The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

<h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yi...
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Autor*in:	Ole S Søgaard [verfasserIn] Mette E Graversen [verfasserIn] Steffen Leth [verfasserIn] Rikke Olesen [verfasserIn] Christel R Brinkmann [verfasserIn] Sara K Nissen [verfasserIn] Anne Sofie Kjaer [verfasserIn] Mariane H Schleimann [verfasserIn] Paul W Denton [verfasserIn] William J Hey-Cunningham [verfasserIn] Kersten K Koelsch [verfasserIn] Giuseppe Pantaleo [verfasserIn] Kim Krogsgaard [verfasserIn] Maja Sommerfelt [verfasserIn] Remi Fromentin [verfasserIn] Nicolas Chomont [verfasserIn] Thomas A Rasmussen [verfasserIn] Lars Østergaard [verfasserIn] Martin Tolstrup [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2015

Übergeordnetes Werk:	In: PLoS Pathogens - Public Library of Science (PLoS), 2005, 11(2015), 9, p e1005142
Übergeordnetes Werk:	volume:11 ; year:2015 ; number:9, p e1005142

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1371/journal.ppat.1005142

Katalog-ID:	DOAJ070921865

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allfields	10.1371/journal.ppat.1005142 doi (DE-627)DOAJ070921865 (DE-599)DOAJc852dcea536446258fe42e2747519f95 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Ole S Søgaard verfasserin aut The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116. Immunologic diseases. Allergy Biology (General) Mette E Graversen verfasserin aut Steffen Leth verfasserin aut Rikke Olesen verfasserin aut Christel R Brinkmann verfasserin aut Sara K Nissen verfasserin aut Anne Sofie Kjaer verfasserin aut Mariane H Schleimann verfasserin aut Paul W Denton verfasserin aut William J Hey-Cunningham verfasserin aut Kersten K Koelsch verfasserin aut Giuseppe Pantaleo verfasserin aut Kim Krogsgaard verfasserin aut Maja Sommerfelt verfasserin aut Remi Fromentin verfasserin aut Nicolas Chomont verfasserin aut Thomas A Rasmussen verfasserin aut Lars Østergaard verfasserin aut Martin Tolstrup verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 11(2015), 9, p e1005142 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:11 year:2015 number:9, p e1005142 https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/article/c852dcea536446258fe42e2747519f95 kostenfrei https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 9, p e1005142
spelling	10.1371/journal.ppat.1005142 doi (DE-627)DOAJ070921865 (DE-599)DOAJc852dcea536446258fe42e2747519f95 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Ole S Søgaard verfasserin aut The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116. Immunologic diseases. Allergy Biology (General) Mette E Graversen verfasserin aut Steffen Leth verfasserin aut Rikke Olesen verfasserin aut Christel R Brinkmann verfasserin aut Sara K Nissen verfasserin aut Anne Sofie Kjaer verfasserin aut Mariane H Schleimann verfasserin aut Paul W Denton verfasserin aut William J Hey-Cunningham verfasserin aut Kersten K Koelsch verfasserin aut Giuseppe Pantaleo verfasserin aut Kim Krogsgaard verfasserin aut Maja Sommerfelt verfasserin aut Remi Fromentin verfasserin aut Nicolas Chomont verfasserin aut Thomas A Rasmussen verfasserin aut Lars Østergaard verfasserin aut Martin Tolstrup verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 11(2015), 9, p e1005142 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:11 year:2015 number:9, p e1005142 https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/article/c852dcea536446258fe42e2747519f95 kostenfrei https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 9, p e1005142
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allfieldsGer	10.1371/journal.ppat.1005142 doi (DE-627)DOAJ070921865 (DE-599)DOAJc852dcea536446258fe42e2747519f95 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Ole S Søgaard verfasserin aut The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116. Immunologic diseases. Allergy Biology (General) Mette E Graversen verfasserin aut Steffen Leth verfasserin aut Rikke Olesen verfasserin aut Christel R Brinkmann verfasserin aut Sara K Nissen verfasserin aut Anne Sofie Kjaer verfasserin aut Mariane H Schleimann verfasserin aut Paul W Denton verfasserin aut William J Hey-Cunningham verfasserin aut Kersten K Koelsch verfasserin aut Giuseppe Pantaleo verfasserin aut Kim Krogsgaard verfasserin aut Maja Sommerfelt verfasserin aut Remi Fromentin verfasserin aut Nicolas Chomont verfasserin aut Thomas A Rasmussen verfasserin aut Lars Østergaard verfasserin aut Martin Tolstrup verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 11(2015), 9, p e1005142 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:11 year:2015 number:9, p e1005142 https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/article/c852dcea536446258fe42e2747519f95 kostenfrei https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 9, p e1005142
