Systemic HIV-1 Infection Produces a Unique Glial Footprint in Humanized Mouse Brains

Abstract

Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are hindered by the availability of relevant small-animal models. To overcome this hindrance, a mouse model reconstituted with humanized brain and immune systems was created. Newborn NOD/SCID/IL2R{gamma}c-/- mice of both sexes were transplanted with human neuroglial progenitors (NPC) and hematopoietic stem cells. Intraventricular injection of NPC yielded an anatomical symmetrical glia (human astrocyte and oligodendrocyte) repopulation of the mouse brain. The human glia were observed in periventricular areas, white matter tracts, the olfactory bulb and brain stem. HIV-1 infection of these dual humanized mice led to meningeal and perivascular human leukocyte infiltration into brain. The species-specific viral-neuroimmune interactions in the infected animals were identified by deep RNA sequencing. In the corpus callosum and hippocampus overlapping human-specific transcriptional alterations were seen for interferon type 1 and 2 signaling pathways (STAT1, 2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) in infected animals. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG and ZNF488) were downregulated. The data sets were confirmed by real-time PCR. The viral defense signaling patterns observed in these mice parallels the neuroimmune communication networks present in the HIV-1 infected human brain. In this manner, the new mouse model can facilitate discovery of therapeutics, viral eradication targets for virus induced nervous system diseases, and simplify HIVCure research approaches.\n\nSummary StatementWe created mice with both a humanized brain and an immune system. The animals were used to investigate glial responses to HIV-1 infection. At a transcriptional level we defined the interactions between human glia and immune cells in the presence of the systemic HIV-1 infection. Noticeably, altered transcriptional changes were human specific. At five weeks after viral infection humanized mouse brain displayed potent interferon-mediated antiviral innate immune responses and alteration of neuronal progenitors differentiation and myelination. This model can be used to tests both diagnostic and therapeutic interventions for cure HIV-associated brain impairment.