To assess the role of alpha-tumor necrosis factor in the pathogenesis of central nervous system involvement during human immunodeficiency virus type 1 infection, we recorded clinical data and measured alpha-tumor necrosis factor levels in serum and cerebrospinal fluid samples from 45 patients infected with human immunodeficiency virus type 1, classified as group II/III (10), group IV A (5), group IV B (10), and group IV C-1 (20) of the Centers for Disease Control acquired immunodeficiency syndrome classification system and 42 controls. Alpha-tumor necrosis factor was above the limit of detection in only 3 of 15 sera and 3 of 15 cerebrospinal fluid samples from patients in group II/III and group IV A, whereas it was detected in 17 of 30 sera (p <0.05) and 22 of 30 cerebrospinal fluid (p <0.0002) samples from clinically more advanced patients (group IV B and group IV C-1). Alpha-tumor necrosis factor mean values were 21.5 pg/ml in sera and 50.0 pg/ml in cerebrospinal fluid from group IV B patients and 30.4 pg/ml in sera and 24 pg/ml in cerebrospinal fluid from group IV C-1 patients. In 15 of 19 (79%) patients with human immunodeficiency virus type 1 encephalopathy (group IV B, 9 of 10 patients) and with opportunistic infections of the central nervous system (group IV C-1, 6 of 9 patients), alpha-tumor necrosis factor levels were more elevated in cerebrospinal fluid (mean value, 42 pg/ml) than in serum (mean value, 20.7 pg/ml), whereas the opposite (p <0.002) was found in 6 of 7 (86%) patients with systemic opportunistic infections not involving the central nervous system (serum mean value, 38.9 pg/ml vs. cerebrospinal fluid mean value, 15.0 pg/ml). No correlation was found between elevated alpha-tumor necrosis factor levels and clinical evidence of dementia or central nervous system demyelination. We conclude that intrathecal production of alpha-tumor necrosis factor occurs during central nervous system localization of human immunodeficiency virus type 1 infection. Alpha-tumor necrosis factor elevation seems to be related to active infection/inflammation. Measurement of cerebrospinal fluid alpha-tumor necrosis factor levels may thus represent a useful marker for ongoing central nervous system localization of human immunodeficiency virus type 1 infection.
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