Plasma Indoleamine 2,3-Dioxygenase Activity Is Associated With the Size of the Human Immunodeficiency Virus Reservoir in Patients Receiving Antiretroviral Therapy

Abstract

Background: Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that metabolizes tryptophan to immunosuppressive kynurenines. We investigated whether IDO activity is associated with the size of HIV reservoir.

Methods: Total human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells (PBMCs) from 127 HIV-infected patients receiving antiretroviral therapy (ART) was quantified. Tryptophan and kynurenine concentrations, as well as microbial translocation markers, were measured in plasma samples. T-cell activation and exhaustion in PBMCs were assessed by flow cytometry.

Results: Elevated IDO activity prior to ART correlated with on-ART HIV DNA (r = 0.35, P = .004), but was not associated with pre-ART HIV DNA. A median duration of 15 months of ART significantly decreased IDO activity; however, these levels were still higher than those observed in HIV-uninfected controls. Among treated participants, IDO activity positively correlated with their concurrent HIV DNA (r = 0.36, P < .0001). Multivariate model showed an independent association of pre-ART CD4/CD8 ratio (adjusted odds ratio [aOR], 0.75 per 0.1 increase [95% confidence interval {CI}, .62-.91]) and on-ART IDO activity (aOR, 1.09 per nM/μM increase [95% CI, 1.04-1.14]) with higher levels of HIV DNA on-ART. A lack of association of the microbial translocation markers was observed with the size of HIV reservoir. HIV DNA positively correlated with the proportions of activated CD4 T and CD8 T cells and exhausted CD4 T cells.

Conclusions: We observed a positive correlation between IDO activity and total HIV DNA in blood, highlighting the important role of immunometabolic aberrations in HIV persistence.

Keywords: ART; HIV reservoir; indoleamine 2,3-dioxygenase; kynurenine; microbial translocation.

Figure 1.

Indoleamine 2,3-dioxygenase (IDO) activity and its association with total human immunodeficiency virus (HIV) DNA. A, Elevated IDO activity in HIV-infected patients and longitudinal changes in IDO activity pre–antiretroviral therapy (ART) and on-ART. Pre-ART IDO activity predicted on-ART HIV DNA (B) but was not associated with total pre-ART HIV DNA (C). On-ART IDO activity was positively correlated with on-ART HIV DNA (D). *P < .05, ****P < .0001. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; IDO, indoleamine 2,3-dioxygenase; Kyn/Trp, kynurenine/tryptophan; PBMC, peripheral blood mononuclear cell; UC, human immunodeficiency virus–uninfected controls.

Figure 2.

No association between microbial translocation and human immunodeficiency virus (HIV) persistence. A, Changes of microbial translocation markers. B, Pre– antiretroviral therapy (ART) levels of microbial translocation could not predict on-ART total HIV DNA. C, Microbial translocation markers were not associated with on-ART total HIV DNA. D, On-ART but not pre-ART sCD163 was associated with on-ART total HIV DNA. Microbial translocation markers were quantified in 64 patients with paired samples available both before and after ART. *P < .05, **P < .01, ***P < .001, ****P < .0001. Abbreviations: ART, antiretroviral therapy; EndoCAb, endogenous endotoxin-core antibody; HIV, human immunodeficiency virus; LBP, lipopolysaccharide-binding protein; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cell; sCD14, soluble CD14; sCD163, soluble CD163; UC, human immunodeficiency virus–uninfected controls.

Figure 3.

T-cell activation and exhaustion were associated with human immunodeficiency virus (HIV) persistence (A) but not indoleamine 2,3-dioxygenase activity (B). HLA-DR, CD38, and PD-1 were assessed in samples from 50 of the participants. Abbreviations: ART, antiretroviral therapy; CD38, cluster of differentiation 38; HIV, human immunodeficiency virus; HLA-DR, human leukocyte antigen – DR isotype; IDO, indoleamine 2,3-dioxygenase; Kyn/Trp, kynurenine/tryptophan; PBMC, peripheral blood mononuclear cell; PD-1, programmed cell death 1.