Activation of the kynurenine pathway (KP) of tryptophan catabolism likely contributes to HIV-associated neurological disorders. However, KP activation in brain tissue during HIV infection has been understudied, and the effect of combination antiretroviral therapy (cART) on KP induction in the brain is unknown. To examine these questions, tryptophan, kynurenine, 3-hydroxykynurenine, quinolinic acid, and serotonin levels were measured longitudinally during SIV infection in the striatum and CSF from untreated and cART-treated pigtailed macaques. Messenger RNA (mRNA) levels of KP enzymes also were measured in the striatum. In untreated macaques, elevations in KP metabolites coincided with transcriptional induction of upstream enzymes in the KP. Striatal KP induction was also temporally associated—but did not directly correlate—with serotonin losses in the brain. CSF quinolinic acid/tryptophan ratios were found to be the earliest predictor of neurological disease in untreated SIV-infected macaques, outperforming other KP metabolites as well as the putative biomarkers interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Finally, cART did not restore KP metabolites to control levels in the striatum despite the control of the virus, though CSF metabolite levels were normalized in most animals. Overall, these results demonstrate that cerebral KP activation is only partially resolved with cART and that CSF QUIN/TRP ratios are an early, predictive biomarker of CNS disease.
|Number of pages||15|
|Journal||Journal of NeuroVirology|
|State||Published - Aug 28 2015|
Bibliographical noteFunding Information:
We thank Bristol-Myers Squibb for the gift of atazanavir, Merck for the gift of L-870812, Hoffman-La Roche for the gift of saquinavir, and Gilead for the gift of PMPA. We also thank Suzanne Queen, Brandon Bullock, Erin Shirk, Chris Bartizal, and Elizabeth Engle for their excellent technical assistance in the pigtailed macaque studies. This work was supported by the following National Institutes of Health grants: R01 MH085554, R01 MH087233, and P01 MH070306, as well as the National Center for Research Resources and the Office of Research Infrastructure Programs (ORIP) of the National Institutes of Health through Grant Number P40 OD013117.
© 2015, Journal of NeuroVirology, Inc.
- Quinolinic acid
ASJC Scopus subject areas
- Clinical Neurology
- Cellular and Molecular Neuroscience