The central nervous system (CNS) is a target for human immunodeficiency virus infection, and, in individuals with acquired immune deficiency syndrome, this can lead to a devastating dementia. Only certain viral variants appear capable of invading the CNS and infecting microglia and brain macrophages. To determine whether the virus entering the brain may be particularly pathogenic to the CNS, we isolated microglia from the brains of simian immunodeficiency virus-infected rhesus monkeys. Serial transfer of these cells into naive animals indicated that productive simian immunodeficiency virus infection could indeed be transferred. Furthermore, CNS infection occurred within a relatively short time span and was associated with viral gene expression in the brain and pathology characteristic of human immunodeficiency virus encephalitis. While demonstrating that neuropathogenic variants partition into the CNS, our approach will allow the dissection of functional neuropathogenic elements present in these viruses.