Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART

Abstract

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 anti-retroviral 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 striatum and CSF from untreated and cART-treated pigtailed macaques. mRNA levels of KP enzymes also were measured in 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 striatum despite control of 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.

Distinct Patterns of Tryptophan Maintenance in Tissues during Kynurenine Pathway Activation in Simian Immunodeficiency Virus-Infected Macaques

“…Concordant with our previous data in brain tissue (32), we found that upstream enzymes in the KP ( IDO1, KMO , and KYNU ) displayed more upregulation during acute infection than downstream enzymes ( HAAO and QPRT ). Intriguingly, we also found that IDO1 expression in the spleen actually peaked prior to peak spleen viral loads (days 4 vs. 7 p.i.)…”

“…We thus analyzed the expression of IDO1 mRNA as well as other key enzymes in the KP in spleens of the SIV-infected macaques by NanoString. Paralleling trends in the CNS of these animals (32), we found that upstream enzymes ( IDO1, KMO , and KYNU ) displayed significant mRNA upregulation during at least one phase of infection (Figures 5A–C), while downstream enzymes ( HAAO and QPRT ) were either downregulated or unchanged (Figures 5D,E). Importantly, IDO1 was significantly elevated only during acute infection (Figure 5A, p  = 0.012 at day 4 p.i.…”

“…To further understand the dynamics of KP flux occurring at different sites in the body, we compared KP metabolites in plasma and spleen with our previous data from CSF and striatal brain tissue from these animals (32) (Figures 3A–E). The striatal region (a component of the basal ganglia) was chosen because it harbors abundant viral replication and demonstrates hallmarks of HIV-associated neurological disease in both HIV and SIV infection, likely in part due to the striatum’s susceptibility to the neurotoxic KP metabolites 3HK and QUIN, as well as other sources of oxidative stress and neurotoxicity (33–36).…”

“…Light gray shading represents the acute phase of infection (0–14 dpi), and dark gray shading represents the chronic phase of infection (≥35 dpi) in our model. Striatal brain and CSF metabolite data have been modified from a previously published version (32). …”

Metabolic profiling during HIV-1 and HIV-2 infection of primary human monocyte-derived macrophages

“…The depletion of tryptophan at the site of infection can be a protective immune mechanism for microorganisms, however prolonged depletion of tryptophan can lead to immunosuppression by T cell exhaustion. The quinolinic acid/tryptophan ratio was reported to be a biomarker of neurological disease in SIV-infected macaques (Drewes et al, 2015). In HIV-1 infected individuals, cART was shown to normalize the tryptophan metabolism (Jenabian et al, 2015).…”