BACKGROUND Encephalitis is a common and devastating sequela of HIV infection in humans and of simian immunodeficiency virus (SIV) infection in rhesus macaques. We used the SIV-infected rhesus macaque model to study early intrathecal events in the pathogenesis of lentiviral encephalitis. METHODS To examine early events and to compare the neuroinvasiveness and neurovirulence of pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of SIV and the role of host immunity in the early postinfection period, we inoculated groups of rhesus macaques with each of these clones and compared them with a third group of animals inoculated with pathogenic uncloned SIV (SIVmac). We collected paired cerebrospinal fluid and sera before and at intervals after inoculation and determined albumin and IgG concentrations, SIV-specific humoral immune response, and concentrations of quinolinic acid. Two animals from each group were killed and necropsied at 2, 8, 13, and 23 weeks after inoculation. Routine histopathology and semi-quantitative in situ hybridization were performed on tissue from multiple levels of the central nervous system (CNS). RESULTS SIVmac and SIVmac-239 invaded both the meninges and the CNS parenchyma simultaneously within 2 weeks of inoculation, whereas nonpathogenic SIVmac-1A11 was not neuroinvasive. Gross disruption of the blood-brain barrier was not detected at any time. However, elevated IgG indices and high levels of cerebrospinal fluid quinolinic acid denoted intrathecal immune activation soon after viral neuroinvasion. Virus load in the CNS declined as the immune response peaked but subsequently increased with waning immunity. One macaque that never developed an SIV-specific immune response died with severe SIV encephalitis. CONCLUSIONS Our findings support the following hypotheses of early events in SIV neuropathogenesis: (a) Pathogenic virus invades the CNS within days of i.v. inoculation and elicits an intrathecal immune response, including intrathecal synthesis of IgG and macrophage activation; (b) the immune response initially is associated with a decreased virus load in the CNS; (c) as immunodeficiency develops, virus load in the CNS increases once again; and (d) both virus and host factors are important in determining the course of events.