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 1

Clinical correlates of TB reactivation in ART-treated NHPs with M. tuberculosis/SIV coinfection.

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Clinical correlates of TB reactivation in ART-treated NHPs with M. tuber...
(A) Study outline. Sixteen Indian-origin rhesus macaques infected with low-dose M. tuberculosis CDC1551 via the aerosol route developed LTBI. Nine weeks after M. tuberculosis challenge, 12 these NHPs were challenged with intravenous SIVmac239. In week 13, of the 12 M. tuberculosis/SIV–coinfected NHPs, 4 received ART regimen and 8 served as ART-naive controls. Animals with TB reactivation and signs of disease had to undergo early necropsy to meet the humane endpoints criteria set by the IACUC of TNPRC, whereas animals with no signs of active disease were necropsied in week 24. (B) Plasma viral loads were measured at the peak of SIV infection, i.e., around week 11 of infection and at the endpoint (necropsy). (C) Survival curve shows the time points (in weeks) after M. tuberculosis infection the percentage of survival. (D) Serum CRP levels were measured at 11 weeks and at the endpoint. (E) The BAL SIV RNA load was measured at necropsy. sup., supernatant. (F) An RNAscope ISH assay was performed to examine the presence of SIV RNA in tissues such as lung, BrLN, and spleen. ART treatment substantially reduced the viral particles, vRNA+ cells (red), in spleen and BrLN tissue, whereas the changes were not appreciable in the sparsely infected lung parenchyma. Scale bars: 50 μm (lung), 500 μm (bronchial lymph node), 1 mm (spleen). 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). Data represent the mean ± SEM; error bars in the dot plots indicate the SEM. The log-rank test (Mantel-Cox) was used for comparison of survival curves in C. *P < 0.05 and ****P < 0.0001, by 2-way ANOVA with Holm-Šidák’s multiple comparisons test (D) and 2-tailed Student’s t test (B and E). cp/mL, copies per milliliter.