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Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population
Thesis (PhD)--University of Pretoria, 2015.
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University of Pretoria
2015
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| _version_ | 1867613483511578625 |
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| access_status_str | Open Access |
| author2 | Viljoen, Margaretha |
| author_browse | Viljoen, Margaretha |
| author_facet | Viljoen, Margaretha |
| collection | Thesis |
| dc_rights_str_mv | © 2015 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD)--University of Pretoria, 2015. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/46053 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:36:52.135Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/46053 Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population Viljoen, Margaretha Bipath, Priyesh UCTD Tryptophan Gas chromatography-mass spectrometry (GC-MS) Immune activity Kynurenine HIV/AIDS SDG-03: Good health and well-being SDG-17: Partnerships for the goals Thesis (PhD)--University of Pretoria, 2015. The essential amino acid tryptophan is an important substrate for the synthesis of serotonin, melatonin, tryptamine, proteins and the kynurenines. The aim of this study was to investigate tryptophan metabolism along the kynurenine pathway in a low income sub-Saharan HIV/AIDS patient population from the Gauteng Province of South Africa. The first objective was to develop and validate a novel gas chromatography mass spectrometry method to enable reliable quantification of tryptophan and metabolites of the kynurenine pathway in plasma. Validation parameters for the detection of tryptophan, kynurenine, quinolinic acid and nicotinamide conformed to international criteria for newly developed methods. The next objective of the study was to find an appropriate biomarker against which to express the results. Several substances previously described as indicators were assessed and compared, including plasma neopterin, procalcitonin, C-reactive protein, the cytokines IL-2, IL-4, IL-6, IL-10, TNF, and IFN-gamma, as well as factors routinely measured and elsewhere described as biomarkers in HIV, i.e., albumin, the albumin/globulin ratio, haemoglobin and red cell distribution width. Neopterin was shown to be superior as indicator of pro-inflammatory status, as indicator of the degree of immune deficiency, to predict disease progression, to distinguish between patients with and without tuberculosis co-infection and to reflect the success of highly active antiretroviral treatment (HAART). In the analyses of the kynurenine pathway metabolites, tryptophan levels were seen to be significantly lower (24.36 ± 4.14 vs. 43.57 ± 11.85 μmol/l; p<0.0001), while the activity of the enzyme, indoleamine 2,3 dioxygenase (IDO), (K/T:136.03 vs. 52.18; p<0.001), as well as kynurenine (3.21 ± 1.33 vs. 2.14 ± 0.45 μmol/l; p<0.001) and quinolinic acid (4.46 ± 2.32 vs. 0.25 ± 0.058 μmol/l; p<0.001) levels were significantly higher in the total patient group (n=105) than in the control group (n=60). Patients on HAART showed not only significantly higher CD4 counts (296.21 ± 195.50 vs. 170.05 ± 167.26 cells/μl; p=0.003), but also lower inflammatory activity (neopterin: 35.51 ± 35.70 vs. 66.63 ± 40.73 nmol/l; p<0.001 and IL-6: 9.56 ± 12.54 vs. 15.04 ± 19.34 pg/ml; p<0.05), lower IFN-γ (41.43 ± 14.14 vs. 53.68±34.39 pg/ml; p<0.05), higher tryptophan levels (25.13 ± 3.80 vs. 22.04 ± 4.32 μmol/l; p=0.033), lower kynurenine levels (3.08 ± 1.28 vs. 3.58 ± 1.42 μmol/l; p=0.144) and lower quinolinic acid levels (4.03 ± 2.04 vs. 5.77 ± 2.65μmol/l; p=0.072) than patients not on HAART. Tryptophan depletion and IDO activity, as well as the levels of kynurenine and quinolinic acid, were generally greater than in populations from developed countries. Indications are that this can be ascribed to higher levels of inflammatory activity at comparable levels of immune deficiency in the disadvantaged population of this study. The degree of tryptophan depletion and quinolinic acid accumulation found could negatively impact on the physical and neuropsychiatric wellness of the population. Correlations between quinolinic acid, and nicotinamide levels showed a significant contribution of kynurenine pathway metabolism to the plasma levels of nicotinamide. This de novo synthesis of nicotinamide could offer protection against niacin deficiency and NAD depletion in populations with inadequate dietary intake. This is the first study to assess plasma tryptophan, kynurenine, quinolinic acid and nicotinamide levels, as well as IDO activity, pro-inflammatory status and IFN-γ levels, simultaneously in one population and to compare it to that of HIV/AIDS patients in developed countries. tm2015 em2026 Physiology PhD Unrestricted SDG-03: Good health and well-being SDG-17: Partnerships for the goals 2015-07-02T11:06:42Z 2015-07-02T11:06:42Z 2015/04/24 2015 Thesis Bipath, P 2015, Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population, PhD Thesis, University of Pretoria, Pretoria, viewed yymmdd <http://hdl.handle.net/2263/46053> A2015 http://hdl.handle.net/2263/46053 en © 2015 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD Tryptophan Gas chromatography-mass spectrometry (GC-MS) Immune activity Kynurenine HIV/AIDS SDG-03: Good health and well-being SDG-17: Partnerships for the goals Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population |
| title | Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population |
| title_full | Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population |
| title_fullStr | Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population |
| title_full_unstemmed | Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population |
| title_short | Dysregulation of tryptophan metabolism in a sub-Saharan HIV/AIDS population |
| title_sort | dysregulation of tryptophan metabolism in a sub saharan hiv aids population |
| topic | UCTD Tryptophan Gas chromatography-mass spectrometry (GC-MS) Immune activity Kynurenine HIV/AIDS SDG-03: Good health and well-being SDG-17: Partnerships for the goals |
| url | http://hdl.handle.net/2263/46053 |