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...
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The Company of Biologists
2020-12-01
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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 |
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