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dc.contributor.advisorKuritzkes, Danielen_US
dc.contributor.advisorAllen, Todden_US
dc.contributor.advisorCoffin, Johnen_US
dc.contributor.authorJurado, Kellie Annen_US
dc.date.accessioned2015-12-04T18:42:46Z
dc.date.created2015-11en_US
dc.date.issued2015-09-20en_US
dc.date.submitted2015en_US
dc.identifier.citationJurado, Kellie Ann. 2015. Allosteric Integrase Inhibitors Reveal a Role for Integrase During HIV-1 Maturation. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:23845485
dc.description.abstractIntegration of the DNA copy of the HIV-1 genome is an essential step for virus replication and is mediated by a homotetrameric complex of the viral protein integrase (IN) in association with the ends of linear viral DNA (vDNA). HIV-1 integrates into actively transcribed genes, a trait mediated by cellular host cofactor LEDGF/p75. LEDGF/p75 engages IN in a pocket formed by dimerization of the IN catalytic core domain, a region that has been validated as a drug target for allosteric IN inhibitors (ALLINIs). Previous in vitro work suggested that ALLINIs function through disruption of two integration-associated functions: IN-vDNA complex formation and the IN-LEDGF/p75 interaction. We now demonstrate that ALLINI potency is accounted for during the late phase of HIV-1 replication where the inhibitors block the formation of the viral core, converting the normally electron-dense conical core to an eccentric phenotype where the electron-density exists as a condensate situated between a translucent core and the viral membrane. We have further elucidated the eccentric condensates to represent non-packaged viral ribonucleoprotein (vRNP) complexes and that either genetic or pharmacological inhibition of IN can impair vRNP encapsidation. Supplying IN in trans as part of a Vpr-IN fusion protein partially restored the formation of conical cores with the internal electron density. Moreover the ability of ALLINIs to induce eccentric condensate formation required both IN and viral RNA. Based on these observations, we propose an active role for IN during HIV-1 maturation that involves initiating core morphogenesis and vRNP encapsidation.en_US
dc.description.sponsorshipMedical Sciencesen_US
dc.format.mimetypeapplication/pdfen_US
dc.language.isoenen_US
dash.licenseLAAen_US
dc.subjectBiology, Microbiologyen_US
dc.titleAllosteric Integrase Inhibitors Reveal a Role for Integrase During HIV-1 Maturationen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorJurado, Kellie Annen_US
dc.date.available2015-12-04T18:42:46Z
thesis.degree.date2015en_US
thesis.degree.grantorGraduate School of Arts & Sciencesen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
dc.type.materialtexten_US
thesis.degree.departmentMedical Sciencesen_US
dash.identifier.vireohttp://etds.lib.harvard.edu/gsas/admin/view/651en_US
dc.description.keywordsHIV-1; integrase; allosteric integrase inhibitors; LEDGF/p75en_US
dash.author.emailkelliejurado@gmail.comen_US
dash.identifier.drsurn-3:HUL.DRS.OBJECT:25142725en_US
dash.contributor.affiliatedJurado, Kellie A.


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