”

“…Thus, we focused on the impact of EPZ-719 on HIV infection in activated primary CD4 T cells. To investigate this, we used a primary CD4 T cell model of HIV infection and latency that we have previously established ( Figure 5C ) [16,17,37]. In this model, primary CD4 T cells are activated for two days then infected with HIV-dreGFP.…”

“…Histone-modifying enzymes have been examined for specific roles in HIV latency and reactivation and various complexes have been found to play positive or negative roles in HIV expression. In particular, the role of histone deacetylases (HDACs) in the establishment and maintenance of latency is well known, and HDAC inhibitors potently reverse and prevent HIV latency, both in cell-based model systems and in PWH [17,19,52–55]. The histone methyltransferase EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), may also play a role in HIV silencing [11,56–58].…”

The sounds of silencing: dynamic epigenetic control of HIV latency

“…In an interesting new development, Peterson et al used combinations of HDAC3-directed PROTAC and CRISPR-Cas9 knockout experiments. They showed that while either HDAC1/2 or HDAC3 targeting can prevent latency, all three enzymes must be targeted to achieve latency reversal [30 ▪▪ ]. Latency prevention is associated with increased H3K9ac at the proviral LTR promoter region and decreased H3K9me3, emphasizing an unexpected role of H3K9 modifications in the establishment of latency.…”