Investigating The link Between High-Risk Protein Kinase R-Like Endoplasmic Reticulum Kinase (PERK) Haplotypes, Periodontal Inflammation and Depression in People With HIV (PWH) on Antiretroviral Therapy ( ART)

People with HIV (PWH) who are on antiretroviral therapy (ART) continue to suffer from chronic inflammation, dental diseases, and increased rates of depression, despite substantial viral suppression. The endoplasmic reticulum (ER) stress sensor, protein kinase R–like endoplasmic reticulum kinase (PERK), encoded by EIF2AK3, is a crucial part of the integrated stress response (ISR) that regulates cellular adaptation to viral and inflammatory stimuli. Genetic variations in EIF2AK3 are linked to increased PERK activity and susceptibility to chronic inflammation and neurobehavioral diseases. This dissertation examines the link between high-risk PERK haplotypes and periodontal inflammation, systemic and local immunological activation, and depression in PWH on ART, while also exploring the molecular significance of PERK signaling in HIV-induced inflammation through peripheral and central immune cell models. In this study, 96 PWH on ART were evaluated for periodontal inflammation and depressive symptoms/diagnosis, determination of PERK haplotypes was perform from collected stimulated saliva, and cytokine profiling from serum and gingival crevicular fluid (GCF) via Olink proteomics. Although high-risk PERK haplotypes did not show a significant correlation with clinical periodontitis or depression, carriers showed a higher prevalence of gingivitis and increased concentrations of proinflammatory cytokines (CCL11, CCL19, CD8A, CXCL8, and FGF-19) in serum and (CSF3 and IL-1β) in gingival crevicular fluid (GCF). Race- and sex-stratified analyses demonstrated unique cytokine profiles, with elevated levels of CCL23, CXCL5, FGF5, and DNER in individuals of African ancestry, and increased IL-4 and MMP-10 in individuals of White origin, underlining ancestry-dependent immune regulation. Moreover, to clarify the cellular mechanisms linking PERK signaling to HIV-related stress responses, peripheral blood mononuclear cells (PBMCs) and induced pluripotent stem cell-derived microglia (iMg) were treated with HIV and pharmacological PERK modulators. Following HIV infection, PBMCs from risk haplotype carrier, showed a non-significant trend toward increased early eIF2α phosphorylation (p-eIF2α) and slightly higher expression of activating Transcription Factor 4 (ATF4). In addition, HIV-infected iMg showed an increase in the expression of ATF4, C/EBP Homologous Protein (CHOP), and Binding Immunoglobulin Protein (BiP) mRNA, consistent with partial activation of ISR. Inhibition of PERK via treatment with a pharmacologic inhibitor (GSK2606414) reduced cytokine release and enhanced viral replication, whereas activation of PERK via treatment with a pharmacologic activator (CCT020312) elevated ISR markers and limited viral replication, demonstrating PERK's dual function in modulating inflammation and viral persistence. These data indicate that whereas PERK haplotypes may not directly anticipate overt disease, they influence inflammatory state and stress sensitivity in PWH on ART. The combination of genetic, cytokine, and in vitro evidence establishes PERK as a molecular regulator of inflammation that connects systemic, oral, and neurobehavioral consequences. This dissertation highlights the necessity for population-specific, mechanistically informed intervention approaches aimed at ER-stress pathways to reduce chronic inflammation and associated depression in PWH on ART.