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Functional and Proteomic Characterization of CSF Astrocyte Derived Extracellular Vesicles in HIV-associated Cognitive Impairment

Award Number: R16NS151899
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Functional and Proteomic Characterization of CSF Astrocyte Derived Extracellular Vesicles in HIV-associated Cognitive Impairment - Project Summary HIV-associated cognitive impairment (HIV-CI) affects approximately half of people living with HIV (PWH) despite sustained viral suppression with antiretroviral therapy, and there are currently no validated biomarkers or effective therapeutic strategies. Growing evidence indicates that astrocyte dysfunction and altered neuroimmune communication contributes to the persistence of cognitive impairment in PWH. Astrocyte-derived extracellular vesicles (ADEs) have emerged as critical mediators of brain–periphery signaling and may reflect pathological processes occurring within the central nervous system. Using quantitative proteomics of plasma- derived ADEs, our laboratory identified novel protein signatures associated with HIV-CI, including dysregulation of proteins involved in cytoskeletal dynamics, vesicular trafficking, and oxidative stress responses. Notably, queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) was downregulated in PWH and CI, while sex- dependent differences revealed increased TRAPPC4 and decreased WRAP73 in women with HIV-CI compared to men. These pathways are essential for astrocyte homeostasis, and disruption of QTRT1 has been linked to memory and learning deficits in vivo. However, whether plasma ADEs protein signatures accurately reflect pathological processes within the brain remains unknown. The overall objective of this project is to validate and characterize ADEs-associated protein dysregulation in cerebrospinal fluid (CSF) from PWH and CI and to determine the neurotoxic and neuroinflammatory effects of these ADEs. We hypothesize that CSF-derived ADEs from PWH and CI will exhibit downregulation of QTRT1, sex-dependent alterations in TRAPPC4 and WRAP73, and enhanced neurotoxicity and neuroinflammation, with greater detrimental effects observed in HIV-CI group. To test this hypothesis, we will perform quantitative proteomic profiling of CSF- derived ADEs from a well-characterized cohort, followed by functional assessment of ADEs-induced neuronal injury and neuroinflammation using human iPSC-derived cortical brain organoids. This study is significant because it will establish whether plasma ADEs can serve as reliable, minimally invasive biomarkers of HIV-CI. The proposed work is innovative as it represents a quantitative proteomics analysis of ADEs isolated from CSF in PWH with CI and directly links ADEs protein signatures to functional neurotoxicity and neuroinflammation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $447,000 )
2026	2026	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/10/2026	NEW	$447,000
														Subtotal = $447,000

Grand Total All Awards = $447,000

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Functional and Proteomic Characterization of CSF Astrocyte Derived Extracellular Vesicles in HIV-associated Cognitive Impairment

Award Number: R16NS151899

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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