Combination antiretroviral therapy and indoleamine 2,3-dioxygenase in HIV infections

Lee et al.[1], in this issue, report genetic variations that predict high plasma kynurenine/tryptophan (Kyn/Trp) ratios in HIV-infected Ugandans initiating combination antiretroviral therapy (cART). They also show that Kyn/Trp ratio, a surrogate plasma marker for the enzymatic activity of indoleamine 2,3-dioxygenase (IDO)-1, is a strong and independent predictor of mortality in these patients. The authors measured the plasma Kyn/Trp ratios within 6–12 months after cART initiation. They investigated associations of more than 16 million single nucleotide polymorphisms with log10 Kyn/Trp ratios using linear mixed models, and adjusting for cohort, gender, pregnancy, and ancestry. Polymorphisms in genes encoding TNFα, toll-like receptor (TLR)-4, IFNγ receptor I, protein tyrosine phosphatases (PTPRM and PTPN2) and an enzyme involved in vitamin D metabolism (CYP24A1) correlated with enhanced Kyn/Trp ratios. The genetic variations also correlated with markers of monocyte activation, coagulation, and inflammation. IDO-1 is an inflammation-inducible protein in myeloid cells, including dendritic cells and possesses enzymatic and signaling activities [2]. The enzyme is implicated in the oxidative cleavage of Trp into Kyn; a first rate limiting step in the immunosuppressive Trp catabolic pathway. Two other proteins with similar enzymatic activities, Trp 2,3-dioxygenase and IDO-2 are also found in the body. Trp 2,3-dioxygenase is liver specific and is sensitive to substrate concentrations [3]. The other enzyme, IDO-2 is 20–30 times less active than IDO-1 (hereafter referred to as IDO). IDO plays an important role in viral immunity, neurological disorders, and cancer [4–6]. Trp is an essential amino acid and, is required in the synthesis of proteins and important metabolites like serotonin, melatonin, niacin, and tryptamine [7]. One of the immediate effects of increased IDO activity is a decrease in Trp concentrations within cells, cellular microenvironment, and in the circulation. This results in accumulation of uncharged t-RNAs, activation of the general control nonderepressible-2 kinase, phosphorylation of the eukaryotic translation initiation factor-2α and arrest of protein synthesis and cell cycle [8,9]. Dendritic cells with increased IDO activity promote proliferation and differentiation of regulatory T cells and suppress development of Th17 and Th22 cells [4,10]. Kyn is further catabolized into 3-hydroxynurenine (3-HK), 3-hydroxyanthranilic acid and quinolinic acid. Kyn, 3-HK, and 3-hydroxyanthranilic acid activate aryl hydrocarbon receptor, and exert cytotoxic and immunosuppressive effects on CD8+ T lymphocytes (CTL), natural killer (NK) cells and natural killer-T (NKT) cells, whereas 3-HK and quinolinic acid are neurotoxic and have been implicated in dementia [11,12]. Furthermore, decreased serotonin production because of decreased Trp concentration lead to depression and mood changes [13]. We provide here a short overview of the potential role of IDO in HIV infections and in this context underlie implications of the findings of Lee et al.[1]. Inflammatory stimuli mediated by IFNγ, TLR, Retinoic acid-inducible gene-like helicases etc. and the like induce expression of IDO in human cells [2,3]. HIV activates IDO gene both directly and indirectly. The viral transactivator Tat activates this gene independent off proinflammatory mediators [14]. Interestingly, Tat proteins from different viral clades possess differential abilities to induce IDO expression. For example, Tat from clade B viral strains is more potent in this activity as compared with the one from clade C strains [15]. Furthermore, other viral proteins (e.g. gp120), nucleic acids and induced proteins (e.g. high mobility group box 1 protein) are sensed by a variety of innate sensors of the cells, induce production of IFN-1, IL-6, TNFα, IFNγ, etc. all of which induce IDO expression [4,16]. A number of studies have documented that the expression and functional activities of IDO are increased early in the course of HIV infection resulting in increased Kyn/Trp ratios and plasma quinolinic acid levels [17–19]. The studies have also shown that the increased IDO activities correlate with decreases in Th17 and Th22 subsets and increases in frequencies of regulatory T cells. As both IL-17 and IL-22 induce antimicrobial peptides from the intestinal epithelial cells, and play an important role in maintaining integrity of intestinal barriers, increased IDO activity may represent a single molecular event underlying increased intestinal permeability in HIV-infected individuals [20]. The increased gut permeability results in increased translocation of microbial products (like LPS, lipoteichoic acid, and bacterial DNA) that cause aberrant immune activation. Not surprisingly, increased Kyn/Trp ratios correlate with markers of microbial translocation and immune activation in in these patients [19–21]. Compromised mucosal immunity leads to a decrease in microbial diversity accompanied by an abundance of proinflammatory bacteria like Prevotella relative to anti-inflammatory ones like Bacteroides [16]. Relevant to the Trp catabolic pathway, the gut-resident bacteria with IDO-like activity were also found enriched in HIV-infected individuals [16]. cART decreases Kyn/Trp ratios in these patients, however, they often remain above normal [13,19,22]. Importantly, early cART initiation in the primary infection was shown to normalize Kyn/Trp ratio [21]. Higher IDO activity in patients on suppressive cART contributes toward developing non-AIDS-associated comorbidities like accelerated aging, frailty, cardiovascular diseases, and cancer. Potential impact of blocking IDO in simiam immunodeficiency virus (SIV)-infected rhesus macaques was investigated; however, the results have not been consistent. The blockade had either no effect or marginally improved immune and virological parameters only in combination with cART [23]. In a preclinical study, combined use of 1-methyl-D-Trp (a competitive IDO inhibitor) and CTLA4-blocking antibodies caused deaths (because of hyperglycemia and pancreatitis) in SIV-infected macaques undergoing cART [24]. So far, a racemic mixture of 1-methyl-D-Trp or its D isomer has been used for inhibiting IDO activity. The D-isomer has also been suggested to exert IDO-independent immune-stimulating effects [25]. Little is known concerning the impact of the L-isomer that specifically blocks conversion of L-Trp to L-Kyn by IDO-1. Importantly, several second generation, more effective, and safer IDO inhibitors have been developed that are in phase-I and II clinical trials in cancer patients [25]. They should be tested in animal models of HIV-infection. Furthermore, potentially beneficial effects of Trp-supplemented diets are also worth investigations. Whereas HIV researchers need to investigate the use of safer and more potent IDO inhibitors in animal models, the results from Lee et al.[1] suggest that the patients with genetic susceptibility to increased Kyn/Trp ratios could be predicted. IDO inhibitors are likely to be more beneficial for such patients. We anticipate that studies on personalized use of IDO inhibitors in HIV-infected individuals should be forthcoming. Acknowledgements We thank our colleagues who participated in discussion on the subject. A.A. wrote the first draft. All the coauthors read the draft, suggested modifications, read, and approved the final manuscript. Conflicts of interest There are no conflicts of interest.

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