Simian immunodeficiency virus strain smmPGm can induce neuropathology in macaques and is a model for the development of human HIV-related brain injury. For quantitative studies of proviral presence and expression in the central nervous system (CNS), we inoculated 8 macaques intravenously with the virus. Three animals were necropsied 2 to 4 weeks after development of infection, and we obtained lymphoid tissue biopsies from 5 animals before 5 weeks after infection. Peak plasma viral loads averaged 10 viral RNA Eq/mL at week 2, whereas cerebrospinal fluid viral loads peaked at 10 viral RNA Eq/mL. The proviral DNA loads and viral gag mRNA expression in tissues were quantified by real-time polymerase chain reaction. Two animals developed neurologic disease characterized by meningoencephalitis and meningitis. Proviral DNA levels in CNS tissues of these animals at necropsy revealed 10 and 10 copies/microg of DNA, respectively, whereas viral RNA expression in the CNS reached 100 to 1000 times higher levels than those seen in early necropsies. In sharp contrast, in 2 animals necropsied at later times without CNS disease, virus mRNA expression was not detected in any CNS tissue. Our results are consistent with the hypothesis that active virus expression in the CNS is strongly correlated with neurologic disease and that the event occurs at variable periods after infection.