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dc.contributor.advisorLieberman, Judy
dc.contributor.authorWheeler, Lee Adam
dc.date.accessioned2013-02-08T14:57:17Z
dash.embargo.terms2014-06-21en_US
dc.date.issued2013-02-08
dc.date.submitted2012
dc.identifier.citationWheeler, Lee Adam. 2012. CD4 Aptamer-SiRNA Chimeras (CD4-AsiCs) Knockdown Gene Expression in CD4+ Cells and Inhibit HIV Transmission. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:10272en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10288421
dc.description.abstractThe continued spread of HIV underscores the need to interrupt transmission. One attractive strategy is a topical microbicide. Sexual transmission of herpes simplex virus type 2 (HSV-2) in mice can be inhibited by intravaginal small inhibitory RNA (siRNA) application. To overcome the challenges of using siRNAs to knock down gene expression in immune cells susceptible to HIV infection, we used chimeric RNAs composed of an aptamer fused to an siRNA for targeted gene knockdown in cells bearing an aptamer-binding receptor. Here, we showed that CD4 aptamer-siRNA chimeras (CD4-AsiCs) specifically suppress gene expression in CD4+ T cells and macrophages in vitro, in polarized cervicovaginal tissue explants, and in both the genital and rectal tracts of humanized mice. CD4-AsiCs do not activate lymphocytes or stimulate innate immunity, provide durable target gene silencing for up to three weeks in vitro, and maintain effectiveness in a hydroxyethyl cellulose (HEC) gel formulation. CD4-AsiCs that knock down HIV genes and/or CCR5 inhibited HIV infection in vitro and in cervicovaginal explants. When applied intravaginally to humanized mice, CD4-AsiCs provided durable protection against transmission of the virus. Thus, CD4-AsiCs could be used as the active ingredient of a microbicide to prevent the sexual transmission of HIV.en_US
dc.language.isoen_USen_US
dash.licenseMETA_ONLY
dc.subjectaptameren_US
dc.subjectaptamer siRNA chimeraen_US
dc.subjectCCR5en_US
dc.subjectCD4en_US
dc.subjectHIV microbicideen_US
dc.subjectsiRNAen_US
dc.subjectimmunologyen_US
dc.subjectmedicineen_US
dc.subjectbiomedical engineeringen_US
dc.titleCD4 Aptamer-SiRNA Chimeras (CD4-AsiCs) Knockdown Gene Expression in CD4+ Cells and Inhibit HIV Transmissionen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorWheeler, Lee Adam
dash.embargo.until10000-01-01
thesis.degree.date2012en_US
thesis.degree.disciplineImmunologyen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberDranoff, Glennen_US
dc.contributor.committeeMemberMempel, Thorstenen_US
dc.contributor.committeeMemberFarzan, Michaelen_US
dc.contributor.committeeMemberSzostak, Jacken_US
dc.contributor.committeeMemberRamratnam, Bharaten_US
dc.contributor.committeeMemberEngelman, Alanen_US
dash.contributor.affiliatedWheeler, Lee Adam


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