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Multicenter Study
. 2021 Aug;69(6):1238-1244.
doi: 10.1136/jim-2021-001794. Epub 2021 Apr 19.

Indoleamine 2,3 dioxygenase, age, and immune activation in people living with HIV

Stephanie L Baer  1   2 , Rhonda E Colombo  2   3   4 , Maribeth H Johnson  5 , Sushama Wakade  2 , Gabriela Pacholczyk  2 , Cheryl Newman-Whitlow  2 , Stuart A Thompson  2 , Michael S Saag  6 , Jeffrey N Martin  7 , Michelle Floris-Moore  8 , Lei Huang  9   10 , Andrew L Mellor  9   10
Affiliations
Multicenter Study

Indoleamine 2,3 dioxygenase, age, and immune activation in people living with HIV

Stephanie L Baer et al. J Investig Med. 2021 Aug.

Abstract

Immune activation complicates HIV despite antiretroviral therapy (ART). Indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan (T) to kynurenine (K), regulating immune activity, and IDO activity increases with age. This study examines the relationship of IDO activity, bacterial translocation, and aging in people living with HIV (PLWH) on ART. Samples and data from PLWH on ART from the Centers for AIDS Research Network of Integrated Clinical Systems and from matched HIV-uninfected patients (controls) from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study were analyzed. The ratio of K to T (K:T) and neopterin were indicators of inflammation; 16S ribosomal DNA (16S rDNA) and lipopolysaccharide (LPS) were markers of bacterial translocation. Samples and data from 205 PLWH and 99 controls were analyzed. PLWH had higher K:T values across all ages, with a significant relationship between age and K:T for both groups. CD4 count or CD4 nadir had no association with K:T. There was no positive association between level of 16S rDNA or LPS detection and K:T. K:T and neopterin were associated. PLWH had elevated IDO activity, at younger ages, despite ART. This study suggests K:T ratio increases with age in both groups and is elevated in PLWH at all ages compared with age-matched controls.

Keywords: aging; immune tolerance; inflammation.

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Conflict of interest statement

Competing interests: SB is an Editorial Board Member of the Journal of Investigative Medicine. ALM is a shareholder in NewLink Genetics and receives licensing income from this source. All other authors declare no conflicts.

Figures

Figure 1
Figure 1
Distribution of log K:T for control (CNT) and people living with HIV (PLWH). PLWH had higher K:T ratios than HIV-uninfected CNT subjects. A log10 transformation (log K:T) was used to minimize the influence of the outlying higher K:T values, especially in PLWH. K, kynurenine; T, tryptophan.
Figure 2
Figure 2
Association between age and K:T ratio. There was a significant positive association between age and K:T (p<0.0001) for both people living with HIV (PLWH) (dotted line and open circles) and control (CNT) (solid line and filled squares). PLWH had higher K:T across ages (p<0.0001). K, kynurenine; T, tryptophan.
Figure 3
Figure 3
Association between LPS and K:T. The relationship between LPS and K:T is significantly different for HIV-infected and HIV-uninfected (CNT) subjects (p=0.0071 for the interaction). There is no association for HIV-uninfected subjects (solid line and filled squares) and a significant negative relationship for HIV-infected subjects (dotted line and open circles). As LPS increases in HIV-infected subjects, K:T decreases. K, kynurenine; LPS, lipopolysaccharide; T, tryptophan.
Figure 4
Figure 4
Association between 16S rDNA PCR and K:T. There is not a significant association between 16S rDNA PCR cycle threshold gene expression and K:T levels (p=0.28) for both people living with HIV (dotted line and open circles) and control (CNT) (solid line and filled squares). 16S rDNA PCR, PCR for 16S ribosomal DNA; K, kynurenine; T, tryptophan.
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