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Principal Investigator: JUDITH B GRINSPAN
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $870,237
Funding agency: National Institute of Mental Health
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.
Terms: <AIDS Virus><ATP-protein phosphotransferase><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Anti-HIV Positivity><Anti-Retroviral Agents><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Behavioral><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Death><Cell Membrane Lipids><Cell Signaling><Cells><Ceramides><Cerebrospinal Fluid><Cessation of life><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Consequences of HIV><Data><Death><Defect><Development><Diagnosis><Disturbance in cognition><Drug usage><Drugs><Dysfunction><Encephalon><Endoplasmic Reticulum><Enzyme Gene><Enzymes><Ergastoplasm><Exhibits><Exposure to><Functional disorder><Gene variant><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Diversity><Genetic Variation><Goals><HIV><HIV 1 associated neurocognitive disorder><HIV Infections><HIV Positive><HIV Positivity><HIV Seroconversion><HIV Seropositivity><HIV antibody positive><HIV associated neurocognitive deficit><HIV associated neurocognitive impairment><HIV induced neurocognitive deficit><HIV induced neurocognitive impairment><HIV neurocognitive impairment><HIV-1 associated neurocognitive deficit><HIV-1 associated neurocognitive disorder><HIV-1 associated neurocognitive impairment><HIV-associated neurocognitive disorder><HTLV-III Infections><HTLV-III Seroconversion><HTLV-III Seropositivity><HTLV-III-LAV Infections><Health><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IQ Deficit><Impaired cognition><In Vitro><Inflammation><Intracellular Communication and Signaling><Kinase Family Gene><Kinases><LAV-HTLV-III><Lesion><Lipids><Lymphadenopathy-Associated Virus><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Membrane><Membrane Lipids><Memory Deficit><Memory impairment><Mental Health><Mental Hygiene><Messenger RNA><Mice><Mice Mammals><Minor><Modeling><Murine><Mus><Myelin><Myelin Proteins><Myelin Sheath><NMR Imaging><NMR Tomography><Nerve><Neurocognitive Deficit><Neurocognitive Impairment in HIV><Neurocognitive Impairment in HIV-1><Neurologic><Neurological><Nuclear Magnetic Resonance Imaging><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><OmpR protein><Organelles><Pathology><Patients><Persons><Pharmaceutical Preparations><Phosphotransferase Gene><Phosphotransferases><Physiopathology><Process><Production><Protein Kinase><Proteins><Psychological Health><Regulation><Reporting><Role><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Stress><System><Therapeutic Intervention><Thick><Thickness><Transcript><Transcription Factor Proto-Oncogene><Transcription factor genes><Translational Inhibition><Translational Repression><Transphosphorylases><Viral><Virus-HIV><Zeugmatography><allele variant><allelic variant><anti-retroviral><antiretroviral therapy><antiretroviral treatment><arm><attenuate><attenuates><biological adaptation to stress><biological signal transduction><cell type><cerebral spinal fluid><cognitive change><cognitive dysfunction><cognitive loss><cohort><developmental><drug use><drug/agent><fat metabolism><genetic variant><genomic variant><global gene expression><global transcription profile><glycogen synthase a kinase><gray matter><hydroxyalkyl protein kinase><in vitro Model><in vitro testing><in vivo><in vivo Model><intelligence quotient deficit><intervention therapy><lipid metabolism><mRNA><membrane structure><memory dysfunction><model of animal><motor disease><motor disorder><motor dysfunction><myelination><necrocytosis><neural imaging><neuro-imaging><neurocognitive decline><neurocognitive impairment><neuroimaging><neurological imaging><pathophysiology><phosphorylase b kinase kinase><prevent><preventing><protein expression><protein kinase R><re-myelinate><re-myelination><reaction; crisis><remyelinate><remyelination><response><response regulator protein><social role><spinal fluid><stress granule><stress response><stress; reaction><substantia alba><substantia grisea><therapy duration><transcription factor><transcriptome><white matter><white matter change>