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Mechanisms of reactivation of latent tuberculosis infection due to SIV coinfection
Allison N. Bucşan, … , Shabaana A. Khader, Deepak Kaushal
Allison N. Bucşan, … , Shabaana A. Khader, Deepak Kaushal
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(12):5254-5260. https://doi.org/10.1172/JCI125810.
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Concise Communication AIDS/HIV Infectious disease

Mechanisms of reactivation of latent tuberculosis infection due to SIV coinfection

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Abstract

HIV is a major driver of tuberculosis (TB) reactivation. Depletion of CD4+ T cells is assumed to be the basis behind TB reactivation in individuals with latent tuberculosis infection (LTBI) coinfected with HIV. Nonhuman primates (NHPs) coinfected with a mutant simian immunodeficiency virus (SIVΔGY) that does not cause depletion of tissue CD4+ T cells during infection failed to reactivate TB. To investigate the contribution of CD4+ T cell depletion relative to other mechanisms of SIV-induced reactivation of LTBI, we used CD4R1 antibody to deplete CD4+ T cells in animals with LTBI without lentiviral infection. The mere depletion of CD4+ T cells during LTBI was insufficient in generating reactivation of LTBI. Instead, direct cytopathic effects of SIV resulting in chronic immune activation, along with the altered effector T cell phenotypes and dysregulated T cell homeostasis, were likely mediators of reactivation of LTBI. These results revealed important implications for TB control in HIV-coinfected individuals.

Authors

Allison N. Bucşan, Ayan Chatterjee, Dhiraj K. Singh, Taylor W. Foreman, Tae-Hyung Lee, Breanna Threeton, Melanie G. Kirkpatrick, Mushtaq Ahmed, Nadia Golden, Xavier Alvarez, James A. Hoxie, Smriti Mehra, Jyothi Rengarajan, Shabaana A. Khader, Deepak Kaushal

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Figure 3

Peripheral and BAL CD4+ T cells reflect a proportional shift toward effector profile during CD4R1 administration.

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Peripheral and BAL CD4+ T cells reflect a proportional shift toward effe...
The proportions of residual effector (CD95+CD28–, circles), memory (CD95+CD28+, squares), and naive (CD95–CD28+, triangles) (A) CD4+ and (B) CD8+ T cells in the peripheral blood and (C) CD4+ and (D) CD8+ T cells in the BAL of SIVmac239-coinfected (n = 15, black) and CD4R1-administered NHPs (n = 8, red) compared with LTBI NHPs (n = 10, blue) at week 11 after TB. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 2-way ANOVA with Tukey’s multiple testing correction. BAL (E) effector and (F) memory CD4+ cells quantification every 4 weeks starting at week 7 after TB. Coinfection and antibody administration shown by the dotted line. (G) qRT-PCR analysis of IL-2, IL-12B, and IL-17A collected from BAL cells at week 11 and week 15 after TB from SIV reactivators (n = 3, yellow) and CD4R1-administered NHPs (n = 3, red). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, multiple t tests with Holm-Sidak method for multiple comparison correction. Data represent mean ± SEM.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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