| dc.description | 1 Laborato´ rio de Inflamac¸ão e Biomarcadores, Instituto Gonc¸alo Moniz, Fundac¸ão Oswaldo Cruz, Salvador, Brazil,
2 Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador,
Brazil, 3 Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil, 4 Curso de Medicina, Universidade
Salvador (UNIFACS), Salvador, Brazil, 5 Programa de Po´ s-Graduac¸ão em Cl´ınica Me´ dica, Universidade Federal do Rio de
Janeiro, Rio de Janeiro, Brazil, 6 Department of Clinical Research, National Institute for Research in Tuberculosis, Chennai,
India, 7 Center of Data and Knowledge Integration for Health (CIDACS), Instituto Gonc¸alo Moniz, Fundac¸ão Oswaldo Cruz,
Salvador, Brazil, 8 ICGEB-Emory Vaccine Centre, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf
Ali Marg, India, 9 Government Hospital of Thoracic Medicine, Chennai, India, 10 Laborato´ rio de Biologia e Imunologia de
Doenc¸as Infecciosas e Parasita´ rias, Instituto Rene´ Rachou, Fundac¸ão Oswaldo Cruz, Belo Horizonte, Brazil, 11 HIV
Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, MD, United States, 12 Immunobiology Section, Laboratory of Parasitic Diseases, National
Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States, 13 Wellcome Trust
Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape
Town, Cape Town, South Africa, 14 Curso de medicina, Escola Bahiana de Medicina e Sau´ de Pu´ blica (EBMSP), Salvador,
Brazil, 15 Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN,
United States | |
| dc.description | 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+ Tlymphocytes,
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 TBIRIS.
We confirmed previous observations demonstrating that TB-IRIS individuals display
pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ARTinduced
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. | |
