Chronic Immune Activation in TB/HIV Co-infection

Abstract

HIV co-infection is the most critical risk factor for the reactivation of latent tuberculosis (TB) infection (LTBI). While CD4⁺ T cell depletion has been considered the major cause of HIV-induced reactivation of LTBI, recent work in macaques co-infected with Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) suggests that cytopathic effects of SIV resulting in chronic immune activation and dysregulation of T cell homeostasis correlate with reactivation of LTBI. This review 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 highlights the need to have optimum translational interventions directed at reactivation due to co-infection.

Keywords: Mtb; SIV; chronic immune activation; co-infection; nonhuman primates.

Figure 1.. Chronic immune activation in Mtb/SIV co-infection

HIV co-infection of Mtb is characterized by immune activation encompassing a wide array of tissues and cells. HIV co-infection leads to a drastic depletion of CD4+ T cells by loss of mucosal integrity and in turn, a loss of immune function in the gastrointestinal tract. This causes a translocation of resident microbial products into the systemic circulation leading to activation of several cell types including T, B, NK cells, plasmacytoid dendritic cells and monocytes. In addition to producing pro-inflammatory cytokines, these activated cell subsets also demonstrate increased apoptosis and turnover. The integrity of the granuloma structure in a reactivated macaque is maintained by this increased monocyte turnover that replaces the apoptotic macrophages. The HIV infection promotes macrophage killing, leading to the breakdown of granulomas, which in turn, leads to a breach of Mtb containment and reactivation. While ART successfully contains the virus, it fails to resolve the chronic immune activation completely. Concurrent therapy with isoniazid and/or IL-21 could contain both bacterial containment and immune activation. While isoniazid treatment in conjunction with ART could restore CCR5⁺ T_RM cells in the lung tissues leading to a better control of Mtb replication in the macrophages, IL-21 could serve to promote the maintenance and functionality of Th17 cells, B cells and CD8+ T cells. Together, this novel therapy could potentially lead to a better immune reconstitution and resolve virus-driven residual immune activation in a Mtb/HIV co-infection.

Figure 2.. Pathogenesis of LTBI and its reactivation upon 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. Inhaled droplet Mtb nuclei are engulfed by the macrophages and dendritic cells in the terminal alveoli in the lungs. In the latent phase, the replication is contained with 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 a severe immunosuppression and a drastic decrease in CD4⁺ T cell counts in the granulomas. 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. A reduced expression of CD25 on B cells during SIV infection results in perturbation of the B cell response to CD4⁺ T cells. A reduced antigen presentation from CD4+ T cells impairs the generation of memory B cells. Taken together, SIV co-infection of Mtb leads to chronic immune activation, immune dysbiosis and a skewed T_reg/T_H17 balance resulting in reactivation of LTBI. Following the SIV-induced immune perturbation, there is a reduction in the generation of lung homing Mtb-specific T_EM 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 leading to dissemination.