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Title: Tryptophan metabolism and its relationship with central nervous system parameters in people living with HIV
Author: Keegan, Michael
ISNI:       0000 0004 7658 7055
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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HIV-1 enters the central nervous system (CNS) during the early stages of HIV-infection and has been associated with neurological and neuropsychiatric effects, including major depressive disorder and cognitive impairment. However, a clear picture of their neuropathogenesis remains elusive and is thought to be multifactorial in nature. A possible contributing mechanism is immune-mediated degradation of tryptophan (TRP) via the kynurenine (KYN) pathway, resulting in decreased production of serotonin and production of neuroactive KYN pathway catabolites. TRP metabolism has been shown to be disturbed throughout the course of infection in people living with HIV (PLWH) and initiation of antiretroviral therapy has been shown significantly, but incompletely, to reduce its degradation. I aimed to establish whether TRP metabolism, as measured by kynurenine/tryptophan (KYN/TRP) ratios, a marker of indoleamine 2,3-dioxygenase (IDO) enzyme activity, is increased in the presence of the HIV-1 virus or antiretroviral agents and whether increased TRP metabolism is associated with poorer cognitive performance and increased rates of depression in PLWH. In in vitro experiments, no significant effect was observed on TRP metabolism following acute exposure of human peripheral blood mononuclear cells and hepatocyte, astrocyte and microglial cell lines to a range of different antiretroviral agents, both individually and in clinically-relevant combinations, at supratherapeutic and clinically-relevant concentrations. In a cross-sectional analysis of archived cerebrospinal fluid and plasma samples from PLWH, the inflammatory markers (tumour necrosis factor-) TNF- and neopterin (NEO) were associated with increased KYN production, suggesting ongoing immune activation. Lower KYN/TRP ratios in plasma were associated with cognitive impairment and depression in virologically-suppressed subjects, suggesting that KYN catabolites may have a net neuroprotective effect in this population. This was supported by a prospective clinical study in which increased KYN concentrations were associated with decreases in CNS toxicities in subjects following switch from efavirenz to dolutegravir. This observation may be confounded by the inherent neurotoxicity of efavirenz and a possible drug interaction between efavirenz and the tryptophan 2,3-dioxygenase (TDO) enzyme that mediates TRP metabolism in the liver. In contrast, a second prospective clinical study found that KYN/TRP ratios negatively correlated with modest changes in cognitive function, suggesting that KYN metabolites have a net neurotoxic effect in PLWH. In conclusion, these data demonstrate an ongoing disturbance in TRP metabolism in virologically-suppressed PLWH that is mediated by residual immune activation and choice of antiretroviral agents.
Supervisor: Winston, Alan ; Keleher, Peter Sponsor: ViiV Healthcare (Firm)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral