Journal Article

Neuroinflammation generated by HIV-infected microglia promotes dysfunction and death of neurons in human brain organoids

Roan, Nadia R, Helmy, Ekram, Ndhlovu, Lishomwa C, Sohn, Peter, Gan, Li, Xie, Guorui, Frouard, Julie, Greene, Warner C, Schwarzer, Roland, Zhang, Gang, Kong, Weili, Corley, Michael J, Montano, Mauricio

2024

Overview

Abstract Despite the success of combination antiretroviral therapy (ART) for individuals living with HIV, mild forms of HIV-associated neurocognitive disorder (HAND) continue to occur. Brain microglia form the principal target for HIV infection in the brain. It remains unknown how infection of these cells leads to neuroinflammation, neuronal dysfunction, and/or death observed in HAND. Utilizing two different inducible pluripotent stem cell-derived brain organoid models (cerebral and choroid plexus [ChP] organoids) containing microglia, we investigated the pathogenic changes associated with HIV infection. Infection of microglia was associated with a sharp increase in CCL2 and CXCL10 chemokine gene expression and the activation of many type I interferon stimulated genes (MX1, ISG15, ISG20, IFI27, IFITM3 and others). Production of the proinflammatory chemokines persisted at low levels after treatment of the cell cultures with ART, consistent with the persistence of mild HAND following clinical introduction of ART. Expression of multiple members of the S100 family of inflammatory genes sharply increased following HIV infection of microglia measured by single-cell RNA-seq. However, S100 gene expression was not limited to microglia but was also detected more broadly in uninfected stromal cells, mature and immature ChP cells, neural progenitor cells and importantly in bystander neurons suggesting propagation of the inflammatory response to bystander cells. Neurotransmitter transporter expression declined in uninfected neurons, accompanied by increased expression of genes promoting cellular senescence and cell death. Together, these studies underscore how an inflammatory response generated in HIV-infected microglia is propagated to multiple uninfected bystander cells ultimately resulting in the dysfunction and death of bystander neurons.

• Publisher: Oxford University Press
• Subject: Antiretroviral agents / Antiretroviral therapy / Biological response modifiers / Brain / Causes of / Cell culture / Cell death / Chemokines / Choroid plexus / Cognition / Cognition disorders / Complications and side effects / CXCL10 protein / Gene expression / Genes / Health aspects / Highly active antiretroviral therapy / HIV / HIV infection / Human immunodeficiency virus / Infections / Inflammation / Inflammatory response / Microglia / Monocyte chemoattractant protein 1 / Mortality / Neural stem cells / Neurons / Organoids / Pluripotency / Progenitor cells / Senescence / Stem cells / Stromal cells