Characterization and exploitation of host factors to modulate HIV-1 latency
department or school: Medicine, Faculty of
department or school: Biochemistry and Molecular Biology, Department of
data provider: DSpace
degree campus: UBCV
creator: Horvath, Riley Micheal
issued: 2023-08-29T16:06:55Z
issued: 2023
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Despite decades of research, HIV-1 remains an ever-prevalent burden on global human health. For many, antiretroviral therapy (ART) is capable of controlling viral replication. However, ART is not a cure and must be administered life-long with discontinuation resulting in viral rebound. The persistence of HIV-1 is the result of a fraction of provirus establishing latency early upon infection of T cells. This population of transcriptionally silent provirus are undetectable to the immune system, unaffected by ART, and are capable of spurious reactivation and clonal proliferation. It has been hypothesized that latency modulating compounds may produce a sterilizing cure for HIV-1. In this thesis, I identify and characterize transcriptional regulators of HIV-1 and examine the ability of small molecules that target these factors to affect viral latency. RBE3 and RBE1 are two of the most highly conserved cis-elements in the HIV-1 LTR. Binding of these elements by the RBF-2 complex, composed of TFII-I and a USF1/USF2 heterodimer, is essential for reactivation of latent provirus. In my work, TFII-I recruits TRIM24 to the LTR resulting in stimulated transcriptional elongation. Furthermore, inhibition of the TRIM24 bromodomain by IACS-9571 reversed proviral latency, an effect that was associated with increased TRIM24 LTR occupancy and facilitation of RNAPII elongation. Thus, TRIM24 bromodomain inhibitors such as IACS-9571 represent a novel class of HIV-1 LRAs that are of interest to the “shock and kill” strategy of viral elimination. Several LTR bound sequence-specific transcriptional activators are regulated by the Mediator complex kinase, CDK8/19. Here, I show that chemical inhibition of CDK8/19 kinase activity enforces the establishment of HIV-1 latency and hinders viral reactivation in response to latency reversal agents. Similar to kinase inhibition, genetic ablation of CDK8 promoted latency while also suppressing reactivation to several agonists. As such, CDK8/19 kinase a…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/85658
note: Characterization and exploitation of host factors to modulate HIV-1 latency by Riley Micheal Horvath B.Sc., The University of British Columbia, 2016 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Biochemistry and Molecular Biology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2023 © Riley Micheal Horvath, 2023ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Characterization and exploitation of host factors to modulate HIV-1 latency Submitted by Riley Micheal Horvath in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry and Molecular Biology Examining Committee: Ivan Sadowski, Professor, Biochemistry & Molecular Biology, University of British Columbiaiii Supervisor Thibault Mayor, Professor, Biochemistry & Molecular Biology, University of British Columbia Supervisory Committee Member Eric Jan, Professor, Biochemistry & Molecular Biology, University of British Columbiaiii iiiiiIII Supervisory Committee Member LeAnn Howe, Professor, Biochemistry & Molecular Biology, University of British Columbiaiiiii University Examiner Marc Horwitz, Professor, Biochemistry & Molecular Biology, University of British Columbiaiiii University Examiner David Margolis, MD, Professor, Departments of Medicine, Microbiology & Immunology, Epidemiology, University of North Carolina at Chapel Hill iiiiiiiiiiiiiiiiiiiii External Examiner iii Abstract Despite decades of research, HIV-1 remains an ever-prevalent burden on global human health. For many, antiretroviral therapy (ART) is capable of controlling viral replication. However, ART is not a cure and must be administered life-long with discontinuation resulting in viral rebound. The persistence of HIV-1 is the result of a fraction of provirus establishing latency early upon in…
has type: Thesis/Dissertation
date issued: 2023-11
is shown at: 10.14288/1.0435626
language: eng
degree discipline: Biochemistry and Molecular Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Sadowski, Ivan
type: Text
identifier URI: http://hdl.handle.net/2429/85658