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Horvath, Riley Micheal

University of British Columbia

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 activity is an attractive latency promoting target that may contribute to the development of a “block and lock” functional cure. Collectively, in this thesis I have identified novel regulators of proviral expression for which existing drugs can target to either promote or antagonize HIV-1 latency thus exhibiting therapeutic potential.

Text

2023-08-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85658

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/