Abstract
Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.Trial RegistrationClinicalTrials.gov NCT01365065
Highlights
One of the major barriers to a cure for human immunodeficiency virus (HIV) infection are long lived latently infected memory CD4+ T-cells that persist in patients on suppressive antiretroviral therapy (ART) [1,2]
We examined the ability of standard dose vorinostat given daily for 14 days to activate latent HIV infection in unselected HIV-infected individuals on ART
There has been recent data suggesting that Histone deacetylase inhibitors (HDACi) may only activate HIV transcription through stimulation of a host gene promoter leading to the production of chimeric host-HIV transcripts, or read-through transcripts, and not true cell associated unspliced (CA-US) HIV RNA raising a concern that HDACi are unable to induce virion production [12]
Summary
One of the major barriers to a cure for human immunodeficiency virus (HIV) infection are long lived latently infected memory CD4+ T-cells that persist in patients on suppressive antiretroviral therapy (ART) [1,2]. Using resting CD4+ T-cells from HIV-infected patients on cART ex vivo, HDACi induce both virus transcription and production of free virus [11], the amount of virus produced from resting CD4+ T-cells is significantly less than that induced by a T-cell mitogen [12]. Recent data from a clinical trial of the HDACi romidepsin clearly demonstrated that virus could be produced in vivo following intravenous administration of this HDACi to HIV-infected patients on ART [18]
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