Effects of Anti-Retroviral Therapy (ART) on Restoration of Lung Immunity and Tuberculosis Reactivation

While the advent of combination antiretroviral therapy (cART, ART) has significantly improved survival, tuberculosis (TB) still accounts for one-third of deaths in Human Immunodeficiency Virus (HIV)-infected populations, suggesting incomplete restoration of immune function by ART. Mtb/Simian Immunodeficiency Virus (SIV) co-infected macaques have been used to model Mtb/HIV co-infection in humans. To identify the components of TB immunity that remain impaired following HIV-infection and ART treatment, macaques with asymptomatic M. tuberculosis (Mtb) infection were subsequently co-infected with SIV. Animals were then randomly assigned to ART or control groups and studied longitudinally. While ART significantly reduced viral loads and increased CD4+T cell counts in whole blood and BAL samples, it did not reduce the relative risk of SIV- induced TB reactivation (RR 1·23, 95% CI 0·97-1·5) in ART treated macaques. CD4+T cells were poorly restored specifically in the lung interstitial region, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction on myeloid cells in the iBALT likely contributes to dysregulated T cell homing and impaired lung immunity. Thus, while ART is indispensable for controlling viral replication, CD4+T cells restoration and in preventing opportunistic infection, it is however inadequate in reversing Mtb-specific T cell impairment. This warrants modeling concurrent treatment of TB and HIV  to potentially reduce the risk of reactivation of TB due to HIV. The current and  future studies like this have the potential to inform treatment strategies in patients with Mtb/HIV co-infection. The study was funded through grants from the National Institute of Health (NIH). Funding Statement: This work was primarily supported by NIH awards to D.K. and J.R. (R01AI111943, R01AI123047) with additional support from NIH awards R01AI111914, R01AI134240, R01AI135726, U19AI111211 and institutional awards P51OD111033 and P51OD111004. Declaration of Interests: The authors declare that no conflict of interest exists. Ethics Approval Statement: All the animals were housed in the Animal Biosafety level III (ABSL3) at Tulane National Primate Research Center where they were treated as per the standards recommended by Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International and the NIH Guide for the Care and Use of Laboratory Animals. The study was approved by the IACUC of the Tulane National Primate Research Center (protocols P0247R, P0324, P0295R).