Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a Mycobacterium tuberculosis/SIV coinfection model
Riti Sharan, … , Jyothi Rengarajan, Deepak Kaushal
Riti Sharan, … , Jyothi Rengarajan, Deepak Kaushal
Published December 2, 2021
Citation Information: J Clin Invest. 2022;132(3):e153090. https://doi.org/10.1172/JCI153090.
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Research Article AIDS/HIV Infectious disease

Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a Mycobacterium tuberculosis/SIV coinfection model

Abstract

Studies using the nonhuman primate model of Mycobacterium tuberculosis/simian immunodeficiency virus coinfection have revealed protective CD4+ T cell–independent immune responses that suppress latent tuberculosis infection (LTBI) reactivation. In particular, chronic immune activation rather than the mere depletion of CD4+ T cells correlates with reactivation due to SIV coinfection. Here, we administered combinatorial antiretroviral therapy (cART) 2 weeks after SIV coinfection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented reactivation of LTBI compared to cART initiated 4 weeks after SIV. Earlier initiation of cART enhanced survival, led to better control of viral replication, and reduced immune activation in the periphery and lung vasculature, thereby reducing the rate of SIV-induced reactivation. We observed robust CD8+ T effector memory responses and significantly reduced macrophage turnover in the lung tissue. However, skewed CD4+ T effector memory responses persisted and new TB lesions formed after SIV coinfection. Thus, reactivation of LTBI is governed by very early events of SIV infection. Timing of cART is critical in mitigating chronic immune activation. The potential novelty of these findings mainly relates to the development of a robust animal model of human M. tuberculosis/HIV coinfection that allows the testing of underlying mechanisms.

Authors

Riti Sharan, Shashank R. Ganatra, Allison N. Bucsan, Journey Cole, Dhiraj K. Singh, Xavier Alvarez, Maya Gough, Cynthia Alvarez, Alyssa Blakley, Justin Ferdin, Rajesh Thippeshappa, Bindu Singh, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Shabaana A. Khader, Smriti Mehra, Jyothi Rengarajan, Deepak Kaushal

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Figure 3

Impact of timing of cART on lung pathology and TB lesions in Mtb/SIV-coinfected macaques.

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Impact of timing of cART on lung pathology and TB lesions in Mtb/SIV-coi...
To determine the impact of cART timing on lung pathology, lung tissue was collected at necropsy (top images) and stained with H&E (bottom images) to study the cellular and granulomatous pathology in (A) LTBI (n = 4), (B) cART naive (n = 8), (C) cART/2 week (n = 4), and (D) cART/4 week (n = 5). Scale bars: 500 μm. (E) Percentage lung involvement was calculated by a board certified pathologist by quantification of the number of lesions per lung lobe. (F) Computed tomography (CT) imaging was performed on the macaques that received cART 2 weeks after SIV coinfection at different time points throughout the study to examine the TB lesions before SIV, after SIV, and after cART. (G) CT imaging was performed on the macaques that received cART 4 weeks after SIV coinfection at different time points throughout the study to examine the TB lesions before SIV, after SIV, and after cART. Black arrows in A–D indicate inflammation associated with granulomatous region. Yellow marks in F and G indicate the worsening of lung lesions. Significance was determined using 1-way ANOVA with Tukey’s multiple-comparison test. *P < 0.05; **P < 0.01. Data are presented as mean ± SEM.