Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals
Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and...
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doaj-d929319136b64e188d46ab8bc45c16ba2020-11-25T02:51:49ZengMDPI AGViruses1999-49152020-09-01121067106710.3390/v12101067Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved PharmaceuticalsGavin C. Sampey0Sergey Iordanskiy1Michelle L. Pleet2Catherine DeMarino3Fabio Romerio4Renaud Mahieux5Fatah Kashanchi6Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USALaboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USALaboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USALaboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USAInstitute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USAEquipe Oncogenèse Rétrovirale, Equipe Labellisée Ligue Nationale Contre le Cancer, Centre International de Recherche en Infectiologie, INSERM U1111-CNRS UMR5308, 69372 Lyon, FranceLaboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USAHuman immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators.https://www.mdpi.com/1999-4915/12/10/1067HIVlatencytranscriptionactivatorinhibitorfebuxostat |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gavin C. Sampey Sergey Iordanskiy Michelle L. Pleet Catherine DeMarino Fabio Romerio Renaud Mahieux Fatah Kashanchi |
spellingShingle |
Gavin C. Sampey Sergey Iordanskiy Michelle L. Pleet Catherine DeMarino Fabio Romerio Renaud Mahieux Fatah Kashanchi Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals Viruses HIV latency transcription activator inhibitor febuxostat |
author_facet |
Gavin C. Sampey Sergey Iordanskiy Michelle L. Pleet Catherine DeMarino Fabio Romerio Renaud Mahieux Fatah Kashanchi |
author_sort |
Gavin C. Sampey |
title |
Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals |
title_short |
Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals |
title_full |
Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals |
title_fullStr |
Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals |
title_full_unstemmed |
Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals |
title_sort |
identification of modulators of hiv-1 proviral transcription from a library of fda-approved pharmaceuticals |
publisher |
MDPI AG |
series |
Viruses |
issn |
1999-4915 |
publishDate |
2020-09-01 |
description |
Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators. |
topic |
HIV latency transcription activator inhibitor febuxostat |
url |
https://www.mdpi.com/1999-4915/12/10/1067 |
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