PubMed · 11366783
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M Szalavitz. 1999. SAMe as it ever was?. https://pubmed.ncbi.nlm.nih.gov/11366783/
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Injection of human immunodeficiency virus type 1 (HIV-1)-infected human monocyte-derived macrophages (MDMs) into the basal ganglia of severe combined immunodeficient mice recapitulates histopathologic features of HIV-1 encephalitis (HIVE). Here, we show that the neural damage in HIVE mice extends beyond the basal ganglia and is associated with cognitive impairment. Morris water maze tests showed impaired spatial learning 8 d after MDM injection. Moreover, impaired synaptic potentiation in the hippocampal CA1 subregion was demonstrated at 8 and 15 d. By day 15, post-tetanic, short-term, and long-term potentiation were reduced by 14.1, 29.5, and 45.3% in HIVE mice compared with sham-injected or control animals. Neurofilament (NF) and synaptophysin (SP) antigens were decreased significantly in the CA2 hippocampal subregion of HIVE mice with limited neuronal apoptosis. By day 15, the CA2 region of HIVE mice expressed 3.8- and 2.6-fold less NF and SP than shams. These findings support the notion that HIV-1-infected and immune-competent brain macrophages can cause neuronal damage at distant anatomic sites. Importantly, the findings demonstrate the value of the model in exploring the physiological basis and therapeutic potential for HIV-1-associated dementia.
Cell cycle proteins regulate processes as diverse as cell division and cell death. Recently their role in neuronal death has been reported in several models of neurodegeneration. We have reported previously that two key regulators of the cell cycle, the retinoblastoma susceptibility gene product (pRb) and transcription factor E2F1, exhibit altered immunostaining patterns in simian immunodeficiency virus encephalitis (SIVE). Here we show that E2F1 and the inactivated, hyperphosphorylated form of pRb (ppRb) also exhibit altered immunostaining patterns in human immunodeficiency virus encephalitis (HIVE). Quantification of E2F1 and ppRb staining by immunofluorescent confocal microscopy confirms a significant increase in E2F1 and ppRb in both HIVE and the simian model. This increase in E2F1 and ppRb staining correlates with an increase in the presence of activated macrophages, suggesting a link between changes in cell cycle proteins and the presence of activated macrophages. Changes in ppRb and E2F1 staining in SIVE also correlate with alterations in E2F/DNA binding complexes present in the nuclear and cytoplasmic fractions from both midfrontal cortex and basal ganglia. These findings suggest that changes in cell cycle proteins occur in both HIVE and the simian model and that these changes have functional implications for gene expression in neural cells under encephalitic conditions mediated by macrophage activation or infiltration.
BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is elevated in cerebrospinal fluid in HIV- associated dementia; in addition, therapeutic GM-CSF elevates plasma viral load. OBJECTIVE: To assess the effect of GM-CSF on viral replication and the potential ameliorative effect of antiretroviral therapy. DESIGN: A primary human brain aggregate system is used as a model of the in vivo situation. METHOD: Cultured aggregates were infected with the macrophage tropic strain HIV-1SF162 and then exposed to varying GM-CSF concentrations and 0.3 micromol/l stavudine. Viral replication was assessed by p24 expression in the supernatant and aggregates. Immunohistochemistry identified neurons, astrocytes, microglia and oligodendrocytes. RESULTS: A GM-CSF concentration of 1 ng/ml resulted in a fivefold increase in microglial cells, the main HIV cellular reservoir (P = 0.0001). Prior GM-CSF exposure before infection of the aggregates resulted in sixfold increase in p24 levels compared with non-GM-CSF-exposed infected aggregates. Infected aggregates with or without GM-CSF had significant neuronal loss of 50% and 45%, respectively, and astrocytosis. Addition of stavudine to the infected aggregates, even in the presence of GM-CSF, reduced p24 levels to zero and prevented neuronal loss and astrocytosis. CONCLUSIONS: This study demonstrates that GM-CSF enhances viral replication while addition of stavudine prevents this potentially detrimental process.