Broad activation of latent HIV-1 in vivo

Kirston Barton (), Bonnie Hiener, Anni Winckelmann, Thomas Aagaard Rasmussen, Wei Shao, Karen Byth, Robert Lanfear, Ajantha Solomon, James McMahon, Sean Harrington, Maria Buzon, Mathias Lichterfeld, Paul W. Denton, Rikke Olesen, Lars Østergaard, Martin Tolstrup, Sharon R. Lewin, Ole Schmeltz Søgaard and Sarah Palmer ()
Additional contact information
Kirston Barton: Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney
Bonnie Hiener: Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney
Anni Winckelmann: Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney
Thomas Aagaard Rasmussen: Aarhus University Hospital
Wei Shao: Advanced Biomedical Computing Center, Leidos Biomedical Research Inc.
Karen Byth: NWSLHD Research and Education Network
Robert Lanfear: Macquarie University
Ajantha Solomon: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital
James McMahon: Alfred Hospital and Monash University
Sean Harrington: Ragon Institute of MGH, MIT, Harvard
Maria Buzon: Ragon Institute of MGH, MIT, Harvard
Mathias Lichterfeld: Ragon Institute of MGH, MIT, Harvard
Paul W. Denton: Aarhus University Hospital
Rikke Olesen: Aarhus University Hospital
Lars Østergaard: Aarhus University Hospital
Martin Tolstrup: Aarhus University Hospital
Sharon R. Lewin: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital
Ole Schmeltz Søgaard: Aarhus University Hospital
Sarah Palmer: Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12731

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