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dc.contributor.authorJones, Richard Bradley
dc.contributor.authorO'Connor, Rachel
dc.contributor.authorMueller, Stefanie
dc.contributor.authorFoley, Maria Hottelet
dc.contributor.authorKarel, Dan
dc.contributor.authorLichterfeld, Mathias
dc.contributor.authorKovacs, Colin
dc.contributor.authorOstrowski, Mario A.
dc.contributor.authorTrocha, Alicja
dc.contributor.authorWalker, Bruce D.
dc.contributor.authorSzeto, Gregory
dc.contributor.authorIrvine, Darrell J
dc.date.accessioned2014-10-15T20:36:18Z
dc.date.available2014-10-15T20:36:18Z
dc.date.issued2014-08
dc.date.submitted2014-01
dc.identifier.issn1553-7374
dc.identifier.urihttp://hdl.handle.net/1721.1/90954
dc.description.abstractResting memory CD4[superscript +] T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia.en_US
dc.description.sponsorshipRagon Institute of MGH, MIT, and Harvarden_US
dc.description.sponsorshipCanadian Institutes of Health Research (Banting Fellow)en_US
dc.description.sponsorshipOntario HIV Treatment Network (Junior Investigator)en_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.ppat.1004287en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourcePublic Library of Scienceen_US
dc.titleHistone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytesen_US
dc.typeArticleen_US
dc.identifier.citationJones, Richard Brad, Rachel O’Connor, Stefanie Mueller, Maria Foley, Gregory L. Szeto, Dan Karel, Mathias Lichterfeld, et al. “Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes.” Edited by Guido Silvestri. PLoS Pathog 10, no. 8 (August 14, 2014): e1004287.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentRagon Institute of MGH, MIT and Harvarden_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.mitauthorJones, Richard Bradleyen_US
dc.contributor.mitauthorO'Connor, Rachelen_US
dc.contributor.mitauthorMueller, Stefanieen_US
dc.contributor.mitauthorFoley, Maria Hotteleten_US
dc.contributor.mitauthorSzeto, Gregory Leeen_US
dc.contributor.mitauthorKarel, Danen_US
dc.contributor.mitauthorTrocha, Alicjaen_US
dc.contributor.mitauthorIrvine, Darrell J.en_US
dc.contributor.mitauthorWalker, Bruce D.en_US
dc.relation.journalPLoS Pathogensen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsJones, Richard Brad; O'Connor, Rachel; Mueller, Stefanie; Foley, Maria; Szeto, Gregory L.; Karel, Dan; Lichterfeld, Mathias; Kovacs, Colin; Ostrowski, Mario A.; Trocha, Alicja; Irvine, Darrell J.; Walker, Bruce D.en_US
dc.identifier.orcidhttps://orcid.org/0000-0001-7604-1333
dc.identifier.orcidhttps://orcid.org/0000-0003-4083-335X
mit.licensePUBLISHER_CCen_US


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