TY - JOUR
T1 - Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a Mycobacterium tuberculosis/SIV coinfection model
AU - Sharan, Riti
AU - Ganatra, Shashank R.
AU - Bucsan, Allison N.
AU - Cole, Journey
AU - Singh, Dhiraj K.
AU - Alvarez, Xavier
AU - Gough, Maya
AU - Alvarez, Cynthia
AU - Blakley, Alyssa
AU - Ferdin, Justin
AU - Thippeshappa, Rajesh
AU - Singh, Bindu
AU - Escobedo, Ruby
AU - Shivanna, Vinay
AU - Dick, Edward J.
AU - Hall-Ursone, Shannan
AU - Khader, Shabaana A.
AU - Mehra, Smriti
AU - Rengarajan, Jyothi
AU - Kaushal, Deepak
N1 - 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]). SIVmac239 was graciously provided by Preston Marx, Tulane National Primate Research Center. SIV viral load assays were performed by the Nonhuman Primate Core Virology Laboratory for AIDS Research and Development, Division of AIDS, NIAID. PMPA and FTC were provided by Gilead Sciences and DTG was provided by Viiv Healthcare. Research reported in this publication was supported by the Office of The Director, NIH under award number S10OD028653. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2022, Sharan et al
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123968445&partnerID=8YFLogxK
U2 - 10.1172/JCI153090
DO - 10.1172/JCI153090
M3 - Article
C2 - 34855621
AN - SCOPUS:85123968445
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
M1 - e153090
ER -