Keywords

HES4, Alternative splicing, NK92-MI, NICD, HIV, SIV

Abstract

Human immunodeficiency virus (HIV) infection disrupts immune homeostasis and impairs antiviral defenses, partly by compromising natural killer (NK) cell activity, with simian immunodeficiency virus (SIV) infection in rhesus macaques serving as a valuable model to investigate these mechanisms. This research examines the regulatory role of HES4 and its isoforms in NK cell function during retroviral infection, with particular focus on how Notch signaling–dependent regulation of HES4 shapes NK effector responses. HES4, a downstream effector of the Notch signaling pathway, encodes transcriptional repressors central to immune cell differentiation, yet its contribution to NK cell biology remains poorly understood. Using molecular and cellular approaches, we demonstrate that retroviral infection alters HES4 isoform expression, consequently affecting NK cytokine production and cytotoxicity. In NK92-MI cells, resveratrol modulated Notch signaling as reflected by shifts in Notch intracellular domain (NICD) levels, though HES4 expression followed a complex, non-dose-dependent pattern. CRISPR-Cas9–mediated HES4 knockout further revealed that loss or redistribution of HES4 isoforms meaningfully alters NK cytotoxicity, assessed against H358 lung carcinoma targets through live-cell imaging. Collectively, these findings indicate that HES4 isoform expression critically influences NK effector function during retroviral infection and illuminate the dynamic interplay between Notch signaling, HES4 regulation, and NK cell activity, positioning HES4-linked pathways as promising targets for enhancing NK-mediated immunity in HIV/SIV infection and broader retroviral disease contexts.

Completion Date

2026

Semester

Spring

Committee Chair

Dr. Daniel Ram

Degree

Master of Science (M.S.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Document Type

Dissertation/Thesis

Identifier

DP0053211

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