Modeling HIV-1 Neuropathogenesis and neuronal dysregulation using 3D-organoids containing multiple CNS cell lineages

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Project Summary HIV-associated neurocognitive disorder (HAND) range 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 a cutting-edge tri-culture human 3D-brain organoids (hBORGs) that contains 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 oipoid 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 the how 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.