The kynurenine pathway activities in a sub-Saharan HIV/AIDS population

Bipath et al. BMC Infectious Diseases (2015) 15:346 DOI 10.1186/s12879-015-1087-5 RESEARCH ARTICLE Open Access The kynurenine pathway activities in a sub-Saharan HIV/AIDS population Priyesh Bipath1, Peter F. Levay2 and Margaretha Viljoen3* Abstract Background: Tryptophan is an essential amino acid for the synthesis of proteins and important metabolites such as serotonin, melatonin, tryptamine and niacin. After protein synthesis, more than 90 % of tryptophan catabolism occurs along the kynurenine pathway. The inflammation-inducible enzyme indoleamine 2,3 dioxygenase (IDO) is responsible for the first rate-limiting step in the kynurenine pathway, i.e., oxidation of tryptophan to kynurenine. Excessive IDO activity in conditions such as HIV/AIDS may lead to tryptophan depletion and accumulation of metabolites downstream from kynurenine. Little is known about the kynurenine pathway of HIV/AIDS patients in sub-Saharan regions. This study, in a low income sub-Saharan HIV/AIDS population, examined the effects of activities in the kynurenine pathway on plasma levels of tryptophan, kynurenine and the neurotoxin quinolinic acid, and on de novo synthesis of nicotinamide. Methods: Plasma samples were obtained from a cohort of 105 HIV patients and 60 controls. Kynurenine pathway metabolites were analysed using gas chromatography – mass spectrometry. ELISA and flow cytometry were used to assess plasma inflammatory markers. Results: IDO activity, depletion of tryptophan, as well as accumulation of kynurenine and the neurotoxin quinolinic acid, were not only significantly greater in the patients than in the controls, but also markedly greater than in HIV/AIDS patients from developed countries. Tryptophan levels were 12.3 % higher, kynurenine levels 16.2 % lower, quinolinic acid levels 43.2 % lower and nicotinamide levels 27,2 % lower in patients on antiretroviral treatment than in antiretroviral-naïve patients. Patients’ kynurenine pathway metabolites correlated with the levels of inflammatory markers, including that of the major IDO-inducer, interferon-gamma. Indications are that the rate of de novo synthesis of nicotinamide in the kynurenine pathway correlates with increases in quinolinic acid levels up to a point where saturation of the enzyme quinolinate phosphoribosyl transferase occurs. Conclusions: Higher levels of inflammatory activity in this low income sub-Saharan HIV/AIDS population than in patients from developed countries lead to greater tryptophan depletion and greater accumulation of metabolites downstream from tryptophan with quinolinic acid levels often reaching levels associated with the development of HIV/AIDS-associated neurocognitive dysfunction. De novo synthesis of nicotinamide from quinolinic acid contributes to the maintenance of nicotinamide, and by implication NAD levels, in HIV/AIDS patients from low income populations. Antiretroviral treatment partially corrects disturbances in the kynurenine pathway. * Correspondence: 3 Department of Psychiatry, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa Full list of author information is available at the end of the article © 2015 Bipath et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bipath et al. BMC Infectious Diseases (2015) 15:346 Background The essential amino acid tryptophan is important for protein synthesis and serves as substrate for the synthesis of serotonin, melatonin and tryptamine. In addition, it also serves as substrate for the de novo synthesis of nicotinamide adenine dinucleotide (NAD) and niacin in the kynurenine pathway of tryptophan metabolism. After protein synthesis, more than 90 % of tryptophan catabolism occurs along the kynurenine pathway [1]. The kynurenine pathway starts with the oxidative degradation of tryptophan (Fig. 1). Kynurenine is the first stable metabolite formed when tryptophan is oxidized under influence of either L-tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO) [2]. Excess tryptophan, i.e., at levels above the requirement for protein and serotonin synthesis, is oxidized in the liver under influence of the liver-specific enzyme TDO, to ATP, CO2 and water. In contrast, tryptophan oxidation under influence of the inflammation-inducible enzyme IDO occurs in various cell types, is not limited by a decrease in tryptophan levels and may even lead to tryptophan depletion [2]. The main cytokines for the induction of IDO are interferon-gamma (IFN-γ) in the periphery and interleukin-6 (IL-6) in the central nervous system, but other pro-inflammatory cytokines, as well as the HIV tat and nef proteins, may also have an influence [3, 4]. After conversion of tryptophan to kynurenine, kynurenine is converted to 3-hydroxy-kynurenine by the enzyme kynurenine 3-monoxygenase; 3-hydroxy-kynurenine is converted under the influence of kynureninase to 3hydroxy-anthranilic acid and the latter converted under the influence of 3-hydroyxanthranilate 3,4-dioxygenase to α-amino-ß-carboxymuconate-ε-semialdehyde (ACMS) which, in turn, is converted to α-aminomuconate-εsemialdehyde under the influence of the rate-limiting enzyme ACMS decarboxylase (ACMSD). Some ACMS, not metabolized to α-aminomuconate-ε-semialdehyde is non-enzymatically converted to quinolinic acid, the precursor of NAD and niacin (Fig. 1) [5–7]. Physical disorders such as autoimmune diseases, cancer, AIDS, pellagra, rheumatoid arthritis and cardiovascular abnormalities, as well as a host of neurodegenerative/ neuropsychiatric disorders, have been linked to alterations in the kynurenine pathway of tryptophan metabolism [2, 4, 8]. Excessive activities in the kynurenine pathway, especially increases in quinolinic acid, are implicated in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, schizophrenia and related disorders, multiple sclerosis, epilepsy, attention deficit-hyperactivity disorder, anxiety, depression and in the AIDS dementia complex [2, 8, 9]. Kynurenine pathway metabolites can either act as neuroactive substances or affect neuronal function through their oxidative/reductive properties, or Page 2 of 12 through the supply of adequate NAD in conditions of a deficient dietary niacin [2, 8, 9]. Excessive stimulation of the kynurenine pathway may lead to tryptophan depletion, accumulation of the neurotoxin quinolinic acid and to a decline in se (...truncated)