Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1
Abstract Reactivation of HIV gene expression in latently infected cells together with an efficient cART has been proposed as an adjuvant therapy aimed at eliminating/decreasing the reservoir size. Results from HIV clinical trials using deacetylase inhibitors (HDACIs) question the efficiency of these...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201505557 |
| _version_ | 1797225447924170752 |
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| author | Sophie Bouchat Nadège Delacourt Anna Kula Gilles Darcis Benoit Van Driessche Francis Corazza Jean‐Stéphane Gatot Adeline Melard Caroline Vanhulle Kabamba Kabeya Marion Pardons Véronique Avettand‐Fenoel Nathan Clumeck Stéphane De Wit Olivier Rohr Christine Rouzioux Carine Van Lint |
| author_facet | Sophie Bouchat Nadège Delacourt Anna Kula Gilles Darcis Benoit Van Driessche Francis Corazza Jean‐Stéphane Gatot Adeline Melard Caroline Vanhulle Kabamba Kabeya Marion Pardons Véronique Avettand‐Fenoel Nathan Clumeck Stéphane De Wit Olivier Rohr Christine Rouzioux Carine Van Lint |
| author_sort | Sophie Bouchat |
| collection | DOAJ |
| description | Abstract Reactivation of HIV gene expression in latently infected cells together with an efficient cART has been proposed as an adjuvant therapy aimed at eliminating/decreasing the reservoir size. Results from HIV clinical trials using deacetylase inhibitors (HDACIs) question the efficiency of these latency‐reversing agents (LRAs) used alone and underline the need to evaluate other LRAs in combination with HDACIs. Here, we evaluated the therapeutic potential of a demethylating agent (5‐AzadC) in combination with clinically tolerable HDACIs in reactivating HIV‐1 from latency first in vitro and next ex vivo. We showed that a sequential treatment with 5‐AzadC and HDACIs was more effective than the corresponding simultaneous treatment both in vitro and ex vivo. Interestingly, only two of the sequential LRA combinatory treatments tested induced HIV‐1 particle recovery in a higher manner than the drugs alone ex vivo and at concentrations lower than the human tolerable plasmatic concentrations. Taken together, our data reveal the benefit of using combinations of 5‐AzadC with an HDACI and, for the first time, the importance of treatment time schedule for LRA combinations in order to reactivate HIV. |
| first_indexed | 2024-03-13T03:12:19Z |
| format | Article |
| id | doaj.art-db67ed8a899c414c9c5e30cb5ab57e78 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T14:09:10Z |
| publishDate | 2016-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-db67ed8a899c414c9c5e30cb5ab57e782024-04-03T09:38:20ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-02-018211713810.15252/emmm.201505557Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1Sophie Bouchat0Nadège Delacourt1Anna Kula2Gilles Darcis3Benoit Van Driessche4Francis Corazza5Jean‐Stéphane Gatot6Adeline Melard7Caroline Vanhulle8Kabamba Kabeya9Marion Pardons10Véronique Avettand‐Fenoel11Nathan Clumeck12Stéphane De Wit13Olivier Rohr14Christine Rouzioux15Carine Van Lint16Service of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumLaboratory of Immunology IRISLab CHU‐Brugmann Université Libre de Bruxelles (ULB) Brussels BelgiumService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumService de Virologie EA7327 AP‐HP Hôpital Necker‐Enfants‐Malades Université Paris‐Descartes Paris FranceService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumService des Maladies Infectieuses CHU St‐Pierre Université Libre de Bruxelles (ULB) Brussels BelgiumService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumService de Virologie EA7327 AP‐HP Hôpital Necker‐Enfants‐Malades Université Paris‐Descartes Paris FranceService des Maladies Infectieuses CHU St‐Pierre Université Libre de Bruxelles (ULB) Brussels BelgiumService des Maladies Infectieuses CHU St‐Pierre Université Libre de Bruxelles (ULB) Brussels BelgiumIUT Louis Pasteur de Schiltigheim University of Strasbourg Schiltigheim FranceService de Virologie EA7327 AP‐HP Hôpital Necker‐Enfants‐Malades Université Paris‐Descartes Paris FranceService of Molecular Virology Department of Molecular Biology (DBM) Université Libre de Bruxelles (ULB) Gosselies BelgiumAbstract Reactivation of HIV gene expression in latently infected cells together with an efficient cART has been proposed as an adjuvant therapy aimed at eliminating/decreasing the reservoir size. Results from HIV clinical trials using deacetylase inhibitors (HDACIs) question the efficiency of these latency‐reversing agents (LRAs) used alone and underline the need to evaluate other LRAs in combination with HDACIs. Here, we evaluated the therapeutic potential of a demethylating agent (5‐AzadC) in combination with clinically tolerable HDACIs in reactivating HIV‐1 from latency first in vitro and next ex vivo. We showed that a sequential treatment with 5‐AzadC and HDACIs was more effective than the corresponding simultaneous treatment both in vitro and ex vivo. Interestingly, only two of the sequential LRA combinatory treatments tested induced HIV‐1 particle recovery in a higher manner than the drugs alone ex vivo and at concentrations lower than the human tolerable plasmatic concentrations. Taken together, our data reveal the benefit of using combinations of 5‐AzadC with an HDACI and, for the first time, the importance of treatment time schedule for LRA combinations in order to reactivate HIV.https://doi.org/10.15252/emmm.201505557demethylating agentepigeneticsHDACIsHIV latencyHIV reservoir |
| spellingShingle | Sophie Bouchat Nadège Delacourt Anna Kula Gilles Darcis Benoit Van Driessche Francis Corazza Jean‐Stéphane Gatot Adeline Melard Caroline Vanhulle Kabamba Kabeya Marion Pardons Véronique Avettand‐Fenoel Nathan Clumeck Stéphane De Wit Olivier Rohr Christine Rouzioux Carine Van Lint Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1 EMBO Molecular Medicine demethylating agent epigenetics HDACIs HIV latency HIV reservoir |
| title | Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1 |
| title_full | Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1 |
| title_fullStr | Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1 |
| title_full_unstemmed | Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1 |
| title_short | Sequential treatment with 5‐aza‐2′‐deoxycytidine and deacetylase inhibitors reactivates HIV‐1 |
| title_sort | sequential treatment with 5 aza 2 deoxycytidine and deacetylase inhibitors reactivates hiv 1 |
| topic | demethylating agent epigenetics HDACIs HIV latency HIV reservoir |
| url | https://doi.org/10.15252/emmm.201505557 |
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