Chronic immune activation in TB/HIV

Overview

HIV co-infection is the most critical risk factor for the reactivation of latent tuberculosis (TB) infection (LTBI). Our recent work in macaques coinfected with Mtb/ SIV suggests that cytopathic effects of SIV resulting in chronic immune activation and dysregulation of T cell homeostasis correlate with reactivation of LTBI. Our lab builds on compelling data that the reactivation of LTBI during HIV co-infection is likely to be driven by the events of HIV replication and therefore focuses on the need to have optimum translational interventions directed at reactivation due to co-infection.

Pathogenesis of Latent Tuberculosis (TB) Infection (LTBI) and Its Reactivation on HIV Co-infection
Figure: Pathogenesis of Latent Tuberculosis (TB) Infection (LTBI) and Its Reactivation on HIV Co-infection

LTBI is characterized by a dynamic balance between the pathogen and the host as a consequence of limited bacterial replication due to its containment within granulomas. In the latent phase, the replication is contained in the granuloma by the activated T lymphocytes and macrophages. This leads to an arrest of the disease progression and an immune balance is attained. Co-infection with SIV leads to severe immunosuppression and as a result, there is an increase in the number of CD8+ T cells with increased expression of activation markers, CD95, CD38, and HLA-DR. Together, SIV co-infection with Mtb leads to chronic immune activation, immune dysbiosis, and a skewed Treg/TH17 balance resulting in reactivation of LTBI. Following the SIV-induced immune perturbation, there is a reduction in the generation of lung-homing Mtb-specific TEM CD4+ T cells. This preferred depletion of Mtb-specific CD4+ T cells and viral infection of the macrophages in the granulomas causes the integrity of the granuloma to disintegrate, leaking the contained Mtb and leading to dissemination.

Highlighted Publications

  • Ganatra, Shashank R, Allison N Bucsan, Xavier Alvarez, Shyamesh Kumar, Ayan Chatterjee, Melanie Quezada, Abigail Fish, et al. (2020) 2020. “Antiretroviral Therapy Does Not Reduce Tuberculosis Reactivation in a Tuberculosis-HIV Coinfection Model”. The Journal of Clinical Investigation 130 (10): 5171-79. https://doi.org/10.1172/JCI136502.
    Publisher's Version

    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.

  • Sharan, Riti, Shashank R Ganatra, Allison N Bucsan, Journey Cole, Dhiraj K Singh, Xavier Alvarez, Maya Gough, et al. (2022) 2022. “Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation in a Mycobacterium Tuberculosis SIV Coinfection Model”. The Journal of Clinical Investigation 132 (3). https://doi.org/10.1172/JCI153090.
    Publisher's Version

    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.

  • Sharan, Riti, and Deepak Kaushal. (2020) 2020. “Vaccine Strategies for the Mtb HIV Copandemic”. NPJ Vaccines 5: 95. https://doi.org/10.1038/s41541-020-00245-9.
    Publisher's Version

    One-third of world's population is predicted to be infected with tuberculosis (TB). The resurgence of this deadly disease has been inflamed by comorbidity with human immunodeficiency virus (HIV). The risk of TB in people living with HIV (PLWH) is 15-22 times higher than people without HIV. Development of a single vaccine to combat both diseases is an ardent but tenable ambition. Studies have focused on the induction of specific humoral and cellular immune responses against HIV-1 following recombinant BCG (rBCG) expressing HIV-1 antigens. Recent advances in the TB vaccines led to the development of promising candidates such as MTBVAC, the BCG revaccination approach, H4:IC31, H56:IC31, M72/AS01 and more recently, intravenous (IV) BCG. Modification of these vaccine candidates against TB/HIV coinfection could reveal key correlates of protection in a representative animal model. This review discusses the (i) potential TB vaccine candidates that can be exploited for use as a dual vaccine against TB/HIV copandemic (ii) progress made in the realm of TB/HIV dual vaccine candidates in small animal model, NHP model, and human clinical trials (iii) the failures and promising targets for a successful vaccine strategy while delineating the correlates of vaccine-induced protection.