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HIV‐1 Tat and opiate‐induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP‐1 and alternative chemokines

Opiates exacerbate human immunodeficiency virus type 1 (HIV‐1) Tat1‐72‐induced release of key proinflammatory cytokines by astrocytes, which may accelerate HIV neuropathogenesis in opiate abusers. The release of monocyte chemoattractant protein‐1 (MCP‐1, also known as CCL2), in particular, is potentiated by opiate–HIV Tat interactions in vitro. Although MCP‐1 draws monocytes/macrophages to sites of CNS infection, and activated monocytes/microglia release factors that can damage bystander neurons, the role of MCP‐1 in neuro‐acquired immunodeficiency syndrome (neuroAIDS) progression in opiate abusers, or nonabusers, is uncertain. Using a chemotaxis assay, N9 microglial cell migration was found to be significantly greater in conditioned medium from mouse striatal astrocytes exposed to morphine and/or Tat1‐72 than in vehicle‐, μ‐opioid receptor (MOR) antagonist‐, or inactive, mutant TatΔ31‐61‐treated controls. Conditioned medium from astrocytes treated with morphine and Tat caused the greatest increase in motility. The response was attenuated using conditioned medium immunoneutralized with MCP‐1 antibodies, or medium from MCP‐1−/− astrocytes. In the presence of morphine (time‐release, subcutaneous implant), intrastriatal Tat increased the proportion of neural cells that were astroglia and F4/80+ macrophages at 7 days post‐injection. This was not seen after treatment with Tat alone, or with morphine plus inactive TatΔ31‐61 or naltrexone. Glia displayed increased MOR and MCP‐1 immunoreactivity after morphine and/or Tat exposure. The findings indicate that MCP‐1 underlies most of the response of microglia, suggesting that one way in which opiates exacerbate neuroAIDS is by increasing astroglial‐derived proinflammatory chemokines at focal sites of CNS infection and promoting macrophage entry and local microglial activation. Importantly, increased glial expression of MOR can trigger an opiate‐driven amplification/positive feedback of MCP‐1 production and inflammation. © 2005 Wiley‐Liss, Inc.