Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal
Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and imm...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396415302309 |
| _version_ | 1819174328052219904 |
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| author | Mateusz Stoszko Elisa De Crignis Casper Rokx Mir Mubashir Khalid Cynthia Lungu Robert-Jan Palstra Tsung Wai Kan Charles Boucher Annelies Verbon Emily C. Dykhuizen Tokameh Mahmoudi |
| author_facet | Mateusz Stoszko Elisa De Crignis Casper Rokx Mir Mubashir Khalid Cynthia Lungu Robert-Jan Palstra Tsung Wai Kan Charles Boucher Annelies Verbon Emily C. Dykhuizen Tokameh Mahmoudi |
| author_sort | Mateusz Stoszko |
| collection | DOAJ |
| description | Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4+ T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal. |
| first_indexed | 2024-12-22T20:37:13Z |
| format | Article |
| id | doaj.art-63201ca417954753afb8c06cb24c4a67 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-22T20:37:13Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-63201ca417954753afb8c06cb24c4a672022-12-21T18:13:26ZengElsevierEBioMedicine2352-39642016-01-013C10812110.1016/j.ebiom.2015.11.047Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency ReversalMateusz Stoszko0Elisa De Crignis1Casper Rokx2Mir Mubashir Khalid3Cynthia Lungu4Robert-Jan Palstra5Tsung Wai Kan6Charles Boucher7Annelies Verbon8Emily C. Dykhuizen9Tokameh Mahmoudi10Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Viroscience, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, the NetherlandsDepartment of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, The NetherlandsDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USADepartment of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The NetherlandsPersistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4+ T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal.http://www.sciencedirect.com/science/article/pii/S2352396415302309HIVLatencyBAF complexChromatin remodelinglatency reversal agents |
| spellingShingle | Mateusz Stoszko Elisa De Crignis Casper Rokx Mir Mubashir Khalid Cynthia Lungu Robert-Jan Palstra Tsung Wai Kan Charles Boucher Annelies Verbon Emily C. Dykhuizen Tokameh Mahmoudi Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal EBioMedicine HIV Latency BAF complex Chromatin remodeling latency reversal agents |
| title | Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal |
| title_full | Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal |
| title_fullStr | Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal |
| title_full_unstemmed | Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal |
| title_short | Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal |
| title_sort | small molecule inhibitors of baf a promising family of compounds in hiv 1 latency reversal |
| topic | HIV Latency BAF complex Chromatin remodeling latency reversal agents |
| url | http://www.sciencedirect.com/science/article/pii/S2352396415302309 |
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