Tryptophan metabolism and its relationship with central nervous system parameters in people living with HIV

Michael Keegan, Alan Winston, Peter Keleher, ViiV Healthcare (Firm)
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
more » ... n 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 i [...]
doi:10.25560/66166 fatcat:tvh4ixxwtbbzdh2gvg4wl7nwr4