Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model
Shashank R. Ganatra, … , Jyothi Rengarajan, Deepak Kaushal
Shashank R. Ganatra, … , Jyothi Rengarajan, Deepak Kaushal
Published June 16, 2020
Citation Information: J Clin Invest. 2020;130(10):5171-5179. https://doi.org/10.1172/JCI136502.
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Research Article AIDS/HIV Infectious disease

Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model

Abstract

While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus–coinfected (M. tuberculosis/SIV–coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4+ T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4+ T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction in myeloid cells in the inducible bronchus-associated lymphoid tissue (iBALT) likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, although ART was indispensable for controlling viral replication, restoring CD4+ T cells, and preventing opportunistic infection, it appeared inadequate in reversing the clinical signs of TB reactivation during the relatively short duration of ART administered in this study. This finding warrants the modeling of concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV to inform treatment strategies in patients with M. tuberculosis/HIV coinfection.

Authors

Shashank R. Ganatra, Allison N. Bucşan, Xavier Alvarez, Shyamesh Kumar, Ayan Chatterjee, Melanie Quezada, Abigail Fish, Dhiraj K. Singh, Bindu Singh, Riti Sharan, Tae-Hyung Lee, Uma Shanmugasundaram, Vijayakumar Velu, Shabaana A. Khader, Smriti Mehra, Jyothi Rengarajan, Deepak Kaushal

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Figure 3

Differential CD4+ T cell restoration in alveolar and interstitial compartments after ART in M. tuberculosis/SIV–coinfected NHPs.

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Differential CD4+ T cell restoration in alveolar and interstitial compar...
Multiparameter flow cytometry was performed on single-cell suspension of various tissue samples, and whole blood was collected at necropsy from M. tuberculosis/SIV–coinfected rhesus macaques treated with ART. The following 3 groups were studied: M. tuberculosis infection only, i.e., LTBI (n = 4, green), M. tuberculosis/SIV coinfection, i.e., ART-naive (n = 8, red), and M. tuberculosis/SIV coinfection with ART, i.e., ART (n = 4, blue). CD4+ T cell frequency was analyzed in (A) whole blood (WB), (B) BAL, (C) lung, (D) BrLN, and (E) spleen. (F) Confocal microscopic analysis of FFPE sections from lungs harvested at the endpoint of LTBI in macaques (n = 3) and from ART-naive (n = 6) and ART-treated (n = 3) macaques showed CD4+ T cells (CD4+ T cells/nuclei) in lung tissue sections, counted using HALO image analysis software (Indica Labs). (G) Representative images of CD4+ T cells (red), CD68+CD163+ macrophages (green), nuclei (gray), and autofluorescent RBCs (yellow). White arrowheads indicate macrophages phagocytosing CD4+ T cells in the lungs of LTBI, ART-naive, and ART groups, respectively. Scale bars: 100 μm. Data represent the mean ± SEM; error bars indicate the SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Tukey’s multiple-comparisons test.