Background:  Neural stem/progenitor cells (NPC) are self-renewing, multi-potent cells that give rise to neurons, astocytes, and oligodendrocytes during development and in the adult brain. Changes in neurogenesis have been associated with multiple neurodegenerative disorders, but how neurogenesis is affected in HIV-1-associated dementia (HAD) has not been addressed. Here we test the hypothesis that cytokines, produced by HIV-1-infected or immune-activated macrophages, affect neurogenesis through influencing NPC proliferation and differentiation.

Methods:  Human monocyte-derived macrophages (MDM) were infected with HIV-1 macrophage-tropic viral strains (ADA, BAL, and JRFL) or immune activated with LPS. Cytokine production was measured by ELISA. Human neural progenitor cell (NPC) cultures were exposed to MDM conditioned media (MCM) and NPC proliferation was quantified by neurosphere initiation assay. NPC differentiation was evaluated by real time polymerase chain reaction (RT-PCR), Western blot, immunocytochemical staining, and FACS using markers for neurons and astrocytes.

Results:  Soluble factors released from MDM induced a dose-dependant increase of NPC proliferation. HIV-1-infected MCM induced a slight increase of NPC proliferation as compared to MCM from control MDM, but showed no significant effect on NPC apoptosis. HIV-1_ADA-infected and LPS-activated MCM induced substantial increases in NPC proliferation. The increase of NPC proliferation is mediated by an increase in production of tumor necrosis factor (TNF) -a and interleukin (IL) -1b by infected/activated MDM. Notably, NPC proliferation mediated by HIV-1/LPS MCM is partially abrogated by TNF-a soluble receptors and neutralizing antibody, indicating the HIV-1/LPS MCM-mediated effect is partially though TNF-a. Moreover, both TNF-a and immune activated MCM inhibit neuronal differentiation while increasing astrocyte differentiation.

Conclusions:  These observations provide evidence that HIV-1-infected and immune-activated macrophages may affect neurogenesis through induction of NPC proliferation, while inhibiting neurogenesis and activating gliogenesis. This effect is partially mediated by TNF-a production during HIV-1 infection and immune activation of macrophage.