Single-Cell Transcriptomics Reveals Depletion and Dysregulation of Mycobacterium tuberculosis–Specific Th1 and Th17 Cells Early After Acquisition of Human Immunodeficiency Virus

Abstract

Human immunodeficiency virus (HIV) significantly increases the risk of developing tuberculosis (TB) and is associated with impaired CD4 T-cell responses to Mycobacterium tuberculosis (Mtb). We evaluated the frequency and functional capacity of Mtb-specific CD4 T cells in individuals with and without HIV using flow cytometry and performed single-cell RNA sequencing on these cells longitudinally in a subset of individuals before and after acquisition of HIV. Our findings reveal preferential depletion and functional impairment of Mtb-specific CD4 T cells early after acquisition of HIV, characterized by reduced cytokine production, loss of effector functions, and transcriptional dysregulation. Mtb-specific T-helper 1 (Th1) and T-helper 17 (Th17) cells decreased, whereas TCF7 + stem-like cells were enriched following acquisition of HIV. Pathway analysis revealed upregulation of hypoxia and Wnt signaling, and downregulation of cell adhesion, migration, antigen processing, and cytokine signaling pathways. These findings provide novel insights into HIV-mediated dysregulation of CD4 T-cell responses to Mtb.