Dataset Information

Histone deacetylase inhibitors impair the elimination of HIV-infected cells by cytotoxic T-lymphocytes.

ABSTRACT: Resting memory CD4+ T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-? production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia.

SUBMITTER: Jones RB

PROVIDER: S-EPMC4133386 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Despite being subjected to high dose chemo and radiotherapy, glioblastoma (GBM) patients still encounter almost inevitable relapse due to the capability of tumor cells to disseminate and invade normal brain tissues. Moreover, the presence of a Cancer Stem Cell (CSC) subpopulation, already demonstrated to better resist and evade treatments, further frustrate potential therapeutic approaches. In this context, we previously demonstrated that GBM is characterized by a tightly regulated balance between the β-catenin cofactors TCF1 and TCF4, with high levels of TCF4 responsible for sustaining CSC in these tumors, thus supporting their aggressive features. Since Histone Deacetylase Inhibitors (HDI) have been reported to strongly reduce TCF4 levels in colon cancer cells, we hypothesized they could exert a similar therapeutic action also in GBM. Here, we treated primary GBM cultures with Trichostatin-A and Vorinostat, demonstrating their ability to strongly suppress the Wnt dependent pathways, thus promoting CSC differentiation, and concomitantly impairing GBM cell viability and proliferation. More interestingly, analysis of their molecular effects suggested a prominent HDI action against GBM cell motility/migration, that we demonstrated to be dependent on the inhibition of the RhoA-GTPase and interferon intracellular cascades. Our results suggest HDI as potential therapeutic agents in GBM through their action on multiple cancer hallmarks. Glioblastoma (GBM) is considered the deadliest brain tumor, with patients displaying a high incidence of relapse and a 3-year survival of only 3-5%. For these reasons, investigation of the molecular basis of the disease could provide novel targets for therapy and improve patient prognosis. Based on our previous data demonstrating that high levels of the transcription factor TCF4 (TCF7L2) sustain the aggressiveness and the stem cell features of these tumors, in this study we tested the ability of the histone deacetylase inhibitors (HDI) Trichostatin-A and Vorinostat to suppress TCF4 levels. We demonstrated that HDI treatment impairs proliferation and viability of GBM cells. Moreover, molecular analysis of HDI effects disclosed their ability to counteract tumor cell motility by affecting the RhoA-GTPase and the interferon pathways, supporting their further characterization as potential anti-GBM agents

Dataset Information

Histone deacetylase inhibitors impair the elimination of HIV-infected cells by cytotoxic T-lymphocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets