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We characterized HIV-specific CD8<jats:sup>+<\/jats:sup>T cells in cerebrospinal fluid (CSF) and peripheral blood among seven HIV-positive antiretroviral therapy-nai\u0308ve subjects. All had grossly normal brain magnetic resonance imaging and spectroscopy and normal neuropsychometric testing. Frequencies of epitope-specific CD8<jats:sup>+<\/jats:sup>T cells by direct tetramer staining were on average 2.4-fold higher in CSF than in blood (<jats:italic>P<\/jats:italic>= 0.0004), while HIV RNA concentrations were lower. Cells from CSF were readily expanded ex vivo and responded to a broader range of HIV-specific human leukocyte antigen class I restricted optimal peptides than did expanded cells from blood. HIV-specific CD8<jats:sup>+<\/jats:sup>T cells, in contrast to total CD8<jats:sup>+<\/jats:sup>T cells, in CSF and blood were at comparable maturation states, as assessed by CD45RO and CCR7 staining. The strong relationship between higher T-cell frequencies and lower levels of viral antigen in CSF could be the result of increased migration to and\/or preferential expansion of HIV-specific T cells within the CNS. 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