Document Type
Dissertation
Date of Award
2026
Degree Name
Doctor of Philosophy (PhD)
Department
Basic Biomedical Science
First Advisor
GRANT Dr CAMPBELL
Abstract
The human immunodeficiency virus (HIV) affects over 39.9 million people worldwide, and 1-2 million new infections occur each year. While Antiretroviral therapy (ART) keeps viral levels at undetectable levels, HIV persists in reservoirs, rebounds with ART interruption, and drives HIV-associated neurocognitive disorder (HAND). Microglia are the macrophages of the central nervous system (CNS), which perform a range of functions, including phagocytosis of invading pathogens and synaptic pruning. Due to their susceptibility and permissiveness to HIV, these cells harbor the virus and ensure lifelong infection and contribute to HAND. Using a reductionist model, we exposed monocyte-derived microglia (MMG) to HIV gp120 to explore apoptotic and inflammatory mechanisms. Gp120 exposure was associated with increased expression of triggering receptor expressed on myeloid cells 1 (TREM1), together with shifts in apoptotic and cytotoxic marker profiles consistent with a persistence phenotype under the conditions tested. TREM1 induction was also associated with upstream engagement of toll-like receptors 2 and 4, required prostaglandin-endoperoxide synthase 2 activity and prostaglandin E₂ synthesis, linking pattern recognition receptor activation to downstream amplification of cellular responses. In parallel, gp120 exposure engaged the inositol-requiring enzyme- 1α/X-box binding protein 1s (IRE-1α/XBP1s) arm of the unfolded protein response and was associated with increased inflammatory transcriptional outputs. Pharmacological inhibition of IRE1α RNase activity reduced XBP1 mRNA splicing and attenuated cytokine transcription, while TREM1 inhibition reduced IRE-1α transcription and accompanying pro-inflammatory gene transcription, without establishing a directional pathway hierarchy between TREM1 and IRE-1α. These findings support a model in which TREM1 functions downstream as an amplifier of signalling pathways initiated by gp120, linking survival-associated and inflammatory responses. Taken together, the data define a TLR2/4–PTGS2/PGE₂–TREM1 signalling axis associated with altered apoptotic and cytotoxic marker profiles and persistent inflammatory activation in gp120-exposed microglia. This framework provides a mechanistic basis for understanding how HIV proteins may contribute to CNS persistence and neuroinflammatory processes, while also defining the limits of interpretation imposed by the experimental model.
Subject Categories
Biochemistry | Molecular Biology
Keywords
GP120 INFLAMMATION MICROGLIA TREM1
Number of Pages
135
Publisher
University of South Dakota
Recommended Citation
Mahama, Ayisha, "THE ROLE OF TREM1 IN HIV GP120-EXPOSED MICROGLIA" (2026). Dissertations and Theses. 398.
https://red.library.usd.edu/diss-thesis/398