ORCID ID
Graduation Date
Summer 8-14-2026
Document Type
Thesis
Degree Name
Master of Science (MS)
Programs
Molecular Genetics & Cell Biology
First Advisor
Dr Palsamy Periyasamy
Abstract
Despite effective combination antiretroviral therapy, people living with HIV continue to experience chronic neuroinflammation and cognitive impairments, potentially due to the persistent expression of viral proteins within the central nervous system. HIV transactivator of transcription (Tat) protein promotes glial activation and cellular injury independently of active viral replication. PANoptosis is an inflammatory cell-death framework involving coordinated pyroptosis-, apoptosis-, and necroptosis-associated machinery, but whether HIV Tat engages this network in astrocytes remains unclear. We hypothesized that HIV Tat activates Z-DNA-binding protein 1 (ZBP1) and induces PANoptosis-related inflammatory signaling in mouse primary astrocytes. Mouse primary astrocytes isolated from neonatal C57BL/6 mice were exposed to recombinant HIV Tat in concentration- and time-dependent experiments. Astrocyte activation and cellular injury were assessed by Glial Fibrillary Acid Protein (GFAP) expression, lactate dehydrogenase release, and propidium iodide uptake. ZBP1 involvement was examined using pathway-directed inhibitors, including disulfiram, necrostatin-1, and Z-VAD-FMK, together with siRNA-mediated ZBP1 knockdown. PANoptosis-associated proteins and the inflammatory cytokines IL-1β and IL-18 were evaluated by Western blotting and ELISA. HIV Tat increased GFAP and ZBP1 expression and induced concentration-dependent cellular injury, as demonstrated by approximately 24% lactate dehydrogenase release and an eight- to tenfold increase in propidium iodide-positive cells relative to controls. HIV Tat also increased the abundance of NLRP6, ASC, caspase-1 p20, GSDMD, mature IL-1β, IL-18, FADD, caspase-8, caspase-3, caspase-7, RIPK1, RIPK3, and phosphorylated MLKL. Individual pharmacological inhibitors partially reduced HIV Tat-induced cellular injury, whereas combined pathway inhibition produced a greater protective effect, supporting the concurrent involvement of multiple programmed cell-death pathways. ZBP1 knockdown attenuated HIV Tat-associated increases in PANoptosis-related proteins and reduced extracellular IL-1β and IL-18 release. Collectively, these findings identify ZBP1 as an upstream regulator of HIV-1 Tat-associated inflammatory cell-death signaling in astrocytes and support PANoptosis-related signaling as a potentially novel mechanism of astrocytic injury in NeuroHIV. The findings further highlight ZBP1 as a promising therapeutic target for mitigating chronic neuroinflammation in people living with HIV.
Rights
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Recommended Citation
Oladipo, Elizabeth Kehinde, "HIV Tat-Mediated Astrocytic PANoptosis Involves Neuroinflammation" (2026). Theses & Dissertations. 1105.
https://digitalcommons.unmc.edu/etd/1105