Date of Award
1-17-2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Microbiology and Immunology
First Advisor
Edward Campbell
Abstract
The host-pathogen interactions underlying Human Immunodeficiency Virus type 1 (HIV-1) infection are complex and involve the exploitation of host cellular machinery. This thesis investigates the roles of dynein adaptors, microtubule acetylation, and TRIM69-mediated restriction in HIV-1 infection. Through a series of detailed experiments, we explore how HIV-1 utilizes multiple dynein adaptors, such as BICDR1 and Hook3, for intracellular transport, and reveal that these adaptors are critical for efficient viral trafficking. Conversely, the knockdown of Ninein surprisingly enhances HIV-1 infectivity, suggesting a nuanced regulatory role for this adaptor in viral transport. Further, this thesis challenges the prevailing paradigm that microtubule acetylation is essential for HIV-1 infection. Using CRISPR-Cas9 technology to knock out the αTAT1 enzyme responsible for microtubule acetylation, and overexpressing an αTAT1-mCherry construct, we demonstrate that HIV-1 can replicate effectively without microtubule acetylation. This finding prompts a re-evaluation of the role of microtubule modifications in HIV-1 pathogenesis. Additionally, we investigate the antiviral mechanisms of TRIM69, a member of the tripartite motif (TRIM) family of proteins. Our results show that TRIM69 restricts HIV-1 independently of microtubule acetylation, indicating alternative pathways and mechanisms at play. By using a doxycycline-inducible TRIM69 expression system in conjunction with CRISPR-Cas9 knockout of αTAT1, we confirm that TRIM69 retains its antiviral function even in the absence of acetylated microtubules. Moreover, TRIM69 demonstrates broad-spectrum antiviral activity, restricting viruses such as chikungunya virus (CHIKV), Coxsackie virus B3 (CVB3), and Zika virus (ZIKV). This comprehensive examination provides significant insights into the adaptability and complexity of HIV-1 in hijacking host cellular machinery, the dispensability of microtubule acetylation in HIV-1 infection, and the multifaceted antiviral mechanisms of TRIM69. These findings not only advance our understanding of HIV-1 biology but also highlight potential targets for novel therapeutic interventions aimed at disrupting the virus's interaction with the host cell. Future research directions include expanding the range of dynein adaptors studied, investigating other post-translational modifications of microtubules, and further elucidating the broad antiviral mechanisms of TRIM69.
Recommended Citation
Lichon, Drew Michael, "Discerning the Role of Microtubule Acetylation During HIV-1 Infection" (2025). Dissertations. 4162.
https://ecommons.luc.edu/luc_diss/4162
