Background:  The main target of HIV replication in the brain appears to be microglial cells and infiltrating macrophages. But, whether the predominant cell type in the central nervous system, astrocytes, can support HIV infection is still controversial despite considerable postmortem study detecting HIV DNA and p24 in astrocytes. We investigated the effect of some of the cytokines elevated in HIV-associated dementia on modulating HIV replication in astrocytes.

Methods:  Human fetal astrocytes and an astroglioma cell line (U87MG) were stimulated for 24 hours with varying doses of:  interferon-g (IFN-g), granulocyte monocyte colony stimulating factor (GM-CSF), tumor necrosis factor-a (TNF-a), interleukin (IL)-2, or IL-7. Then they were infected with HIV BaL, and propagated in the presence of the respective cytokine. HIV core antigen (p24) production was measured by ELISA 7 days post-infection. Human fetal astrocytes and U87MG were pre-treated with IFN-g and GM-CSF, or left untreated for 24 hours then the expression of the respective cytokine receptor, or receptors relevant to HIV entry (CD4, human mannose receptor [hMR], CXCR4, CCR1, CCR2,CCR3, CCR5), were evaluated by immunostaining and flow cytometry.

Results:  IFN-g induced HIV replication in U87MG and human fetal astrocytes by approximately 10- and 3-fold, respectively. This effect was dose dependant in U87MG but effective at only 100 ng/mL in HFA. While GM-CSF induced HIV infection in U87MG its effects were minimal on HFA. Other cytokines evaluated (TNFa, IL-7, IL-2) had no effect on augmenting HIV replication in astrocytes. IFN-g receptor expression on U87MG and HFA was down-regulated in response to INF-g stimulation. Cell surface expression of CD4 and hMR was negative on both U87MG and HFA and was not modulated by IFN-g or GM-CSF. CCR1, CCR2, CCR3, CCR5, and CXCR4 were all negative on U87MG, but IFN-g up-regulated CCR1 and CCR3 expression. On HFA, only CXCR4 expression was positive and its expression was not modulated by IFN-g. 

Conclusions:  Pre-stimulatory cytokine signals can prime astrocytes for HIV productive infection, the extent of which depends on the astrocytic model and the nature of the cytokine used. IFN-g specifically enhanced HIV replication in astrocytes and modulated the expression of specific chemokine co-receptors.