Dynamics of T-Lymphocyte Activation Related to Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in Persons With Advanced HIV

Abstract

Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4+ T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8+ T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR+) and profilerative (Ki-67+) CD4+ T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4+ T cells counts and the frequencies of Cytotoxic CD8+ T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4+ T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4+ T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4+ and CD8+ T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.

Frequency of CXCR3+ CD8+ T-Lymphocyte Subsets in Peripheral Blood Is Associated With the Risk of Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Development in Advanced HIV Disease

“…Others have suggested the possible participation of CD8 + T cells in the pathogenesis of TB-IRIS, by demonstrating that activation of these cells was associated with robust protective immune responses concomitant to limited immunopathology in the context of TB-IRIS (10). Consistent with this, we have recently identified increased frequencies of cytotoxic Granzyme B-expressing (GzB +) CD8 + T cells in TB-IRIS patients that arguably could be a compensatory mechanism in the face of severe CD4 + lymphopenia (11). Nevertheless, few reports contemplate the impact of ART-mediated reconstitution of memory CD8 + T lymphocyte subsets and whether this could significantly result in an augmented risk for TB-IRIS development.…”

“…There is robust evidence on the contributions of CD8 + T cells in the mobilization of appropriate immune responses in several infectious diseases, including HIV infection and TB (16)(17)(18). A previous study by our group addressed the nuances of T lymphocyte activation in TB-IRIS development and outlined the participation of cytotoxic CD8 + T cells during ART-promoted immune reconstitution (11).…”

Inflammasome genetic variants are associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

“…However, treatment with anti-TB drugs followed by cART initiation can lead to a paradoxical immune reconstitution inflammatory syndrome (IRIS) ( Shelburne et al., 2005 ). Current research has established some pathological mechanisms that are related to IRIS development, such as high viral loads, low baseline CD4+ T-cell counts (<50–100 cells/mm3) ( Antonelli et al., 2010 ; Luetkemeyer et al., 2014 ) with high levels of CD4 activation and replication ( Tibúrcio et al., 2021 ), and short time intervals between TB treatment and cART ( French et al., 2004 ; Chang et al., 2014 ; Tan et al., 2016 ). The genetic basis of host susceptibility to infectious diseases has received enormous attention ( Fellay et al., 2009 ; Seaby et al., 2016 ; Wu et al., 2017 ).…”

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

“…Comparing the degrees of connection from the bootstrap analysis highlighted the increased connectivity of CCL3, CCL4, and CXCL12 in co-infected granulomas, while IL-1b showed increased connectivity in mono-infected granulomas (Figure 2E). Such increased network density has previously been shown to reflect heightened inflammatory states (Bruyn et al, 2021;Tiburcio et al, 2021;Vinhaes et al, 2021). Interestingly, IFN-a was not detected in the granulomas from either group of animals, so we are unable to implicate virus-induced type IFN response in these changes in the granuloma inflammatory milieu after SIV infection (Figure 2F).…”