With the increased survival of human immunodeficiency virus (HIV)-infected individuals resulting from therapy, disorders in other target organs of the virus, such as the brain, are becoming more prevalent. Here the author reviews his laboratory's work on the simian immunodeficiency virus (SIV)/nonhuman model of acquired immunodeficiency syndrome (AIDS), which has revealed unique characteristics of both the virus that infects the brain, and the innate and adaptive immune response within the central nervous system (CNS) to infection. Similar to findings in humans, neurocognitive/neurobehavioral disorders during the chronic phase of infection can be detected in monkeys, and recent findings reveal potential mechanisms of CNS damage due to the virus-host interaction.