Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are limited by a dearth of human disease relevant small-animal models. To overcome this obstacle, newborn NOD/SCID/IL2Rγc−/− (NSG) mice were reconstituted with a humanized brain and immune systems. NSG animals of both sexes were transplanted with human neuroglial progenitors (NPC) and hematopoietic stem cells. Intraventricular injection of NPC symmetrically repopulated the mouse brain parenchyma with human astrocytes and oligodendrocytes. Human glia were in periventricular areas, white matter tracts, the olfactory bulb and the brain stem. HIV-1 infection led to meningeal and perivascular human leukocyte infiltration into brain. Species-specific viral-neuroimmune interactions were identified by deep RNA sequencing. In the corpus callosum and hippocampus overlapping human-specific transcriptional alterations 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) were seen 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. These viral defense-signaling patterns paralleled neuroimmune communication networks seen in HIV-1 infected human brains. In this manner, new mouse model of neuroAIDS can facilitate diagnostic, therapeutic and viral eradication strategies for an infected nervous system.