Advancing basic and translational research to deepen understanding of the molecular immune‐mediated mechanisms regulating long‐term persistence of HIV‐1 in microglia in the adult human brain

Knowledge about the diversity microglia (MG) type and function in the rodent and human brain has advanced significantly in the last few years. Nevertheless, we have known for 40 years that MG, monocytes, and macrophages in the brain play crucial roles in the pathogenesis of the HIV‐1 in all tissues. HIV enters and spreads in the brain early, long before the initiation of antiviral therapy. As a result, many people with HIV continue to experience neurologic and neuropsychiatric comorbid conditions collectively known as HIV‐associated neurocognitive disorder (HAND). HIV pathogenic sequelae in the CNS pose a challenge for cure strategies. Detailed understanding at a mechanistic level of how low‐level and latent HIV‐1 infection in MG negatively impacts neuroglial function has remained somewhat elusive. Direct rigorous in vivo experimental validation that the virus can integrate into MG and assume a latent but reactivatable state has remained constrained. However, there is much excitement that human in vitro models for MG can now help close the gap. This review will provide a brief background to place the role of MG in the ongoing neurologic complications of HIV infection of the CNS, then focus on the use and refinement of human postmitotic monocyte‐derived MG‐like cells and how they are being applied to advance research on HIV persistence and proinflammatory signaling in the CNS. Critically, an understanding of myeloid plasticity and heterogeneity and rigorous attention to all aspects of cell handling is essential for reproducibility. Summary Sentence: This review focuses on human postmitotic monocyte‐derived microglia‐like cells as tools to advance research on HIV persistence and neuroinflammatory signaling. KEY CONCEPTS Myeloid plasticity: The phenotype and function of myeloid cells (monocytes, macrophages, and microglia) are shaped and regulated by intercellular signals. These include cytokines, chemokines, and other cues from neighboring cells in the tissue microenvironment. In addition, paracrine and autocrine signals under the homeostatic state are altered with injury, stress, infection, or chronic disease conditions. In responding to these cues, myeloid cells undergo some or all of the following: morphologic changes, altered metabolism, variation of components released into the extracellular matrix, increased migration, cytokine/chemokine production, and phagocytosis. Human monocyte‐derived microglia (hMMGS): Purified subpopulations of bone marrow‐deriv