CNS abnormalities can be detected during chronic human immunodeficiency virus (HIV) infection, before the development of opportunistic infections or other sequelae of immunodeficiency. However, although end-stage dementia caused by HIV has been linked to the presence of infected and activated macrophages and microglia in the brain, the nature of the changes resulting in the motor and cognitive disorders in the chronic stage is unknown. Using simian immunodeficiency virus-infected rhesus monkeys, we sought the molecular basis for CNS dysfunction. In the chronic stable stage, nearly 2 years after infection, all animals had verified CNS functional abnormalities. Both virus and infiltrating lymphocytes (CD8+ T-cells) were found in the brain. Molecular analysis revealed that the expression of several immune response genes was increased, including CCL5, which has pleiotropic effects on neurons as well as immune cells. CCL5 was significantly upregulated throughout the course of infection, and in the chronic phase was present in the infiltrating lymphocytes. We have identified an altered state of the CNS at an important stage of the viral–host interaction, likely arising to protect against the virus but in the long term leading to damaging processes.