MCP-3/CCL7 production by astrocytes: implications for SIV neuroinvasion and AIDS encephalitis

Monocyte/macrophages and activated lymphocytes traffic through normal brain, and this trafficking is increased in inflammatory conditions such as HIV encephalitis (HIVE). HIVE is characterized in part by perivascular accumulations of macrophages. The earliest events in this process are poorly understood and difficult or impossible to address in humans. The SIV-infected macaque model of neuroAIDS has demonstrated migration of monocytes into the brain early in disease, coincident with peak SIV viremia. The chemotactic signals that initiate the increased emigration of mononuclear cells into the CNS have not been described. Here, we describe astrocytes as a primary source of chemokines to facilitate basal levels of monocyte trafficking to CNS and that increased chemokine (C-C motif) ligand 7 (CCL7) production may be responsible for initiating the increased trafficking in neuroAIDS. We have previously published complementary in vivo work demonstrating the presence of monocyte chemoattractant protein 3 (MCP-3)/CCL7 within the brain of SIV-infected macaques. Here, we demonstrate that MCP-3/CCL7 is a significant chemokine produced by astrocytes, that basal monocyte migration may be facilitated by astrocyte-derived CCL7, that production of CCL7 is rapidly increased by TNF-alpha and thus likely plays a critical role in initiating neuroinvasion by SIV/HIV.