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To compare the viral genotypes present in RNA from brain and peripheral blood mononuclear cells (PBMC) and DNA from brain during acute, asymptomatic and late stages of SIV infection of macaques.Eighteen pigtailed macaques were intravenously inoculated with SIV. At 10, 21 and 56 days postinoculation, six were euthanized and the severity of encephalitis was assessed by microscopic examination. DNA and RNA were isolated from brain and PBMC, and the V1 region of env was amplified by the polymerase chain reaction and sequenced from over 800 different clones.Similar genotypes were detected in RNA from brain and PBMC at 10 days postinoculation, suggesting an unrestricted exchange of virus between the periphery and the brain during acute infection. There was a progressive increase in the percentage of neurovirulent genotypes in brain RNA from acute (14% of all genotypes detected in brain RNA) to early asymptomatic (45%), to late asymptomatic (52%) and to terminal (95%) infection. Fewer different genotypes were found in brain RNA than in PBMC RNA from macaques euthanized during early asymptomatic (2.5 and 5 different genotypes, respectively; P = 0.007), late asymptomatic (2 and 5 different genotypes, respectively; P = 0.003) and terminal (2 and 4 different genotypes, respectively; P < 0.001) infection.These data demonstrate that the almost exclusive replication of neurovirulent genotypes in the brain seen at late-stage infection is a progressive process that begins early in infection and continues to late stage disease.