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

• Published in: Clinical infectious diseases Vol. 68; no. 8; pp. 1274 - 1281
• Main Authors: Chen, Jun, Xun, Jingna, Yang, Junyang, Ji, Yongjia, Liu, Li, Qi, Tangkai, Wang, Zhenyan, Zhang, Renfang, Shen, Yinzhong, Ponte, Rosalie, Mehraj, Vikram, Routy, Jean-Pierre, Lu, Hongzhou
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 08.04.2019
• Subjects: and Commentaries; microbial translocation; kynurenine; ART; indoleamine 2,3-dioxygenase; HIV reservoir
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciy676

Identification of factors associated with the size of the Human Immunodeficiency Virus reservoir remains a priority for HIV cure research. We report that the activity of Indoleamine 2,3-Dioxygenase, an immunoregulatory enzyme that metabolizes tryptophan to kynurenines, is associated with the size of the HIV reservoir. 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.