TY - JOUR
T1 - Antiretroviral therapy does not reduce tuberculosis reactivation in a tuberculosis-HIV coinfection model
AU - Ganatra, Shashank R.
AU - Bucşan, Allison N.
AU - Alvarez, Xavier
AU - Kumar, Shyamesh
AU - Chatterjee, Ayan
AU - Quezada, Melanie
AU - Fish, Abigail
AU - Singh, Dhiraj K.
AU - Singh, Bindu
AU - Sharan, Riti
AU - Lee, Tae Hyung
AU - Shanmugasundaram, Uma
AU - Velu, Vijayakumar
AU - Khader, Shabaana A.
AU - Mehra, Smriti
AU - Rengarajan, Jyothi
AU - Kaushal, Deepak
N1 - Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85092218817&partnerID=8YFLogxK
U2 - 10.1172/JCI136502
DO - 10.1172/JCI136502
M3 - Article
C2 - 32544085
AN - SCOPUS:85092218817
SN - 0021-9738
VL - 130
SP - 5171
EP - 5179
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -