Chemokine expression in the CNS of SIV-infected macaques

Central nervous system (CNS) disease is one of the most common manifestations of infection with the human immunodeficiency virus (HIV). HIV encephalopathy (HIVE) occurs in over half of all untreated HIV-infected patients and in a smaller, yet significant number of patients treated with highly active antiretroviral therapy (HAART). HIVE results from the infection and activation of infiltrating and resident macrophages in the brain and the resultant secretion of neurotoxic factors resulting in neuronal loss, and the formation of microglial nodules and multinucleated giant cells. Multiple studies have demonstrated upregulation of chemokines that attract macrophages in the CNS of patients with HIVE at autopsy, but their role early in the disease is poorly understood. A similar disease, SIV encephalitis (SIVE), occurs in macaques infected with the related simian immunodeficiency virus (SIV). To better understand the role of chemokines in the early stages of HIVE, we used the SIV/macaque model to evaluate the expression of two macrophage-attractant chemokines in the brain: fractalkine (CX3CL1), a constitutively expressed chemokine, and monocyte chemoattractant protein-3 (MCP-3 [CCL-7]), a chemokine produced de novo by activated macrophages, microglia and astrocytes. Our studies demonstrated a unique chemokine response to infection in that fractalkine expression was downregulated in SIV-infected macaques. Downregulated fractalkine expression was consistently correlated with the presence and severity of encephalitis suggesting that its primary role in the brain is homeostatic rather than inflammatory. On the other hand, MCP-3 expression was upregulated in macaques with encephalitis and increased with the severity of encephalitis. Possible explanations for the downregulation of fractalkine expression in SIV infection may be (1) to reduce its competition with induced chemokines such as MCP-3, RANTES, MIP-1α, etc., (2) as an early marker of neurodegeneration that is independent of other chemokine expression, or (3) disruption of fractalkine expression may lead to microglial activation and production of proinflammatory mediators that result in neurodegeneration or inflammation. Lack of MCP-3 upregulation prior to the development of encephalitis is evidence that its expression is not an initiating event in SIVE. Its upregulation with increased severity, however, suggests that it is important in prolonging or exacerbating encephalitis once SIVE develops.