Broad activation of latent HIV-1 in vivo.
The 'shock and kill' approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy to purge infected cells. The administration of LRAs (panobinostat or vorinostat) to HIV-1-infected individuals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) HIV-1 RNA from CD4(+) T cells. However, it is important to discern whether the increases in CA-US HIV-1 RNA are due to limited or broad activation of HIV-1 proviruses. Here we use single-genome sequencing to find that the RNA transcripts observed following LRA administration are genetically diverse, indicating activation of transcription from an extensive range of proviruses. Defective sequences are more frequently found in CA HIV-1 RNA than in HIV-1 DNA, which has implications for developing an accurate measure of HIV-1 reservoir size. Our findings provide insights into the effects of panobinostat and vorinostat as LRAs for latent HIV-1.
Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Road, Sydney, New South Wales 2145, Australia.
Kirston
K
Barton
Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Road, Sydney, New South Wales 2145, Australia.
Bonnie
B
Hiener
Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Road, Sydney, New South Wales 2145, Australia.|Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.
Anni
A
Winckelmann
Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.|The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia.
Thomas Aagaard
TA
Rasmussen
Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., PO Box B, Frederick, Maryland 21702, USA.|HIV Dynamics and Replication Program, National Cancer Institute, PO Box B, Frederick, Maryland 21702, USA.
Wei
W
Shao
NWSLHD Research and Education Network, Darcy Road, Westmead, NSW 2145, Australia.|NHMRC Clinical Trials Centre, University of Sydney, NSW 2006, Australia.
Karen
K
Byth
Department of Biological Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Robert
R
Lanfear
The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia.|Department of Infectious Diseases, Alfred Hospital and Monash University, 55 Commercial Road, Melbourne, Victoria 3181, Australia.
Ajantha
A
Solomon
Department of Infectious Diseases, Alfred Hospital and Monash University, 55 Commercial Road, Melbourne, Victoria 3181, Australia.
James
J
McMahon
Ragon Institute of MGH, MIT, Harvard, 400 Technology Square, Cambridge, Massachusetts 02139, USA.|Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
Sean
S
Harrington
Ragon Institute of MGH, MIT, Harvard, 400 Technology Square, Cambridge, Massachusetts 02139, USA.|Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
Maria
M
Buzon
Ragon Institute of MGH, MIT, Harvard, 400 Technology Square, Cambridge, Massachusetts 02139, USA.|Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
Mathias
M
Lichterfeld
Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.|Aarhus Institute of Advanced Studies, Høegh-Guldbergs Gade 6B, Aarhus C 8000, Denmark.|Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard 82 Building B, Aarhus N 8200, Denmark.
Paul W
PW
Denton
Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.
Rikke
R
Olesen
Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.|Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard 82 Building B, Aarhus N 8200, Denmark.
Lars
L
Østergaard
Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.|Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard 82 Building B, Aarhus N 8200, Denmark.
Martin
M
Tolstrup
The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia.|Department of Infectious Diseases, Alfred Hospital and Monash University, 55 Commercial Road, Melbourne, Victoria 3181, Australia.
Sharon R
SR
Lewin
Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.|Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard 82 Building B, Aarhus N 8200, Denmark.
Ole Schmeltz
OS
Søgaard
Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Road, Sydney, New South Wales 2145, Australia.
Sarah
S
Palmer
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D004279:DNA, Viral / Q000235:genetics*; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D000077767:Panobinostat; D012367:RNA, Viral / Q000235:genetics*; D014766:Viremia; D017735:Virus Latency; D000077337:Vorinostat
D019380:Anti-HIV Agents; D004279:DNA, Viral; D006877:Hydroxamic Acids; D007211:Indoles; D012367:RNA, Viral; D000077337:Vorinostat; D000077767:Panobinostat