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dc.contributor.authorZhou, J
dc.contributor.authorLazar, D
dc.contributor.authorLi, H
dc.contributor.authorXia, X
dc.contributor.authorSatheesan, S
dc.contributor.authorCharlins, P
dc.contributor.authorO'Mealy, D
dc.contributor.authorAkkina, R
dc.contributor.authorSaayman, S
dc.contributor.authorWeinberg, MS
dc.contributor.authorRossi, JJ
dc.contributor.authorMorris, KV
dc.date.accessioned2020-12-10T04:55:13Z
dc.date.available2020-12-10T04:55:13Z
dc.date.issued2018
dc.identifier.issn1838-7640
dc.identifier.doi10.7150/thno.23085
dc.identifier.urihttp://hdl.handle.net/10072/400155
dc.description.abstractGene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy. Methods: We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR). TGS differs from traditional RNA interference (RNAi) in that it is characterized by concomitant silent-state epigenetic marks on histones and DNA. To deliver TGS-inducing RNAs, we developed functional RNA conjugates based on the previously reported dual function of the gp120 (A-1) aptamer conjugated to 27-mer Dicer-substrate anti-HIV-1 siRNA (dsiRNA), LTR-362. Results: We demonstrate here that high levels of processed guide RNAs localize to the nucleus in infected T lymphoblastoid CEM cell line and primary human CD4+ T-cells. Treatment of the aptamer-siRNA conjugates induced TGS with an ~10-fold suppression of viral p24 levels as measured at day 12 post infection. To explore the silencing efficacy of aptamer-siRNA conjugates in vivo, HIV-1-infected humanized NOD/SCID/IL2 rYnull mice (hu-NSG) were treated with the aptamer-siRNA conjugates. Systemic delivery of the A-1-stick-LTR-362 27-mer siRNA conjugates suppressed HIV-1 infection and protected CD4+ T cell levels in viremia hu-NSG mice. Principle conclusions: Collectively these data suggest that the gp120 aptamer-dsiRNA conjugate design is suitable for systemic delivery of small RNAs that can be used to suppress HIV-1.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherIvyspring International Publisher
dc.relation.ispartofpagefrom1575
dc.relation.ispartofpageto1590
dc.relation.ispartofissue6
dc.relation.ispartofjournalTheranostics
dc.relation.ispartofvolume8
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode1112
dc.subject.keywordsAptamer
dc.subject.keywordsHIV-1
dc.subject.keywordsRNAi
dc.subject.keywordsgp120
dc.subject.keywordstranscriptional gene silencing
dc.titleReceptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationZhou, J; Lazar, D; Li, H; Xia, X; Satheesan, S; Charlins, P; O'Mealy, D; Akkina, R; Saayman, S; Weinberg, MS; Rossi, JJ; Morris, KV, Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1, Theranostics, 2018, 8 (6), pp. 1575-1590
dcterms.dateAccepted2017-12-09
dcterms.licensehttps://creativecommons.org/licenses/by-nc/4.0/
dc.date.updated2020-12-10T04:20:09Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorMorris, Kevin V.


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