Assistant Professor Texas Biomedical Research Institute San Antonio, Texas, United States
Introduction/Rationale: HIV co-infection in individuals with LTBI poses a significant challenge to immune control, increasing susceptibility to TB reactivation. Here, we use NHP model to investigate how SIV co-infection disrupts immune responses in LTBI, and whether adjunctive therapies can enhance immune reconstitution.
Methods: Rhesus macaques were infected with low dose Mtb via aerosol and co-infected with SIV. After peak viremia, animals received cART, with a subset treated with cART+3HP. Bronchoalveolar lavage and lung tissue samples were collected longitudinally to profile immune cell populations, cytokine responses, and transcriptional signatures. scRNA-seq enabled high-resolution analysis of immune cell heterogeneity and functional state, while spatial transcriptomics provided insight into the organization of immune responses within granulomatous niches.
Results: Despite cART-mediated viral suppression, immune reconstitution remained incomplete. Functionally, this translated into impaired Mtb-specific T cell responses, with reduced TH1 response and increased TH17-biased immune environment. TH1-associated transcription factors, T-bet, STAT4 were downregulated, whereas TH17-related RORγt and IL-17 were upregulated. SIV infection increased macrophage and monocyte populations with robust Type I interferon signaling. Persistent inflammatory signatures, including elevated NFKB1 and KLF6, remained despite cART, highlighting incomplete restoration of immune homeostasis. Spatial transcriptomics revealed in cART-naïve macaques, granulomas exhibited TH17/TH1 imbalance, marked by elevated STAT3 expression and reduced CD4, IL-21, and NCAM1.
Conclusion: Our findings demonstrate that SIV co-infection in LTBI induces compartmentalized immune dysregulation, characterized by TH17/TH1 imbalance, impaired myeloid function. While cART partially restores immune cell numbers, it does not fully recover pathogen-specific T cell function, highlighting the need for adjunctive interventions.
