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 4

Dysregulation of homing of CD4+ T cells to iBALT in lung interstitium of M. tuberculosis/SIV–coinfected macaques.

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Dysregulation of homing of CD4+ T cells to iBALT in lung interstitium of...
IHC staining and confocal imaging of FFPE lung sections from M. tuberculosis/SIV–infected macaques with or without ART. The figure is representative of 3 experimental replicates. (A) Nuclei/DAPI (gray), SIV RNA+ (red), CD3+ T lymphocytes (blue), and CD68+CD163+ macrophages (Macs, green) show macrophages phagocytosing vRNA+ cells present in iBALT. Scale bars: 100 μm. (B) Nuclei/DAPI (gray), IDO1-expressing cells (red), CD20+ B lymphocytes (blue), and CD68+CD163+ macrophages (green) identify well-organized B cell zones of iBALT and the presence of IDO1-expressing macrophages in the T cell zone of iBALT. Scale bars: 100 μm. (C) Nuclei/DAPI (gray), IDO1-expressing cells (red), and CD68+CD163+ macrophages (green) of granuloma in a M. tuberculosis/SIV–coinfected animal showing that the majority of the IDO1 expression is in the CD68+CD163+ macrophage-rich layer of granulomas in macaques with TB reactivation. Scale bars: 500 μm and 100 μm (enlarged inset). (D) Nuclei/DAPI (blue), IDO1-expressing cells (green), and CD141+ tolerogenic DCs (red) show IDO1 expression by DCs. Scale bars: 50 μm. IHC staining was performed on sections of lungs from macaques with M. tuberculosis infection only, i.e., LTBI (n = 3), M. tuberculosis/SIV coinfection, i.e., ART-naive (n = 3), and M. tuberculosis/SIV coinfection with ART treatment, i.e., ART (n = 3) groups.