Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation
Abstract Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through th...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-07814-4 |
| _version_ | 1818750840051073024 |
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| author | Brice J. Albert Austin Niu Rashmi Ramani Garland R. Marshall Paul A. Wender Robert M. Williams Lee Ratner Alexander B. Barnes George B. Kyei |
| author_facet | Brice J. Albert Austin Niu Rashmi Ramani Garland R. Marshall Paul A. Wender Robert M. Williams Lee Ratner Alexander B. Barnes George B. Kyei |
| author_sort | Brice J. Albert |
| collection | DOAJ |
| description | Abstract Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells. |
| first_indexed | 2024-12-18T04:26:04Z |
| format | Article |
| id | doaj.art-51c1c2571b74471db5299a641c3986a0 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-18T04:26:04Z |
| publishDate | 2017-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-51c1c2571b74471db5299a641c3986a02022-12-21T21:21:07ZengNature PortfolioScientific Reports2045-23222017-08-017111210.1038/s41598-017-07814-4Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activationBrice J. Albert0Austin Niu1Rashmi Ramani2Garland R. Marshall3Paul A. Wender4Robert M. Williams5Lee Ratner6Alexander B. Barnes7George B. Kyei8Department of Chemistry, Washington University in St. LouisDepartment of Medicine, Washington University School of Medicine in St. LouisDepartment of Medicine, Washington University School of Medicine in St. LouisDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine in St. LouisDepartments of Chemistry and Chemical and Systems Biology, Stanford UniversityDepartment of Chemistry, Colorado State UniversityDepartment of Medicine, Washington University School of Medicine in St. LouisDepartment of Chemistry, Washington University in St. LouisDepartment of Medicine, Washington University School of Medicine in St. LouisAbstract Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.https://doi.org/10.1038/s41598-017-07814-4 |
| spellingShingle | Brice J. Albert Austin Niu Rashmi Ramani Garland R. Marshall Paul A. Wender Robert M. Williams Lee Ratner Alexander B. Barnes George B. Kyei Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation Scientific Reports |
| title | Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation |
| title_full | Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation |
| title_fullStr | Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation |
| title_full_unstemmed | Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation |
| title_short | Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation |
| title_sort | combinations of isoform targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent hiv without global t cell activation |
| url | https://doi.org/10.1038/s41598-017-07814-4 |
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