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

• Type of Material: Article
• Authors: Riti Sharan, Texas Biomedical Research Institute; Shashank Ganatra, Texas Biomedical Research Institute; Allison N Bucsan, Washington University; Journey Cole, Texas Biomedical Research Institute; Dhiraj K Singh, Texas Biomedical Research Institute; Xavier Alvarez, Texas Biomedical Research Institute; Maya Gough, Texas Biomedical Research Institute; Cynthia Alvarez, Texas Biomedical Research Institute; Alyssa Blakley, Texas Biomedical Research Institute; Justin Ferdin, Texas Biomedical Research Institute; Rajesh Thippeshappa, Texas Biomedical Research Institute; Bindu Singh, Texas Biomedical Research Institute; Ruby Escobedo, Texas Biomedical Research Institute; Vinay Shivanna, Texas Biomedical Research Institute; Edward J Dick, Texas Biomedical Research Institute; Shannan Hall-Ursone, Texas Biomedical Research Institute; Shabaana A Khader, Washington University; Smriti Mehra, Texas Biomedical Research Institute; Jyothi Rengarajan, Emory University; Deepak Kaushal, Texas Biomedical Research Institute
• Language: English
• Date: 2022-02-01
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Sharan et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI153090
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 132
• Issue: 3
• Grant/Funding Information: This research was funded by NIH awards R01AI136814-01, R01AI111943, and R01AI123047 (to DK and JR), with additional support from NIH grants R01AI111914, R01AI134240, and R01AI138587 (to DK), K01OD031898-01 (to RS), and institutional grants from the Office of the Director, NIH P51OD011133 (to the Southwest National Primate Research Center), P30 RR00165 and P51OD011132 (to the Yerkes National Primate Research Center), and P30AI050409 (Emory University Center for AIDS Research [CFAR]).
• Keywords: ISONIAZID PREVENTIVE THERAPY; ADULTS; INDIVIDUALS; DOUBLE-BLIND; MECHANISMS; SIV INFECTION; Medicine, Research & Experimental; RHESUS MACAQUES; T-CELLS; INITIATION; Science & Technology; Research & Experimental Medicine; Life Sciences & Biomedicine; HIV-1 INFECTION
• Research Categories: Biology, Microbiology

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.