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


BACKGROUND
ClinicalTrials.gov NCT01365065.
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.
Julian H
JH
Elliott
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia; Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
Fiona
F
Wightman
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia; Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
Ajantha
A
Solomon
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Khader
K
Ghneim
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Jeffrey
J
Ahlers
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Mark J
MJ
Cameron
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia; Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
Miranda Z
MZ
Smith
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.
Tim
T
Spelman
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.
James
J
McMahon
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.
Pushparaj
P
Velayudham
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.
Gregor
G
Brown
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.
Janine
J
Roney
National Association of People Living with HIV Australia, Sydney, New South Wales, Australia.
Jo
J
Watson
Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia; Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Miles H
MH
Prince
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia.
Jennifer F
JF
Hoy
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Nicolas
N
Chomont
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Rémi
R
Fromentin
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Francesco A
FA
Procopio
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Joumana
J
Zeidan
Westmead Millenium Institute, University of Sydney, Westmead, New South Wales, Australia; Karolinska Institutet, Stockholm, Sweden.
Sarah
S
Palmer
Karolinska Institutet, Stockholm, Sweden.
Lina
L
Odevall
Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia; Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Ricky W
RW
Johnstone
Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia; Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Ben P
BP
Martin
University of California San Francisco, San Francisco, California, United States of America.
Elizabeth
E
Sinclair
University of California San Francisco, San Francisco, California, United States of America.
Steven G
SG
Deeks
Merck Research Laboratories, West Point, Pennsylvania, United States of America.
Daria J
DJ
Hazuda
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia; Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
Paul U
PU
Cameron
Vaccine Gene Therapy Institute Florida, Port St Lucie, Florida, United States of America.
Rafick-Pierre
RP
Sékaly
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia; Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
Sharon R
SR
Lewin
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012367:RNA, Viral; D000077337:Vorinostat