Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosisfactor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 disease

The chronic immune activation state in HIV disease leads to increased activ ity of the rate-limiting tryptophan-kynurenine pathway enzyme indoleamine 2 ,3-dioxygenase (2,3-IDO), thereby increasing the formation of neurotoxic tr yptophan metabolites such as kynurenine and quinolinic acid. We investigate d whether highly active antiretroviral therapy (HAART) (median duration, 10 0 days; range, 50-188 days) lowers serum levels of these metabolites in HIV -infected individuals and if so, whether this was paralleled by changes in a surrogate marker for immune activation, i.e., soluble tumor necrosis fact or receptor p75 (sTNFR p75) concentrations. Baseline quinolinic acid (848 n M, 95% CI 567-1130 vs. 303 nM, 95% CI 267.1-339.5) and kynurenine (4.1 mM, 95% CI 3.3-4.9 vs. 2.7 mM, 95% CI 2.4-2.9) concentrations as well as the me an kynurenine-to-tryptophan ratio (108.2, 95% CI 76.1-140.4 vs. 51.4, 95% C I 47.6-55.3) in 17 HIV-1-infected outpatients (7 with AIDS) were significan tly higher than those in 55 healthy age-matched controls (p<0.01), respecti vely. Serum quinolinic acid concentrations in 14 of 17 patients decreased ( mean, -44.4%) during HAART in comparison with baseline (471.2 nM, 95% CI 28 8-654.3; p = 0.022). Thirteen of these 14 patients also had decreases in sT NFR p75 concentrations. Overall, the mean sTNFR p75 concentration decreased by 36.3% (13.5 ng/ml, 95% CI 9.3-17.8 vs. 8.6 ng/ml, 95% CI 5.9-11.4; p = 0.01, n = 17). Reduction in viral load through HAART and subsequent mitigat ion of the pathological immune activation state in HIV disease may have red uced 2,3-IDO over activation. This eventually led to a decrease in quinolin ic acid formation. The parallel reduction of the immune activation marker s TNFR p75 supports this hypothesis.