Arachidonic Acid Cascade and Eicosanoid Production Are Elevated While LTC4 Synthase Modulates the Lipidomics Profile in the Brain of the HIVgp120-Transgenic Mouse Model of NeuroHIV

Abstract

Background: Combination antiretroviral therapy (cART) has transformed HIV infection from a terminal disease to a manageable chronic health condition, extending patients’ life expec-tancy to that of the general population. However, the incidence of HIV-associated neurocognitive disorders (HANDs) has persisted despite virological suppression. Patients with HIV display persis-tent signs of immune activation and inflammation despite cART. The arachidonic acid (AA) cascade is an important immune response system responsible for both pro-and anti-inflammatory pro-cesses. Methods: Lipidomics, mRNA and Western blotting analysis provide valuable insights into the molecular mechanisms surrounding arachidonic acid metabolism and the resulting inflammation caused by perturbations thereof. Results: Here, we report the presence of inflammatory eico-sanoids in the brains of a transgenic mouse model of NeuroHIV that expresses soluble HIV-1 envelope glycoprotein in glial cells (HIVgp120tg mice). Additionally, we report that the effect of LTC4S knockout in HIVgp120tg mice resulted in the sexually dimorphic transcription of COX-and 5-LOX-related genes. Furthermore, the absence of LTC4S suppressed ERK1/2 and p38 MAPK signaling activity in female mice only. The mass spectrometry-based lipidomic profiling of these mice reveals beneficial alterations to lipids in the brain. Conclusion: Targeting the AA cascade may hold potential in the treatment of neuroinflammation observed in NeuroHIV and HANDs.