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Transcriptional modulation of human endogenous retroviruses in primary CD4+ T cells following vorinostat treatment

Transcriptional modulation of human endogenous retroviruses in primary CD4+ T cells following vorinostat treatment
Transcriptional modulation of human endogenous retroviruses in primary CD4+ T cells following vorinostat treatment

The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A "shock and kill" approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to "shock" the silent provirus into active replication to permit "killing" by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor-vorinostat. Potentially, pathological off-target effects of vorinostat may result from the activation of human endogenous retroviruses (HERVs), which share common ancestry with exogenous retroviruses including HIV. To explore the effects of HDAC inhibition on HERV transcription, an unbiased pharmacogenomics approach (total RNA-Seq) was used to evaluate HERV expression following the exposure of primary CD4+ T cells to a high dose of vorinostat. Over 2,000 individual HERV elements were found to be significantly modulated by vorinostat, whereby elements belonging to the ERVL family (e.g., LTR16C and LTR33) were predominantly downregulated, in contrast to LTR12 elements of the HERV-9 family, which exhibited the greatest signal, with the upregulation of 140 distinct elements. The modulation of three different LTR12 elements by vorinostat was confirmed by droplet digital PCR along a dose-response curve. The monitoring of LTR12 expression during clinical trials with vorinostat may be indicated to assess the impact of this HERV on the human genome and host immunity.

Histone deacetylase inhibitor, Human endogenous retroviruses, Long terminal repeat, Primary CD4 T cells, Total RNA-Seq
1664-3224
1-10
White, Cory H.
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Beliakova-Bethell, Nadejda
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Lada, Steven M.
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Breen, Michael S.
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Hurst, Tara P.
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Spina, Celsa A.
c8449eb5-acfe-4ecf-b09f-838687908459
Richman, Douglas D.
978207ff-1609-4247-96c6-b269b743ea14
Frater, John
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Magiorkinis, Gkikas
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Woelk, Christopher H.
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White, Cory H.
45233a78-f0c9-4696-8aaf-1b2673f83c91
Beliakova-Bethell, Nadejda
72698b03-9c79-4ae8-89a8-2c64fe30e11e
Lada, Steven M.
618bd451-a6e5-40fb-9798-394fb4d9d31f
Breen, Michael S.
2a4241cd-4f16-4f7f-9165-1459ed2c8890
Hurst, Tara P.
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Spina, Celsa A.
c8449eb5-acfe-4ecf-b09f-838687908459
Richman, Douglas D.
978207ff-1609-4247-96c6-b269b743ea14
Frater, John
61192fd6-6b43-45ad-9071-844533c7ecae
Magiorkinis, Gkikas
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Woelk, Christopher H.
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White, Cory H., Beliakova-Bethell, Nadejda, Lada, Steven M., Breen, Michael S., Hurst, Tara P., Spina, Celsa A., Richman, Douglas D., Frater, John, Magiorkinis, Gkikas and Woelk, Christopher H. (2018) Transcriptional modulation of human endogenous retroviruses in primary CD4+ T cells following vorinostat treatment. Frontiers in Immunology, 9 (APR), 1-10, [603]. (doi:10.3389/fimmu.2018.00603).

Record type: Article

Abstract

The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A "shock and kill" approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to "shock" the silent provirus into active replication to permit "killing" by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor-vorinostat. Potentially, pathological off-target effects of vorinostat may result from the activation of human endogenous retroviruses (HERVs), which share common ancestry with exogenous retroviruses including HIV. To explore the effects of HDAC inhibition on HERV transcription, an unbiased pharmacogenomics approach (total RNA-Seq) was used to evaluate HERV expression following the exposure of primary CD4+ T cells to a high dose of vorinostat. Over 2,000 individual HERV elements were found to be significantly modulated by vorinostat, whereby elements belonging to the ERVL family (e.g., LTR16C and LTR33) were predominantly downregulated, in contrast to LTR12 elements of the HERV-9 family, which exhibited the greatest signal, with the upregulation of 140 distinct elements. The modulation of three different LTR12 elements by vorinostat was confirmed by droplet digital PCR along a dose-response curve. The monitoring of LTR12 expression during clinical trials with vorinostat may be indicated to assess the impact of this HERV on the human genome and host immunity.

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fimmu-09-00603
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Accepted/In Press date: 9 March 2018
e-pub ahead of print date: 12 April 2018
Keywords: Histone deacetylase inhibitor, Human endogenous retroviruses, Long terminal repeat, Primary CD4 T cells, Total RNA-Seq

Identifiers

Local EPrints ID: 419944
URI: http://eprints.soton.ac.uk/id/eprint/419944
ISSN: 1664-3224
PURE UUID: a365bbaa-04b6-4086-903f-780eac4f0432

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Date deposited: 24 Apr 2018 16:30
Last modified: 07 Oct 2020 00:41

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Contributors

Author: Cory H. White
Author: Nadejda Beliakova-Bethell
Author: Steven M. Lada
Author: Michael S. Breen
Author: Tara P. Hurst
Author: Celsa A. Spina
Author: Douglas D. Richman
Author: John Frater
Author: Gkikas Magiorkinis

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