Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

PLoS Pathogens

Khader Ghneim¹  Francesco A. Procopio¹  Jo Watson¹  Jennifer F. Hoy¹  Miranda Z. Smith¹  Fiona Wightman¹  Ajantha Solomon²  Janine Roney²  Mark J. Cameron²  Rémi Fromentin²  Sarah Palmer²  Julian H. Elliott²  Nicolas Chomont²  Joumana Zeidan²  Elizabeth Sinclair²  Miles H. Prince³  Jeffrey Ahlers³  Tim Spelman³  Lina Odevall⁴  Ricky W. Johnstone⁵  Ben P. Martin⁶  Rafick-Pierre Sékaly⁷  Paul U. Cameron⁷  Pushparaj Velayudham⁷  James McMahon⁷  Steven G. Deeks⁷  Daria J. Hazuda⁷  Gregor Brown⁷  Sharon R. Lewin⁸ 

[1] Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia;Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia;Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia;National Association of People Living with HIV Australia, Sydney, New South Wales, Australia;Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia;Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia;Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America;Westmead Millenium Institute, University of Sydney, Westmead, New South Wales, Australia

关键词: HIV;    T cells;    Gene expression;    Blood;    DNA transcription;    RNA folding;    Histones;    Blood plasma;   

DOI  :  10.1371/journal.ppat.1004473

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY