Human immunodeficiency virus (HIV)-associated central nervous system (CNS) disease occurs in more than 50% of the people living with HIV (PLWH) that use combination antiretroviral therapy (cART). A lack of appropriate brain/CNS models to study HIV neuropathogenesis limited the understanding of HIV’s effect on cognition and hampered the development of therapeutic approaches. Using recently developed novel tri-culture human 3D-brain organoids (hBORGs) that mimic the brain of HIV infected individuals, McGowan Institute for Regenerative Medicine affiliated faculty member and co-principal investigator Shilpa Sant, PhD (pictured), Associate Professor at University of Pittsburgh School of Pharmacy in the Department of Pharmaceutical Sciences, and the team will assess how HIV exacerbates HIV-associated neurocognitive disorder (HAND) progression and the role of viral, host, and external (opioids) factors in disease development to further develop therapeutic approaches to help PLWH.
This 1-year project entitled “Modeling HIV-1 Neuropathogenesis and Neuronal Dysregulation Using 3D-Organoids Containing Multiple CNS Cell Lineages,” was funded by the National Institute of Neurological Disorders and Stroke. Work began on September 15, 2022.
The abstract of this project follows:
HIV-associated neurocognitive disorder (HAND) ranges from mild to severe deficits in cognition and occurs in more than 60% of HIV-1 subjects receiving combined antiretroviral therapy (cART). Pathological evaluation of the frontal cortex of HIV-1 positive subjects revealed neuroinflammation with presence of HIV-1 infected microglia/macrophages, astrogliosis, dendrites loss and synaptic pruning in neurons. The degradation of dendrites that accompany these neuronal changes leads to synaptic loss, neuronal and cognitive decline, and this causes development of HAND in people living with HIV. Moreover, these effects may be exacerbated by illicit drug use abuse such as opioids, a drug commonly abused by this population, thus, there is a great and increasing need to study HAND and understand HIV-associated neuropathogenesis to develop better treatment options and improve disease management. However, these efforts are significantly hampered by the lack of a physiologically relevant brain/CNS model. To address this need, we developed cutting-edge tri-culture human 3D-brain organoids (hBORGs) that contain primary neurons, astrocytes, and microglia (HIV-1-infected and uninfected) to accurately model the brain environment, chronic virus replication, and neuroinflammatory milieu observed in HIV-1 infected individuals. Using this 3D-BORG model, we propose to test our hypothesis that neuroinflammation caused by HIV-1 infected microglia, induces degeneration of neurons, synaptic pruning and loss of dendrites, astrocytosis and these effects worsen by the addition of opioid drug abuse. We propose the following aims to achieve the goals: Aim 1. Delineate how infected microglia contribute to pruning and scaling of synaptodendrites, loss of synaptic functions and neuronal loss; Aim 2. Determine how use of illicit drugs such as Morphine drives the development and/or worsening of the neuronal dysfunction and pathology; and Aim 3. Identify how the viral and cellular factors from HIV-1 infected microglia cause the HAND-associated pathological features. We have assembled a team of investigators who have expertise in HIV-1 Virology, 3D-Organoids and drug abuse and synaptic function, thus, are poised to define how infected microglia interact with neurons and astrocytes and further delineate the molecular mechanisms involved in dendritic damage, synaptic plasticity and neuronal survival in the presence and absence of drug abuse. This will help us develop novel therapeutics that can prevent neuronal damage and loss of synaptic function and cognitive impairment observed in PLWH.
Congratulations, Dr. Sant!
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