مورد إلكتروني
An In-Depth Comparison of Latency-Reversing Agent Combinations in Various in vitro and ex vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression.
| العنوان: | An In-Depth Comparison of Latency-Reversing Agent Combinations in Various in vitro and ex vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression. |
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| المصدر: | PLoS pathogens, 11 (7 |
| بيانات النشر: | 2015 |
| تفاصيل مُضافة: | Darcis, Gilles Kula, Anna Bouchat, Sophie Fujinaga, Koh Corazza, Francis Ait-Ammar, Amina Delacourt, Nadège Melard, Adeline Kabeya, Kabamba Vanhulle, Caroline Van Driessche, Benoît Gatot, Jean-Stéphane Cherrier, Thomas Pianowski, Luiz F. Gama, Lucio Schwartz, Christian Vila, Jorge Burny, Arsène Clumeck, Nathan Moutschen, Michel De Wit, Stéphane Peterlin, Matija Rouzioux, Christine Rohr, Olivier Van Lint, Carine |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiti SCOPUS: ar.j info:eu-repo/semantics/published |
| مصطلحات الفهرس: | Sciences bio-médicales et agricoles, Bryostatins -- pharmacology, CD4-Positive T-Lymphocytes -- drug effects -- virology, Diterpenes -- metabolism, Gene Expression Regulation, Viral -- drug effects, HIV-1 -- drug effects -- physiology, Humans, Positive Transcriptional Elongation Factor B -- metabolism, Virus Activation -- drug effects, Virus Latency -- drug effects, info:eu-repo/semantics/article, info:ulb-repo/semantics/articlePeerReview, info:ulb-repo/semantics/openurl/article |
| URL: | |
| الإتاحة: | Open access content. Open access content 1 full-text file(s): info:eu-repo/semantics/openAccess |
| ملاحظة: | 1 full-text file(s): application/pdf French |
| أرقام أخرى: | EQY oai:dipot.ulb.ac.be:2013/205174 uri/info:doi/10.1371/journal.ppat.1005063 uri/info:pii/PPATHOGENS-D-15-00502 uri/info:pmid/26225566 uri/info:scp/84938795129 uri/info:pmcid/PMC4520688 https://dipot.ulb.ac.be/dspace/bitstream/2013/205174/3/doi_188801.pdf 915537531 |
| المصدر المساهم: | UNIVERSITE LIBRE DE BRUXELLES From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.ocn915537531 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |