Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy

Julian Elliott, Fiona Wightman, Ajantha Solomon, Ghneim Khader, Jeffrey D Ahlers, Mark J Cameron, Miranda Zoe Denham Smith, Tim Spelman, James Hamilton McMahon, Pushparaj Velayudham, Gregor Brown, Janine Roney, Jo Watson, Miles H Prince, Jennifer Frances Hoy, Nicolas Chomont, Remi Fromentin, Francesco A Procopio, Joumana Zeidan, Sarah PalmerLina Odevall, Ricky W Johnstone, Benjamin P Martin, Elizabeth J Sinclair, Steven G Deeks, Daria Jean Hazuda, Paul Urquhart Cameron, Rafick-Pierre Sekaly, Sharon Ruth Lewin

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Abstract

UNLABELLED: 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 REGISTRATION: ClinicalTrials.gov NCT01365065.

Original languageEnglish
Article numbere1004473
Number of pages19
JournalPLoS Pathogens
Volume10
Issue number11
DOIs
Publication statusPublished - 1 Oct 2014

Cite this

Elliott, J., Wightman, F., Solomon, A., Khader, G., Ahlers, J. D., Cameron, M. J., Smith, M. Z. D., Spelman, T., McMahon, J. H., Velayudham, P., Brown, G., Roney, J., Watson, J., Prince, M. H., Hoy, J. F., Chomont, N., Fromentin, R., Procopio, F. A., Zeidan, J., ... Lewin, S. R. (2014). Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathogens, 10(11), [e1004473]. https://doi.org/10.1371/journal.ppat.1004473