Background:  Loss of natural killer (NK) cell function and adaptive immunity is associated with the pathogenesis of HIV-1 dementia and encephalitis (HIVE). However, the relative roles of each of these in disease remains poorly understood. To this end we used C.B.-17/scid and double knockout Rag2^-/-g_c^-/- as models for HIVE to reflect the deficiency of adaptive immune responses as well as NK cell dysfunction, respectively.

Methods:  C.B.-17/scid (n = 36) and double knockout Rag2^-/-g_c^-/-  (n = 36) mice were injected with HIV-1-infected human monocyte-derived macrophages (MDM) into the basal ganglia and monitored for glial inflammatory responses and neuronal loss by immunohistology and real-time polymerase chain reaction (Q-PCR). Animals were evaluated at 7 and 14 days after HIV-infected MDM injection for human cells (vimentin), viral infection (HIV-1p24), astrocytes (glial fibrillary acidic protein, GFAP), microglia [ionized calcium-binding adaptor molecule (Iba)-1] and neuronal markers (microtubule associated protein-2, MAP-2, neuron-specific nuclear protein, NeuN, and neurofilament, NF). Q-PCR was used to quantitatively evaluate expression of macrophage/microglia marker Mac-1, GFAP, interleukin-1 (IL-1β), tumor necrosis factor-a (TNF-a), IL-6, IL-10, inducible nitric oxide (iNOS), and brain-derived neurotrophic factor (BDNF). Flow cytometry of the injected and corresponding contralateral brain regions were assayed for mouse CD45^low/high, I-A^b, CD3, DX-5, and CD14 antigens.

Results:  C.B.-17/scid HIVE mice showed a lesser number of MDM in the brain tissue (p <0.05), increased activation of microglia (Iba-1 staining and Mac-1 expression, p <0.05) and augmented levels of TNF-a and IL-1β(p <0.05). The levels of human MDM infection, expression of iNOS, and BDNF were not different. These findings corresponded to increased neuronal damage with loss of NeuN/MAP-2 staining compared to Rag2^-/-g_c^-/- animals. The presence of NK cells in C.B.-17/scid mice was confirmed by detection of DX-5⁺ cells. This coincident with enhanced chemoattraction of peripheral MDM detected by FACS as CD14/CD45^high and residual CD3 lymphocytes.

Conclusions:  Loss of both adaptive immunity and NK cell activities defines the fingerprint of HIVE and affects the levels of MDM function, migration, neuroinflammation, and neuronal loss.