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Human microglial models to study HIV infection and neuropathogenesis: a literature overview and comparative analyses
Stephanie B H Gumbs1, Raphael Kübler1,2, Lavina Gharu1
1Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
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.
Insights
Evaluating human microglial models for HIV research is crucial. Primary microglia (pMG), monocyte-derived microglia (MDMi), and organoids (oMG) show promise for studying HIV in the central nervous system (CNS).
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Human immunodeficiency virus (HIV) persistence in the central nervous system (CNS) contributes to neurological disorders and hinders HIV cure efforts.
- Microglia are the primary viral reservoir in the CNS, making their study critical for understanding HIV pathogenesis and developing effective treatments.
- Existing human microglial culture models vary in their suitability for HIV research.
Purpose of the Study:
- To comprehensively compare different human microglial culture models for their utility in HIV research.
- To assess the functional and transcriptional similarities of various microglial models to primary microglia.
- To evaluate the susceptibility of these models to HIV infection and viral replication.
Main Methods:
- Comparison of cultured primary microglia (pMG), microglial cell lines (SV40, HMC3), monocyte-derived microglia (MDMi), induced pluripotent stem cell-derived microglia (iPSC-MG), and 3D cerebral organoids (oMG).
- Functional characterization including phagocytosis and lipopolysaccharide (LPS) responsiveness.
- Transcriptome profiling to assess similarity to uncultured primary microglia.
- Direct HIV infection assays to quantify viral replication.
Main Results:
- Transcriptional profiles showed highest similarity between uncultured pMG and cultured pMG/oMG, followed by iPSC-MG and MDMi.
- Cultured pMG and MDMi exhibited high HIV replication, while oMG showed low replication resembling post-mortem biopsies.
- SV40 and HMC3 cell lines did not support HIV infection.
- All models demonstrated phagocytic capabilities and LPS responsiveness.
Conclusions:
- Monocyte-derived microglia (MDMi) can serve as an initial screening tool due to transcriptional similarity and HIV susceptibility.
- Organoid-derived microglia (oMG), cultured primary microglia (pMG), and iPSC-derived microglia (iPSC-MG) offer more representative models for HIV research.
- Current human microglial cell lines (SV40, HMC3) are not recommended for HIV studies.
