Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA

Infection with human immunodeficiency virus 1 (HIV-1) remains incurable because long-lived, latently-infected cells persist during prolonged antiretroviral therapy. Attempts to pharmacologically reactivate and purge the latent reservoir with latency reactivating agents (LRAs) such as protein kinase...

Full description

Bibliographic Details
Main Authors: Jared P. Taylor, Lucas H. Armitage, Daniel L. Aldridge, Melanie N. Cash, Mark A. Wallet
Format: Article
Language:English
Published: The Company of Biologists 2020-12-01
Series:Biology Open
Subjects:
hiv
Online Access:http://bio.biologists.org/content/9/12/bio052969
id doaj-bf6490caf8cc425da1fef9474b339b54
record_format Article
spelling doaj-bf6490caf8cc425da1fef9474b339b542021-06-02T17:14:23ZengThe Company of BiologistsBiology Open2046-63902020-12-0191210.1242/bio.052969052969Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHAJared P. Taylor0Lucas H. Armitage1Daniel L. Aldridge2Melanie N. Cash3Mark A. Wallet4 Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA Infection with human immunodeficiency virus 1 (HIV-1) remains incurable because long-lived, latently-infected cells persist during prolonged antiretroviral therapy. Attempts to pharmacologically reactivate and purge the latent reservoir with latency reactivating agents (LRAs) such as protein kinase C (PKC) agonists (e.g. ingenol A) or histone deacetylase (HDAC) inhibitors (e.g. SAHA) have shown promising but incomplete efficacy. Using the J-Lat T cell model of HIV latency, we found that the plant-derived compound harmine enhanced the efficacy of existing PKC agonist LRAs in reactivating latently-infected cells. Treatment with harmine increased not only the number of reactivated cells but also increased HIV transcription and protein expression on a per-cell basis. Importantly, we observed a synergistic effect when harmine was used in combination with ingenol A and the HDAC inhibitor SAHA. An investigation into the mechanism revealed that harmine, when used with LRAs, increased the activity of NFκB, MAPK p38, and ERK1/2. Harmine treatment also resulted in reduced expression of HEXIM1, a negative regulator of transcriptional elongation. Thus, harmine enhanced the effects of LRAs by increasing the availability of transcription factors needed for HIV reactivation and promoting transcriptional elongation. Combination therapies with harmine and LRAs could benefit patients by achieving deeper reactivation of the latent pool of HIV provirus.http://bio.biologists.org/content/9/12/bio052969harminelatencyhiv
collection DOAJ
language English
format Article
sources DOAJ
author Jared P. Taylor
Lucas H. Armitage
Daniel L. Aldridge
Melanie N. Cash
Mark A. Wallet
spellingShingle Jared P. Taylor
Lucas H. Armitage
Daniel L. Aldridge
Melanie N. Cash
Mark A. Wallet
Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA
Biology Open
harmine
latency
hiv
author_facet Jared P. Taylor
Lucas H. Armitage
Daniel L. Aldridge
Melanie N. Cash
Mark A. Wallet
author_sort Jared P. Taylor
title Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA
title_short Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA
title_full Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA
title_fullStr Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA
title_full_unstemmed Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA
title_sort harmine enhances the activity of the hiv-1 latency-reversing agents ingenol a and saha
publisher The Company of Biologists
series Biology Open
issn 2046-6390
publishDate 2020-12-01
description Infection with human immunodeficiency virus 1 (HIV-1) remains incurable because long-lived, latently-infected cells persist during prolonged antiretroviral therapy. Attempts to pharmacologically reactivate and purge the latent reservoir with latency reactivating agents (LRAs) such as protein kinase C (PKC) agonists (e.g. ingenol A) or histone deacetylase (HDAC) inhibitors (e.g. SAHA) have shown promising but incomplete efficacy. Using the J-Lat T cell model of HIV latency, we found that the plant-derived compound harmine enhanced the efficacy of existing PKC agonist LRAs in reactivating latently-infected cells. Treatment with harmine increased not only the number of reactivated cells but also increased HIV transcription and protein expression on a per-cell basis. Importantly, we observed a synergistic effect when harmine was used in combination with ingenol A and the HDAC inhibitor SAHA. An investigation into the mechanism revealed that harmine, when used with LRAs, increased the activity of NFκB, MAPK p38, and ERK1/2. Harmine treatment also resulted in reduced expression of HEXIM1, a negative regulator of transcriptional elongation. Thus, harmine enhanced the effects of LRAs by increasing the availability of transcription factors needed for HIV reactivation and promoting transcriptional elongation. Combination therapies with harmine and LRAs could benefit patients by achieving deeper reactivation of the latent pool of HIV provirus.
topic harmine
latency
hiv
url http://bio.biologists.org/content/9/12/bio052969
work_keys_str_mv AT jaredptaylor harmineenhancestheactivityofthehiv1latencyreversingagentsingenolaandsaha
AT lucasharmitage harmineenhancestheactivityofthehiv1latencyreversingagentsingenolaandsaha
AT daniellaldridge harmineenhancestheactivityofthehiv1latencyreversingagentsingenolaandsaha
AT melaniencash harmineenhancestheactivityofthehiv1latencyreversingagentsingenolaandsaha
AT markawallet harmineenhancestheactivityofthehiv1latencyreversingagentsingenolaandsaha
_version_ 1721402659183788032