2. Academic Validation
  3. Broad activation of latent HIV-1 in vivo

Broad activation of latent HIV-1 in vivo

  • Nat Commun. 2016 Sep 8;7:12731. doi: 10.1038/ncomms12731.
Kirston Barton 1,  Bonnie Hiener 1,  Anni Winckelmann 1 2,  Thomas Aagaard Rasmussen 2 3,  Wei Shao 4 5,  Karen Byth 6 7,  Robert Lanfear 8,  Ajantha Solomon 3 9,  James McMahon 9,  Sean Harrington 10 11,  Maria Buzon 10 11,  Mathias Lichterfeld 10 11,  Paul W Denton 2 12 13,  Rikke Olesen 2,  Lars Østergaard 2 13,  Martin Tolstrup 2 13,  Sharon R Lewin 3 9,  Ole Schmeltz Søgaard 2 13,  Sarah Palmer 1
Affiliations

Affiliations

  • 1 Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Road, Sydney, New South Wales 2145, Australia.
  • 2 Department of Infectious Diseases, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, Aarhus N 8200, Denmark.
  • 3 The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia.
  • 4 Advanced Biomedical Computing Center, Leidos Biomedical Research Inc., PO Box B, Frederick, Maryland 21702, USA.
  • 5 HIV Dynamics and Replication Program, National Cancer Institute, PO Box B, Frederick, Maryland 21702, USA.
  • 6 NWSLHD Research and Education Network, Darcy Road, Westmead, NSW 2145, Australia.
  • 7 NHMRC Clinical Trials Centre, University of Sydney, NSW 2006, Australia.
  • 8 Department of Biological Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
  • 9 Department of Infectious Diseases, Alfred Hospital and Monash University, 55 Commercial Road, Melbourne, Victoria 3181, Australia.
  • 10 Ragon Institute of MGH, MIT, Harvard, 400 Technology Square, Cambridge, Massachusetts 02139, USA.
  • 11 Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
  • 12 Aarhus Institute of Advanced Studies, Høegh-Guldbergs Gade 6B, Aarhus C 8000, Denmark.
  • 13 Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard 82 Building B, Aarhus N 8200, Denmark.
PMID: 27605062 DOI: 10.1038/ncomms12731
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.

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