Dendritic cells (DC) are known to modulate antiviral immune responses; however, the knowledge about the role of different DC subsets in antiviral T cell priming in human tissues remains uncompleted. In the context of HIV infection, we determined the phenotype and location of plasmacytoid and CD141+ myeloid DCs (pDCs and mDCs) in lymph nodes of people living with HIV (PLWH). We found an interaction between pDCs and CD141+ mDCs with CD8+ T cells, being associated with participants' viral levels in blood and tissue. Moreover, we demonstrated a higher and more polyfunctional superantigen- and HIV-specific CD8+ T cell response after the coculture with Toll-like receptor (TLR)-primed pDCs and CD141+ mDCs. Last, we showed the potential of programmed cell death-1 (PD-1) blocking using pembrolizumab to further increase antigen-specific CD8+ T cell response along with TLR agonists. Therefore, these results showed a cooperation between pDCs, CD141+ mDCs and CD8+ T cells in lymph nodes of PLWH, which is associated with higher HIV control, highlighting the importance of DC subsets crosstalk to achieve a more potent anti-HIV response and support the use of DC-based immunotherapies for HIV control.

Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS. However, current latency reversing agents are inefficient, and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood. To identify natural activators of latent HIV-1, we screened a comprehensive peptide/protein library derived from human hemofiltrate, representing the entire blood peptidome, using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses. Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4 (RBP4), the carrier of retinol (Vitamin A). We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines. Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production. High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1. Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads. As a potent natural HIV-1 latency-reversing agent, RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure. Subject terms: Preclinical research, Infectious diseases

Tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced hepatocellular carcinoma (HCC). However, their therapeutic efficacy is often limited by drug resistance, primarily driven by tumoral intrinsic mechanisms. In this study, we demonstrate that IFNγ in the tumor microenvironment can potentiate TKI response, and that ablation of IFNγ receptor on HCC cells leads to TKI resistance in vivo. Mechanistically, IFNγ synergizes with TKI to induce GSDME-mediated pyroptosis of HCC cells. The PERK-mediated unfolded protein response (UPR) protects HCC cells from TKI-induced pyroptosis. IFNγ attenuates PERK activation by inducing the expression of PDIA1, which alleviates the stress of protein unfolding. In vivo, PERK inhibition augments TKI therapy, and elevated PERK expression correlates with poor overall survival of patients with HCC. Moreover, IFNγ-producing CD8+ T cells can potentiate TKI efficacy. Combining PD-1 blockade to activate T-cell response with TKI therapy synergistically suppresses the growth of GSDME-expressing HCC tumors, which is further enhanced by the PERK inhibitor. Our findings reveal how IFNγ signaling modulates TKI response and demonstrate the potential of a sequential combination of ICB-mediated immunotherapy and TKI therapy for patients with GSDME+ HCC. T cell-derived IFNγ enhances TKI-induced pyroptosis in HCC. Mechanistic illustration of IFNγ secreted from CD8+ T cells enhancing TKI-induced GSDME-mediated pyroptosis in hepatocellular carcinoma via suppression of the PERK pathway. Created with BioRender.com.