Dissertation
Exploring mechanisms of HIV-1 control and RUNX directed modulation of viral activity in macrophage models
Doctor of Philosophy (Ph.D.), Drexel University
May 2026
DOI:
https://doi.org/10.17918/00011461
Abstract
Despite the success of antiretroviral therapy, human immunodeficiency virus type 1 continues to persist within long-lived cellular reservoirs that evade complete eradication. While latent infection in CD4⁺ T cells has been extensively studied, the mechanisms governing HIV-1 persistence in macrophages and other myeloid populations remain poorly understood. The work presented in this dissertation emerged from an unexpected observation made during studies of suppressive HIV-1 infection in primary human macrophages. Under ART-treated conditions, extracellular viral output progressively declined over time, yet infected cells remained readily detectable. What initially appeared to be a technical inconsistency ultimately evolved into the central theme of this work. Through longitudinal analyses of primary human monocyte-derived macrophages, this dissertation identifies a novel state of HIV-1 infection in which viral production becomes increasingly restricted despite persistent intracellular infection and ongoing viral transcriptional activity. These findings challenged the expectation that declining viral output necessarily reflects transcriptional silencing or loss of infected cells. Instead, HIV-1 within macrophages appeared to remain biologically active. Further investigation demonstrated that the HIV-1 long terminal repeat retained transcriptionally permissive characteristics during this restricted state, supporting the concept that macrophage-associated HIV-1 persistence may fundamentally differ from classical models of T-cell latency. The recognition of this transcriptionally active yet restricted phenotype prompted investigation into host pathways capable of modulating viral behavior within macrophages. Particular focus was placed on RUNX1, a host transcription factor previously implicated in HIV-1 transcriptional regulation. Through collaborative structural, biochemical, and functional studies, novel non-benzodiazepine RUNX1 inhibitors were identified and evaluated as selective modulators of RUNX1 activity. These compounds demonstrated direct interaction with RUNX1, altered host RUNX1-responsive transcriptional programs, exhibited reduced neurotoxicity in central nervous system (CNS)-relevant systems, and promoted increased viral output in suppressive macrophage infection models. Collectively, the studies presented in this dissertation support a model in which HIV-1 persistence in macrophages exists not as complete viral silence, but as a dynamic and restricted state regulated, in part, by host transcriptional machinery. By integrating studies of viral persistence with host-directed therapeutic targeting, this work advances understanding of HIV-1 reservoir biology and establishes a foundation for future strategies aimed at modulating persistent infection within myeloid and CNS-associated reservoirs.
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Details
- Title
- Exploring mechanisms of HIV-1 control and RUNX directed modulation of viral activity in macrophage models
- Creators
- Courtney G. Wallace
- Contributors
- Zachary Klase (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- 201 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022193095604721