Indoleamine-2,3-dioxygenase inhibition improves immunity and is safe for concurrent use with cART during Mtb/SIV coinfection
Bindu Singh, … , Deepak Kaushal, Smriti Mehra
Bindu Singh, … , Deepak Kaushal, Smriti Mehra
Published August 8, 2024
Citation Information: JCI Insight. 2024;9(15):e179317. https://doi.org/10.1172/jci.insight.179317.
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Research Article Immunology Infectious disease

Indoleamine-2,3-dioxygenase inhibition improves immunity and is safe for concurrent use with cART during Mtb/SIV coinfection

Abstract

Chronic immune activation promotes tuberculosis (TB) reactivation in the macaque Mycobacterium tuberculosis (M. tuberculosis)/SIV coinfection model. Initiating combinatorial antiretroviral therapy (cART) early lowers the risk of TB reactivation, but immune activation persists. Studies of host-directed therapeutics (HDTs) that mitigate immune activation are, therefore, required. Indoleamine 2,3, dioxygenase (IDO), a potent immunosuppressor, is one of the most abundantly induced proteins in NHP and human TB granulomas. Inhibition of IDO improves immune responses in the lung, leading to better control of TB, including adjunctive to TB chemotherapy. The IDO inhibitor D-1 methyl tryptophan (D1MT) is, therefore, a bona fide TB HDT candidate. Since HDTs against TB are likely to be deployed in an HIV coinfection setting, we studied the effect of IDO inhibition in M. tuberculosis/SIV coinfection, adjunctive to cART. D1MT is safe in this setting, does not interfere with viral suppression, and improves the quality of CD4+ and CD8+ T cell responses, including reconstitution, activation and M. tuberculosis–specific cytokine production, and access of CD8+ T cells to the lung granulomas; it reduces granuloma size and necrosis, type I IFN expression, and the recruitment of inflammatory IDO+ interstitial macrophages (IMs). Thus, trials evaluating the potential of IDO inhibition as HDT in the setting of cART in M. tuberculosis/HIV coinfected individuals are warranted.

Authors

Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra

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Figure 1

Survival characteristics and clinical correlates in D1MT+cART- relative to cART-treated M. tuberculosis/SIV–coinfected untreated control and SIV monoinfected RMs.

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Survival characteristics and clinical correlates in D1MT+cART- relative ...
(A) Survival curve depicting survival of RMs among the study groups. PET/CT scans were performed at wk6, wk10/11, wk16, and wk22/endpoint. (B–L) Shown are the representative PET/CT images from an untreated reactivator (B–D), an untreated nonreactivator (E–H), and a D1MT+cART-treated (I–L) RM at wk6 (B, E, and I), wk10/11 (C, F, and J), wk16 (D, G, and K), and wk22/endpoint (H and L). (M–O) Burgundy dotted line marks SIV infection in the coinfected groups, while the gray area represents cART phase and black dotted line represents D1MT treatment end. Data are represented as mean ± SEM. (M) Graphical representation of weekly serum CRP levels (mg/L) from the study start to the endpoint in D1MT+cART-treated, cART-treated, and untreated M. tuberculosis/SIV–coinfected as well as in SIV monoinfected animals. (N) Graph showing the percent weight change with respect to the baseline over the course of the study timeline. (O) Graphical representation of A/G ratios at different time points of the study.