Περίληψη:
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. © 2018 White, Beliakova-Bethell, Lada, Breen, Hurst, Spina, Richman, Frater, Magiorkinis and Woelk.
Συγγραφείς:
White, C.H.
Beliakova-Bethell, N.
Lada, S.M.
Breen, M.S.
Hurst, T.P.
Spina, C.A.
Richman, D.D.
Frater, J.
Magiorkinis, G.
Woelk, C.H.
Λέξεις-κλειδιά:
vorinostat, antiretroviral therapy; Article; CD4+ T lymphocyte; dose response; down regulation; droplet digital polymerase chain reaction; drug megadose; drug potency; endogenous retrovirus; enzyme inhibition; flow cytometry; human; Human immunodeficiency virus; human tissue; nonhuman; pharmacogenomics; primary cell; provirus; RNA analysis; RNA extraction; RNA isolation; RNA sequence; upregulation; virus replication; virus transcription
