title: Clinical Relevance of Kynurenine Pathway in HIV/AIDS: An Immune Checkpoint at the Crossroads of Metabolism and Inflammation.
abstract: Tryptophan degradation along the kynurenine pathway is associated with a wide variety of pathophysiological processes, of which tumor tolerance and immune dysfunction in several chronic viral infections including HIV are well known. The kynurenine pathway is at the crossroads of metabolism and immunity and plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. In this review we have summarized findings from recent studies reporting modulation of tryptophan degrading the kynurenine pathway in the context of HIV infection. This immuno-metabolic pathway is modulated by three distinct inducible enzymes: indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase. Increased expression of these enzymes by antigen-presenting cells leads to local or systemic tryptophan depletion, resulting in a mechanism of defense against certain microorganisms. Conversely, it can also lead to immunosuppression by antigen-specific T-cell exhaustion and recruitment of T regulatory cells. Recently, among these enzymes, indoleamine 2,3-dioxygenase 1 has been recognized to be an immune response checkpoint that plays an important role in HIV immune dysfunction, even in the context of antiretroviral therapy. In addition to the activation of the kynurenine pathway by HIV proteins Tat and Nef, the tryptophan-degrading bacteria present in the intestinal flora have been associated with dysfunction of gut mucosal CD4 Th17/Th22 cells, leading to microbial translocation and creating a systemic kynurenine pathway activation cycle. This self-sustaining feedback loop has deleterious effects on disease progression and on neurocognitive impairment in HIV-infected patients. Therapy designed to break the vicious cycle of induced tryptophan degradation is warranted to revert immune exhaustion in HIV-infected persons.
authors.affiliation: Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.|Research Institute, McGill University Health Centre, Montreal, QC, Canada.|Division of Hematology, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.|Research Institute, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Vikram
authors.initials: V
authors.lastname: Mehraj
authors.affiliation: Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.|Research Institute, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Kishanda
authors.initials: K
authors.lastname: Vyboh
authors.affiliation: Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.|Research Institute, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ido
authors.initials: I
authors.lastname: Kema
authors.affiliation: Department of Biological Sciences and Center for Biomedical Research, Université du Québec à Montréal (UQAM), Montreal, QC, Canada.
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Jenabian
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001419:Bacteria / Q000378:metabolism; D018988:Bacterial Translocation; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology*; D054884:Host-Pathogen Interactions; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007249:Inflammation; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D007737:Kynurenine / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: C576710:IDO1 protein, human; C576711:IDO2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D054311:nef Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; D007737:Kynurenine; D014364:Tryptophan; D014366:Tryptophan Oxygenase