Broad activation of latent HIV-1 in vivo

Kirston Barton; Bonnie Hiener; Maria Buzon; Mathias Lichterfeld; Paul W. Denton; Rikke Olesen; Lars Østergaard; Martin Tolstrup; Sharon R. Lewin; Ole Schmeltz Søgaard; Sarah Palmer; Anni Winckelmann; Thomas Aagaard Rasmussen; Wei Shao; Karen Byth; Robert Lanfear; Ajantha Solomon; James McMahon; Sean Harrington

doi:10.1038/ncomms12731

Broad activation of latent HIV-1 in vivo

Kirston Barton, Bonnie Hiener, Maria Buzon, Mathias Lichterfeld, Paul W. Denton, Rikke Olesen, Lars Østergaard, Martin Tolstrup, Sharon R. Lewin, Ole Schmeltz Søgaard, Sarah Palmer, Anni Winckelmann, Thomas Aagaard Rasmussen, Wei Shao, Karen Byth, Robert Lanfear, Ajantha Solomon, James McMahon, Sean Harrington

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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.

Original language	English
Pages (from-to)	12731-1-12731-8
Number of pages	8
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12731
Publication status	Published - 2016

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Barton, K., Hiener, B., Buzon, M., Lichterfeld, M., Denton, P. W., Olesen, R., Østergaard, L., Tolstrup, M., Lewin, S. R., Søgaard, O. S., Palmer, S., Winckelmann, A., Rasmussen, T. A., Shao, W., Byth, K., Lanfear, R., Solomon, A., McMahon, J., & Harrington, S. (2016). Broad activation of latent HIV-1 in vivo. Nature Communications, 7, 12731-1-12731-8. https://doi.org/10.1038/ncomms12731

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title = "Broad activation of latent HIV-1 in vivo",

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.",

author = "Kirston Barton and Bonnie Hiener and Maria Buzon and Mathias Lichterfeld and Denton, {Paul W.} and Rikke Olesen and Lars {\O}stergaard and Martin Tolstrup and Lewin, {Sharon R.} and S{\o}gaard, {Ole Schmeltz} and Sarah Palmer and Anni Winckelmann and Rasmussen, {Thomas Aagaard} and Wei Shao and Karen Byth and Robert Lanfear and Ajantha Solomon and James McMahon and Sean Harrington",

note = "Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2016",

doi = "10.1038/ncomms12731",

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Barton, K, Hiener, B, Buzon, M, Lichterfeld, M, Denton, PW, Olesen, R, Østergaard, L, Tolstrup, M, Lewin, SR, Søgaard, OS, Palmer, S, Winckelmann, A, Rasmussen, TA, Shao, W, Byth, K, Lanfear, R, Solomon, A, McMahon, J & Harrington, S 2016, 'Broad activation of latent HIV-1 in vivo', Nature Communications, vol. 7, pp. 12731-1-12731-8. https://doi.org/10.1038/ncomms12731

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T1 - Broad activation of latent HIV-1 in vivo

AU - Barton, Kirston

AU - Hiener, Bonnie

AU - Buzon, Maria

AU - Lichterfeld, Mathias

AU - Denton, Paul W.

AU - Olesen, Rikke

AU - Østergaard, Lars

AU - Tolstrup, Martin

AU - Lewin, Sharon R.

AU - Søgaard, Ole Schmeltz

AU - Palmer, Sarah

AU - Winckelmann, Anni

AU - Rasmussen, Thomas Aagaard

AU - Shao, Wei

AU - Byth, Karen

AU - Lanfear, Robert

AU - Solomon, Ajantha

AU - McMahon, James

AU - Harrington, Sean

N1 - Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

UR - http://purl.org/au-research/grants/nhmrc/1061681

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U2 - 10.1038/ncomms12731

DO - 10.1038/ncomms12731

M3 - Article

C2 - 27605062

SN - 2041-1723

VL - 7

SP - 12731-1-12731-8

JO - Nature Communications

JF - Nature Communications

ER -

Broad activation of latent HIV-1 in vivo

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