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PRODUCTIVE AND LATENT HIV INFECTION OF THE CENTRAL NERVOUS SYSTEM: VIRUS AND HOST WRESTLE FOR CONTROL OF THE SUMOYLATION SYSTEM
Imbert, Fergan
Imbert, Fergan
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Thesis/Dissertation
Date
2025-05
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Biomedical Sciences
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https://doi.org/10.34944/79sx-kj87
Abstract
SUMOylation (small ubiquitin-related modification) is a post-translational modification that involves the covalent attachment of SUMO proteins to target substrates. The dynamic process regulates several aspects of cellular functions, including gene expression, protein stability, subcellular localization, and cellular signaling. SUMOylation is essential in maintaining cellular homeostasis and its dysregulation is implicated in various diseases, including cancer, neurodegeneration, and autoimmune disorders. SUMOylation has also been increasingly recognized in its regulation of innate immune responses. SUMOylation has been shown to regulate the activity of toll-like receptors (TLRs) and transcription factors like NF-B, which are essential in innate immunity. As such, SUMOylation has significant implications in immune regulation for viral infections. Many viruses like, herpesviruses, influenza, and HIV have evolved mechanisms to hijack the host SUMOylation system to enhance their replication and evade host immune responses. Conversely, host cells can use SUMOylation to mount an antiviral response by modifying key immune factors that limit viral replication. This dichotomous role of SUMOylation makes SUMOylation a critical area of research. Despite significant advances in understanding SUMOylation’s role in cellular functions and viral infections, several important questions remain unanswered. What are the precise mechanisms through which SUMOylation regulates immune signaling pathways in response to viral infections, particularly HIV? What are the broader implications of SUMOylation in the context of viral persistence or latency? To what extent can targeting SUMOylation be used as a therapeutic strategy in viral infections? The work presented in this thesis uses a multi-faceted approach to begin to address these questions. First, we explored a relationship between HIV infection and SUMOylation in microglial and T cells. Prior literature suggested an impairment in global SUMO conjugation during HIV infections, though comprehensive evidence from our experiments to support this was lacking. We instead observed a translocation of the SUMO paralogs following HIV infection. One potential explanation is that HIV is capable of manipulating which proteins are modified by SUMO. To further explore this relationship, we performed proteomic analysis on a novel cellular model of HIV latency in microglia. Using quantitative immunoassays, we demonstrate that global SUMO conjugation is significantly increased in HIV latently infected microglia, with global SUMO conjugation levels decreasing following HIV reactivation. Here, we also demonstrate a unique proteomic landscape between HIV latent and HIV induced reactivation cell populations. Finally, we explored targeting SUMOylation as a therapeutic strategy for viral infections. Here, we observed a significant reduction in HIV reactivation in T cells through inhibition of SUMOylation. Both SUMO E1-activating and SUMO E2-conjugating enzymatic inhibition resulted in fewer GFP+ cells in a dose-dependent manner, with almost complete blocking of reactivation at higher concentrations. Altogether, these studies highlight the importance of SUMOylation in cellular processes, its emerging role in innate immunity, and its implications in productive and latent HIV infection. Our work suggests that targeted modulation of SUMOylation may offer new therapeutic strategies for treating viral infections.
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