Review
Tryptophan depletion and HIV Tryptophan depletion and HIV infection: a metabolic link to pathogenesis

https://doi.org/10.1016/S1473-3099(03)00773-4Get rights and content

Summary

HIV-1-infected patients have low circulating tryptophan concentrations despite evidence of adequate dietary intake of this essential aminoacid. A chronic increase in inducible tryptophan oxidation is the basis of HIV-1-associated tryptophan depletion. This metabolic process results in the irretrievable loss of tryptophan molecules from the available pool. Such sustained disruption of normal tryptophan metabolism over time disturbs the many metabolic processes involving this aminoacid, and has been implicated in some features of AIDS pathogenesis. Normal T-cell function is adversely affected by tryptophan depletion, but the extent of the effect in HIV-1-infected patients is still unclear. Attempting to directly supplement tryptophan is not advised given the potential increase in circulating concentrations of neurotoxic intermediates. Although only preliminary data are available, evidence suggests that antiretroviral and nicotinamide treatments can boost plasma tryptophan concentrations in HIV-1-infected patients and impact the secondary effects of tryptophan depletion. Additional study of this metabolism could lead to improved treatment strategies for patients with HIV infection. In this review I focus on the potential links between disturbed tryptophan metabolism and pathogenesis.

Section snippets

Biological stimuli underlying inducible tryptophan oxidation

Cytokines Cytokines stimulate IDO expression and activity. Although interferons α and β, tumour necrosis factor α, and plateletactivating factor can induce tryptophan oxidation, interferon γ seems to be the most important cytokine linked to this catabolism.17, 27, 28, 29 IDO induction can promote the removal of tryptophan in a localised microenvironment or systemically. Tryptophan oxidation driven by interferon γ can take place even when the circulating concentration of tryptophan is already

T-cell hyporesponsiveness

T-cell response to foreign antigens is depressed in the peripheral blood of HIV-1-infected individuals and pregnant women.44, 50 Increased IDO activity in HIV-1 infection results in decreased tryptophan and increased niacin, in a pattern reminiscent of human pregnancy (table 2).25, 26, 42, 53, 54 This pattern of tryptophan-to-niacin metabolism in pregnancy is critical to conferring immune tolerance of foreign paternal antigens.40 Cytokine-induced tryptophan oxidation has also been linked to the

Conclusion

The net advantage of tryptophan oxidation in HIV-1 infection is unclear. Host immune-mediated activation of this metabolism might have as its goal the removal of tryptophan from the available aminoacid pool, the production of the pathway's metabolic end products, the production of the pathway's metabolic intermediates, or some combination of these. This general phenomenon is also seen with other infections, malignant disease, and autoimmunity. The metabolic activation could be harmful to the

Search strategy and selection criteria

Data for this review were identified by searches of Medline, the science citation index, and references from relevant articles. Search terms were “HIV”, “AIDS”, “tryptophan”, “immune function”, “T-cell function”, “metabolism”, “nutrition”, and “pregnancy”. References were not limited by language or year of publication.

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      Tryptophan is an essential amino acid that functions in diverse metabolic, neurological and immunological roles. Tryptophan deprivation has been observed after viral infection, malignant disease and autoimmuity (Murray, 2003; Mehraj and Routy, 2015), consistent with our observation that tryptophan levels decreased markedly 120 h post-BmNPV infection in the susceptible silkworm strain but remained stable in the resistant silkworm strain (Fig. 1). Tryptophan trimers and tetramers have been reported to inhibit dengue and Zika virus by preventing viral envelope glycoprotein from adhering to the host cell membrane (Fikatas et al., 2020).

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