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 2

M. tuberculosis bacterial burden and lung pathology.

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M. tuberculosis bacterial burden and lung pathology. M. tuberculosis ba...
M. tuberculosis bacterial burden was determined by normalizing the CFU counts to log-transformed CFU per gram of tissue. (A) M. tuberculosis CFU in the total BAL sample (cellular plus the acellular components). (B) The M. tuberculosis CFU count was normalized per gram of lung tissue collected at necropsy. (C) Multiple granulomas (n = 1–6) per animal were grouped according to the experimental classification of the animal; each granuloma was weighed, and its CFU count was normalized per gram of granuloma tissue. (D) BrLN M. tuberculosis burden. (E) Splenic M. tuberculosis burden. (F) The percentage of lung involvement was calculated by pathologists through extensive analysis of serially cut fresh lung samples and quantification of the number of lesions at low-power magnification. (G) Gross pathology and H&E staining show the large granulomatous and necrotic lesions in animals with SIV-induced M. tuberculosis reactivation, whereas samples from animals with LTBI show minimal pathology. Scale bars: 500 μm. 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 treatment, i.e., ART (n = 4, blue). (A–F) Data represent the mean ± SEM; error bars indicate the SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA with Tukey’s multiple-comparisons test.