Abstract
HIV persistence in the CNS despite antiretroviral therapy may cause neurological disorders and poses a critical challenge for HIV cure. Understanding the pathobiology of HIV-infected microglia, the main viral CNS reservoir, is imperative. Here, we provide a comprehensive comparison of human microglial culture models: cultured primary microglia (pMG), microglial cell lines, monocyte-derived microglia (MDMi), stem cell–derived microglia (iPSC-MG), and microglia grown in 3D cerebral organoids (oMG) as potential model systems to advance HIV research on microglia. Functional characterization revealed phagocytic capabilities and responsiveness to LPS across all models. Microglial transcriptome profiles of uncultured pMG showed the highest similarity to cultured pMG and oMG, followed by iPSC-MG and then MDMi. Direct comparison of HIV infection showed a striking difference, with high levels of viral replication in cultured pMG and MDMi and relatively low levels in oMG resembling HIV infection observed in post-mortem biopsies, while the SV40 and HMC3 cell lines did not support HIV infection. Altogether, based on transcriptional similarities to uncultured pMG and susceptibility to HIV infection, MDMi may serve as a first screening tool, whereas oMG, cultured pMG, and iPSC-MG provide more representative microglial culture models for HIV research. The use of current human microglial cell lines (SV40, HMC3) is not recommended.Supplementary informationThe online version contains supplementary material available at 10.1007/s13365-021-01049-w.
Highlights
38 million people are estimated to be living with HIV
Despite long-term antiretroviral therapy (ART), HIV-1 persists in the central nervous system (CNS), which upon ART cessation contributes to the rekindling of viral infection and replication
We provide a comprehensive overview of five different human microglial culture models: cultured primary microglia, microglial cell lines (SV40, HMC3, clone 20 (C20)), monocyte-derived microglia (MDMi), stem cell–derived microglia, and microglia grown in 3D cerebral organoids
Summary
Implementation of antiretroviral therapy (ART) resulted in effective suppression of viral replication and substantially reduced AIDS-related morbidity and mortality (Global HIV & AIDS Statistics 2020). Despite long-term ART, HIV-1 persists in the central nervous system (CNS), which upon ART cessation contributes to the rekindling of viral infection and replication. Persistence of HIV in the CNS indirectly and directly results in a wide range of CNS manifestations in up to 50% of ART-treated HIVinfected individuals, collectively termed HIV-associated neurocognitive disorders (HAND) Besides optimizing the antiretroviral drug combination for better CNS penetration and encouraging the patients’ adherence to treatment, no other clear recommendation can be formulated for the treatment of HAND (Calcagno et al 2017; Nosik et al 2021; Ulfhammer et al 2018; Winston and Spudich 2020). To develop novel therapeutic strategies that target this CNS reservoir and diminish HIV-associated pathogenesis in the CNS, it is of primary interest to understand how HIV reservoirs in the brain are established and maintained
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