Immunosuppression and neurotoxicity: how IDO contributes to pathogenesis of SIV infection

In the thirty years since the discovery of human immunodeficiency virus (HIV) as the causative agent of acquired immune deficiency syndrome (AIDS), the world has witnessed one of the most triumphant advances in modern medicine: the transformation of HIV infection from being a death sentence to being a treatable, chronic condition with the advent of combination antiretroviral therapy (cART). However, as the HIV-infected population ages, the face of the epidemic continues to evolve. For example, HIV-infected individuals have an increased rate and earlier onset of a variety of medical complications, particularly in the central nervous system, compared to their peers. The neurological manifestations include neurocognitive impairments as well as neuropsychological disorders such as depression. Understanding the pathogenic mechanisms that persist with and without cART is a critical step towards improving the lives of the aging, HIV-infected population. The kynurenine pathway of tryptophan catabolism has both immunosuppressive and neurotoxic potential and is therefore uniquely positioned to affect a wide range of comorbidities in HIV/SIV infection. In this dissertation, we examined whether this pathway was elevated to pathogenic levels in the periphery and in the central nervous system of SIV-infected pigtailed macaques, utilizing gas chromatography mass spectrometry for the analysis of pathway metabolites and transcriptional assays for the analysis of pathway enzymes. We found evidence for toxic elevations in kynurenine pathway metabolites in all tissues examined and identified specific kynurenine metabolites in the plasma and CSF as predictive biomarkers of disease in the periphery and in the brain. We also tested the efficacy of two drug therapies, a four-drug combination antiretroviral therapy and the tetracycline derivative minocycline, on attenuation of kynurenine pathway activation in SIV-infected macaques. Results from these drug studies revealed that neither cART nor minocycline was able to normalize kynurenine pathway activation. This dissertation provides insights into several unanswered questions regarding the kynurenine pathway during HIV/SIV infection. Additionally, our findings of kynurenine pathway metabolites as predictive biomarkers of disease may translate into useful prognostic indicators in patients