allfieldsSound	10.1371/journal.ppat.1005142 doi (DE-627)DOAJ070921865 (DE-599)DOAJc852dcea536446258fe42e2747519f95 DE-627 ger DE-627 rakwb eng RC581-607 QH301-705.5 Ole S Søgaard verfasserin aut The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116. Immunologic diseases. Allergy Biology (General) Mette E Graversen verfasserin aut Steffen Leth verfasserin aut Rikke Olesen verfasserin aut Christel R Brinkmann verfasserin aut Sara K Nissen verfasserin aut Anne Sofie Kjaer verfasserin aut Mariane H Schleimann verfasserin aut Paul W Denton verfasserin aut William J Hey-Cunningham verfasserin aut Kersten K Koelsch verfasserin aut Giuseppe Pantaleo verfasserin aut Kim Krogsgaard verfasserin aut Maja Sommerfelt verfasserin aut Remi Fromentin verfasserin aut Nicolas Chomont verfasserin aut Thomas A Rasmussen verfasserin aut Lars Østergaard verfasserin aut Martin Tolstrup verfasserin aut In PLoS Pathogens Public Library of Science (PLoS), 2005 11(2015), 9, p e1005142 (DE-627)501074422 (DE-600)2205412-1 15537374 nnns volume:11 year:2015 number:9, p e1005142 https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/article/c852dcea536446258fe42e2747519f95 kostenfrei https://doi.org/10.1371/journal.ppat.1005142 kostenfrei https://doaj.org/toc/1553-7366 Journal toc kostenfrei https://doaj.org/toc/1553-7374 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2015 9, p e1005142
language	English
source	In PLoS Pathogens 11(2015), 9, p e1005142 volume:11 year:2015 number:9, p e1005142
sourceStr	In PLoS Pathogens 11(2015), 9, p e1005142 volume:11 year:2015 number:9, p e1005142
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Immunologic diseases. Allergy Biology (General)
isfreeaccess_bool	true
container_title	PLoS Pathogens
authorswithroles_txt_mv	Ole S Søgaard @@aut@@ Mette E Graversen @@aut@@ Steffen Leth @@aut@@ Rikke Olesen @@aut@@ Christel R Brinkmann @@aut@@ Sara K Nissen @@aut@@ Anne Sofie Kjaer @@aut@@ Mariane H Schleimann @@aut@@ Paul W Denton @@aut@@ William J Hey-Cunningham @@aut@@ Kersten K Koelsch @@aut@@ Giuseppe Pantaleo @@aut@@ Kim Krogsgaard @@aut@@ Maja Sommerfelt @@aut@@ Remi Fromentin @@aut@@ Nicolas Chomont @@aut@@ Thomas A Rasmussen @@aut@@ Lars Østergaard @@aut@@ Martin Tolstrup @@aut@@
publishDateDaySort_date	2015-01-01T00:00:00Z
hierarchy_top_id	501074422
id	DOAJ070921865
language_de	englisch
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author	Ole S Søgaard
spellingShingle	Ole S Søgaard misc RC581-607 misc QH301-705.5 misc Immunologic diseases. Allergy misc Biology (General) The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
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topic_title	RC581-607 QH301-705.5 The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo
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title	The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
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title_full	The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo
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title_sort	depsipeptide romidepsin reverses hiv-1 latency in vivo
callnumber	RC581-607
title_auth	The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
abstract	<h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116.
abstractGer	<h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116.
abstract_unstemmed	<h4<Unlabelled</h4<Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116.
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title_short	The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.
url	https://doi.org/10.1371/journal.ppat.1005142 https://doaj.org/article/c852dcea536446258fe42e2747519f95 https://doaj.org/toc/1553-7366 https://doaj.org/toc/1553-7374
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up_date	2024-07-03T17:27:42.633Z
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However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.<h4<Trial registration</h4<clinicaltrials.gov NTC02092116.</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Immunologic diseases. 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The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

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