# Modeling HIV and methamphetamine-induced neuroinflammation in cerebral organoids > **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $598,815 ## Abstract Combination antiretroviral therapy (cART) has led to dramatic increases in lifespan among HIV-infected individuals. Despite effective cART, however, HIV-associated morbidities exert a significant toll. HIV- associated neurocognitive disorders (HAND) occur in up to 50% of chronically infected individuals despite cART. The pathogenesis of HAND remains under investigation. Neuroinflammation is a hallmark of HAND, as established by clinical studies, autopsy studies, and animal models. Ongoing or intermittent replication of HIV in the CNS is likely to contribute to neuroinflammation through direct effects on the infected cells or through release of viral proteins and inflammatory mediators. Use of neural stimulants including methamphetamine can exacerbate the neurocognitive decline seen in HAND, but the mechanisms underlying this comorbidity are not understood. Microglia are the primary resident myeloid cells of the brain, are infected at early times following acute infection with HIV or SIV, can act as a CNS viral reservoir, and are thought to play a central role in the development of HAND. The pathways responsible for microglial activation and dysfunction following HIV infection remain incompletely defined. Microglia derived from induced pluripotent stem cells (iPSCs) provide a unique opportunity to examine the molecular mechanisms underlying microglial activation. iPSC-derived microglia will be introduced into cerebral organoids, providing the additional opportunity to define the effects of microglial activation on surrounding astrocytes, neurons, and other cells. Tetherin is a host restriction factor that captures HIV during the assembly process in infected cells and generates a proinflammatory signaling cascade within infected cells. Experiments in Aim 1 of this project will evaluate HIV-induced neuroinflammation both in an unbiased way and through a directed evaluation of the role of tetherin-mediated signaling as a trigger of microglial inflammation. RNAseq, cytokine production, and immunofluorescence microscopy will be employed to define microglial activation following HIV infection. In Aim 2, we will introduce HIV-infected microglia into cerebral organoids to define the molecular basis of HIV-induced neuroinflammation and neuronal dysfunction. Single-cell RNAseq and evaluation of neuronal health and electrophysiology will be performed in models representing acute infection and in ART-suppressed, chronic infection of the brain. The potential of methamphetamine to contribute to neuroinflammation and neuronal damage in the HIV-infected microglia/organoid model will then be defined, and the relevant pathways identified. Together, these studies will provide insights into the pathogenesis of HAND and the potential contribution of methamphetamine to neurocognitive decline. ## Key facts - **NIH application ID:** 10528845 - **Project number:** 1R01DA056903-01 - **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR - **Principal Investigator:** PAUL W. SPEARMAN - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $598,815 - **Award type:** 1 - **Project period:** 2022-09-01 → 2027-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10528845 ## Citation > US National Institutes of Health, RePORTER application 10528845, Modeling HIV and methamphetamine-induced neuroinflammation in cerebral organoids (1R01DA056903-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10528845. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*