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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-¦ÊB 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

AbstractBackgroundPublic neoantigens, including KRAS, TP53, and PIK3CA mutations, which are shared across various tumor types, have demonstrated significant immunogenicity and offer great promise for cancer immunotherapy. Clinical trials targeting these public neoantigens have yielded encouraging results, including tumor regression and prolonged relapse-free survival. This study evaluates the human leukocyte antigen (HLA) binding properties of T-cell epitopes derived from these public neoantigens to identify optimal T-cell target and further develops T-cell receptor (TCR)-based therapeutics.MethodsThe binding properties of public neoantigens to HLA-I molecules were evaluated using peptide-HLA binding affinity and stability assays. Naive T-cell repertoires were used to expand and detect neoantigen-specific TCRs. TCR clones were characterized for functionality using TCR-Jurkat cells and TCR-T cells. Peptide specificity was assessed using an HLA transgenic cell panel and the X-scan assay. In vivo antitumor efficacy of TCR-T cells was tested in xenograft mouse models of solid tumors.ResultsThe analysis of HLA binding properties for public neoantigens revealed that HLA-A*11:01-presented KRASG12V epitopes exhibited the strongest HLA binding stability. Four TCR clones specific to the 9-mer KRASG12V peptide (KRASG12V[9]) were identified. All KRASG12V[9]-specific TCRs, both newly identified by us and previously reported, exhibited varying degrees of cross-recognition of the exogenous self-antigen RAB7B. Among the four TCR clones, one TCR (KT18) exhibited superior functional avidity, effectively recognizing and eliminating KRASG12V mutant tumor cells without off-target activity against endogenous RAB7B or similar peptides. Significantly, KT18 TCR-T cells efficiently mediated tumor regression in multiple xenograft models of solid tumors.ConclusionsThese findings highlight significant differences in peptide-HLA binding affinity and stability across public neoantigen-HLA pairings. The cross-recognition of RAB7B13-21 represents a critical safety consideration when developing HLA-A*11:01-restricted KRASG12V[9]-specific TCRs. KT18 TCR-T cells are highly cytotoxic, exhibiting no off-target recognition and significant potential for clinical applications against KRASG12V-driven solid tumors.