Graduation Date

Fall 12-18-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

Santhi Gorantla, Ph.D.

Abstract

Although effective antiretroviral therapy (ART) has substantially reduced the severity of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND), the condition remains highly prevalent. Understanding HAND has been a challenge due to the lack of small animal models capable of supporting productive HIV infection in the brain. Recent advances in humanized mouse models developed in our laboratory, featuring engraftment of human microglia and human immune system now enable systemic HIV infection that extends to the central nervous system (CNS), offering a powerful platform to study HAND pathogenesis and its underlying mechanisms. In this dissertation, we investigated HIV-induced behavioral, neuropathological, molecular, and metabolic alterations in the presence and absence of ART using novel humanized microglial mice. To characterize HIV-induced spontaneous behavioral changes, automated home cage monitoring was employed to measure activity, feeding efficiency, and circadian rhythms. HIV-infected mice exhibited reduced feeding efficiency and disrupted circadian rhythms, with a significant correlation between CNS viral load and increased locomotor activity during the light cycle. A comprehensive behavioral test battery further demonstrated that ART was unable to rescue HIV-induced mood, motor, and cognitive deficits. Neuropathological analyses revealed brain region-specific vulnerability, with the cortex exhibiting pronounced inflammatory and neurodegenerative changes, which persisted despite ART-mediated viral suppression. These findings were supported by transcriptomic profiling, which demonstrated upregulation of inflammatory, interferon-stimulated, and antiviral signaling pathways, along with differentially expressed genes associated with neuroinflammation, neurodegeneration and behavioral deficits. Longitudinal neuroimaging using magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) revealed persistent inflammation, metabolic, and structural abnormalities in the CNS despite effective ART. Together, these findings demonstrate that persistent activation of human microglia and ART administration during HIV infection contributes to ongoing CNS dysfunction and establishes the humanized mouse model as a valuable translational platform for elucidating the mechanisms underlying HAND and for evaluating therapeutic strategies targeting NeuroHIV.

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