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

• Published in: Frontiers in immunology Vol. 12; p. 757843
• Main Authors: Tibúrcio, Rafael, Barreto-Duarte, Beatriz, Naredren, Gopolan, Queiroz, Artur T. L., Anbalagan, Selvaraj, Nayak, Kaustuv, Ravichandran, Narayanan, Subramani, Rajasekaran, Antonelli, Lis R. V., Satagopan, Kumar, Anbalagan, Komathi, Porter, Brian O., Sher, Alan, Swaminathan, Soumya, Sereti, Irini, Andrade, Bruno B.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.10.2021
• Subjects: Acquired Immunodeficiency Syndrome - complications; Acquired Immunodeficiency Syndrome - drug therapy; Acquired Immunodeficiency Syndrome - immunology; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Biomarkers; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cytotoxicity, Immunologic; Humans; Immune Reconstitution Inflammatory Syndrome - blood; Immune Reconstitution Inflammatory Syndrome - etiology; Immune Reconstitution Inflammatory Syndrome - immunology; Immunology; Immunophenotyping; inflammation; IRIS pathogenesis; Lymphocyte Activation; Lymphopenia - etiology; Lymphopenia - immunology; Mycobacterium tuberculosis - immunology; Observational Studies as Topic - statistics & numerical data; Randomized Controlled Trials as Topic - statistics & numerical data; Retrospective Studies; T cell activation; T lymphocytes; T-Lymphocyte Subsets - immunology; TB-HIV coinfection; Tuberculosis - complications; Tuberculosis - immunology; T lymphocytes; IRIS pathogenesis; TB-HIV coinfection; T cell activation; inflammation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.757843

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.