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Principal Investigator: Partha Chandra
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2024
Award: $498,444
Funding agency: National Institute of Neurological Disorders and Stroke
Combined antiretroviral therapy (cART) suppresses HIV replication, but 30-60% of infected patients suffer from
severe HIV-1 associated neurocognitive disorders (HAND). However, the mechanisms underlying HAND are
unclear and this lack of information has prevented the development of effective science-driven treatments. Our
data have provided key information connecting etiology, especially by showing that pathogenic contents of
plasma extracellular vesicles (EVs) from either chronic SHIV-infected and cART treated rhesus macaque (RM)
or HIV(+)–cART treated patients play a key role in the development and progression of HAND. Moreover, our
novel findings provide the first evidence that EVs released by HIV-replication defective cells (HIV-EVs) cause
dysfunction and damage to the primary human brain microvascular endothelial cells (HBMECs) and disrupt
blood-brain barrier (BBB) function via a mitochondrial-dependent mechanism. These results are consistent with
our non-human primates and mice studies, which shown that brain microvessels (MVs: end arterioles, capillaries,
and venules) composed primarily of endothelial cells, are more vulnerable due to SIV-infection and exposure to
HIV-EVs, respectively. Additionally, our data suggest that neuroinflammatory protein fibrinogen (Fgn) and HIV-
Tat are abundant in HIV-associated EVs, which impairs mitochondrial function and ATP production in BMECs
by preventing normal mitochondrial fission/fusion events via direct inhibition of dynamin-related protein 1 (DRP1),
thereby reducing energy production and increasing oxidative stress. These detrimental mitochondrial effects
lead to endothelial cell damage, disruption of the BBB, impaired blood flow regulation, and cognitive impairment.
Interestingly, we observed that EVs released by mesenchymal stem cells (MSC-EVs) rescued the HIV-EV/Fgn-
mediated mitochondrial dysregulation and BBB leakage in HBMECs. Our focus on cerebral MVs is appropriate
since this segment of the circulation is increasingly recognized as an initiation site for the progression of many
neurological diseases, including HAND. Our overall hypothesis is that HIV verion free EVs accelerate cerebral
microvascular endothelial and BBB dysfunction by inducing mitochondrial dysregulation. Moreover, we propose
that MSC-EVs could protect endothelial mitochondria in live mice. We will explore EV-mediated BMEC/BBB
dysregulation in cerebral MVs of humanized NOD/SCID/IL2Rγnull (NSG) mice. In Aim 1, we will determine the
effects of HIV-free EVs on mitochondrial and BBB dysfunction in brain microvasculature of NSG mice. In Aim 2,
we will establish the EV-containing fibrinogen and HIV-Tat dependent mechanism for mitochondrial and BBB
dysregulation in cerebral MVs of NSG mice. In Aim 3, we will establish the therapeutic potential of MSC-EVs to
reverse the EV-mediated mitochondrial and BBB dysfunction in cerebral MVs of NSG mice. Vascular
contributions to cognitive impairment and dementia (VCID) are an integral part of HAND. The NIH has designated
VCID as a critical research area and our application is highly relevant for this research area.
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Vasodilator><Endothelial Cells><Endothelial Nitric Oxide Synthase><Endothelium><Endothelium-Derived Nitric Oxide><Etiology><Event><Exposure to><Extravasation><Factor I><Factor One><Fibrinogen><Functional disorder><HIV><HIV 1 associated neurocognitive disorder><HIV associated neurocognitive deficit><HIV associated neurocognitive impairment><HIV induced neurocognitive deficit><HIV induced neurocognitive impairment><HIV neurocognitive impairment><HIV therapy><HIV-1><HIV-1 associated neurocognitive deficit><HIV-1 associated neurocognitive disorder><HIV-1 associated neurocognitive impairment><HIV-I><HIV-associated neurocognitive disorder><HIV1><Hemato-Encephalic Barrier><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Impaired cognition><Impairment><Infection><Infiltration><Injury><LAV-HTLV-III><Lead><Leakage><Link><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Maintenance><Measures><Mediating><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Metabolic><Mice><Mice Mammals><Mitochondria><Modern Man><Mononitrogen Monoxide><Murine><Mus><NIH><NOS3><NOS3 gene><National Institutes of Health><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocognitive Impairment in HIV><Neurocognitive Impairment in HIV-1><Neurocyte><Neurologic Disorders><Neurologic Dysfunctions><Neurological Disorders><Neurons><Neuropathogenesis><Nitric Oxide><Nitric Oxide Synthase 3><Nitrogen Monoxide><Nitrogen Protoxide><Nutrient><Oxidative Stress><Pathogenicity><Patients><Pb element><Persons><Phosphorylation><Physiopathology><Plasma><Plasma Serum><Play><Predisposition><Production><Protein Phosphorylation><Proteins><Publishing><Regimen><Regulation><Reporting><Research><Respiration><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Role><SHIV><SIV><Science><Simian Immunodeficiency Viruses><Site><Spillage><Susceptibility><Testing><Therapeutic><Toxin><Type III nitric oxide synthase><United States National Institutes of Health><Vascular Brain Injury><Vascular Endothelium><Virus-HIV><abnormal brain function><antiretroviral therapy><antiretroviral treatment><arteriole><blood-brain barrier disruption><blood-brain barrier function><bloodbrain barrier><bloodbrain barrier disruption><bloodbrain barrier function><brain dysfunction><brain endothelial cell><brain endothelium><brain health><brain impairment><brain microvascular endothelial cell><brain microvasculature><brain microvessels><brain vascular endothelial cell><capillary><cardiac disease induced cognitive impairment><causation><cell damage><cell injury><cellular damage><cerebral><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral microvasculature><cerebral microvessels><cerebral vascular endothelial cell><clinical relevance><clinically relevant><cognitive dysfunction><cognitive loss><cortical endothelium><damage to cells><developmental><disease causation><dysfunctional brain><endothelial cell derived relaxing factor><endothelial dysfunction><extracellular vesicles><heavy metal Pb><heavy metal lead><humanized mice><humanized mouse><injuries><injury to cells><innovate><innovation><innovative><knock-down><knockdown><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><mitochondrial><mitochondrial dysfunction><mouse model><murine model><neural inflammation><neuroinflammation><neuroinflammatory><neurological disease><neurological dysfunction><neuronal><non-human primate><nonhuman primate><novel><pathophysiology><prevent><preventing><respiratory mechanism><simian HIV><simian human immunodeficiency virus><social role><therapeutically effective><two photon excitation microscopy><two photon microscopy><uptake><vascular cognitive impairment and dementia><vascular contributions to cognition/dementia><vascular contributions to cognitive impairment and dementia><venule><vesicle release><vesicular release>