Sunday, May 11, 2025
5/11/2025
Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder - Despite effective viral control by Antiretroviral therapy (ART), HIV associated neurocognitive disorder (HAND)persists in 30-50% of people with HIV (PWH). The pathology of HAND includes white matter (WM) changes such as decreased myelin sheath thickness, myelin lesions, and abnormal myelin protein expression. We have found that both HIV infection and a subset of antiretroviral drugs disrupt oligodendrocyte (OL) maturation and myelination. These data support our overarching hypothesis that HIV infection and select ART compounds attenuate OL differentiation and myelin formation, contributing to CNS dysfunction in persons with HIV (PWH) on ART. Our in vitro data on the effects of HIV and ART drugs on OL differentiation align with in vivo evidence for a prominent role of the integrated stress response (ISR) and lipid metabolism in ART drug- and HIV-induced changes in WM. Transcriptome studies reported significant induction of transcripts indicative of activation of the ISR and unfolded protein response coincident with significant decrease in transcripts encoding regulators of lipid metabolism and specific myelin proteins in WM from PWH on ART. We have reported that a subset of ART drugs and a model of HIV infection induce the ISR, particularly the Protein kinase R-Endoplasmic Reticulum Kinase (PERK), in OLs. Our preliminary data demonstrate altered levels of lipid metabolism enzymes and lipids in response to ART drugs. Both processes correlate with inhibition of OL differentiation. Numerous studies have demonstrated that ISR kinase PERK regulates lipid metabolism; however, the role of ISR/PERK-induced stress granule (SG) formation, which are membraneless organelles containing mRNAs that protect a subset of transcripts during ISR activation, has not been investigated. Our preliminary data demonstrate the presence of SGs in OLs in WM of PWH with HAND and in OLs exposed to ART drugs in vitro. These findings have led us to hypothesize that HIV infection and a subset of ART compounds induce the ISR leading to stress granule formation and disruption of lipid metabolism in OL, causing defects in differentiation and myelin formation in PWH, contributing to CNS dysfunction. To address this hypothesis: aim 1 will determine whether HIV or select ART drugs cause the ISR-induced formation of SGs, which mRNAs critical for myelination are sequestered in SGs, and whether SGs are toxic to the cell. These goals will be pursued in our well-tested in vitro model of oligodendrocyte differentiation, in a small animal model and in samples from PWH. In aim 2, we will determine how both HIV and select ART drugs alter lipid composition and lipid regulation in OLs, also employing our in vitro model, a small animal model and samples from PWH. We will also determine the impact of ISR on lipid regulation and composition in this system. Finally, in specific aim 3, we will determine if neuroimaging-based measures of WM health associates with genetic variants of PERK and lipid metabolism in the context of functional subdomains of cognitive and mental health changes in PWH.
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